[Federal Register Volume 81, Number 183 (Wednesday, September 21, 2016)]
[Rules and Regulations]
[Pages 64982-65157]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-22129]



[[Page 64981]]

Vol. 81

Wednesday,

No. 183

September 21, 2016

Part II





Department of Health and Human Services





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42 CFR Part 11





Clinical Trials Registration and Results Information Submission; Final 
Rule

  Federal Register / Vol. 81 , No. 183 / Wednesday, September 21, 2016 
/ Rules and Regulations  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

42 CFR Part 11

[Docket Number NIH-2011-0003]
RIN 0925-AA55


Clinical Trials Registration and Results Information Submission

AGENCY: National Institutes of Health, Department of Health and Human 
Services.

ACTION: Final rule.

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SUMMARY: This final rule details the requirements for submitting 
registration and summary results information, including adverse event 
information, for specified clinical trials of drug products (including 
biological products) and device products and for pediatric postmarket 
surveillances of a device product to ClinicalTrials.gov, the clinical 
trial registry and results data bank operated by the National Library 
of Medicine (NLM) of the National Institutes of Health (NIH). This rule 
provides for the expanded registry and results data bank specified in 
Title VIII of the Food and Drug Administration Amendments Act of 2007 
(FDAAA) to help patients find trials for which they might be eligible, 
enhance the design of clinical trials and prevent duplication of 
unsuccessful or unsafe trials, improve the evidence base that informs 
clinical care, increase the efficiency of drug and device development 
processes, improve clinical research practice, and build public trust 
in clinical research. The requirements apply to the responsible party 
(meaning the sponsor or designated principal investigator) for certain 
clinical trials of drug products (including biological products) and 
device products that are regulated by the Food and Drug Administration 
(FDA) and for pediatric postmarket surveillances of a device product 
that are ordered by FDA.

DATES: These regulations are effective on January 18, 2017. Additional 
information on the effective date and the compliance date can be found 
in Section IV.F.

FOR FURTHER INFORMATION CONTACT:
    Regulatory Process: Jerry Moore, NIH Regulations Officer, Office of 
Management Assessment, telephone (301-496-4607) (not a toll-free 
number), Fax (301-402-0169), or by email at [email protected].
    Technical Information: Kevin Fain, Senior Advisor for Policy and 
Research, ClinicalTrials.gov, National Center for Biotechnology 
Information, NLM, NIH, Department of Health and Human Services, 
telephone (301-402-0650) (not a toll-free number), Fax 301-402-0118, or 
by email at [email protected].

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of This Regulatory Action

    This final rule clarifies and expands requirements for the 
submission of clinical trial registration and results information to 
the ClinicalTrials.gov database, which is operated by the NLM. It 
implements the provisions of section 402(j) of the Public Health 
Service Act (PHS Act) (42 United States Code (U.S.C.) 282(j)) as 
amended by Title VIII of FDAAA and including technical corrections made 
to FDAAA under Public Law 110-316), which were intended to improve 
public access to information about certain clinical trials of U.S. FDA-
regulated drugs, biological products, and devices (also referred to as 
``FDA-regulated drugs, biological products, and devices'' in this 
preamble) and certain pediatric postmarket surveillances of a device. 
Under section 402(j) of the PHS Act, those responsible for specified 
clinical trials of these FDA-regulated products have been required to 
submit registration information to ClinicalTrials.gov since December 
26, 2007, summary results information for clinical trials of approved 
products as of September 27, 2008, and certain adverse events 
information since September 27, 2009. Section 402(j) of the PHS Act 
requires the Secretary of Health and Human Services to use rulemaking 
to expand the requirements for submission of summary results 
information, and authorizes the Secretary to use rulemaking to make 
other changes that enhance, but do not decrease, the available 
information about the specified trials.
    This final rule does not impose requirements on the design or 
conduct of clinical trials or on the data that must be collected during 
clinical trials. Instead it specifies how data that were collected and 
analyzed in accordance with a clinical trial's protocol are submitted 
to ClinicalTrials.gov. No patient-specific data are required to be 
submitted by this rule or by the law this rule is intended to 
implement.
    The major provisions of this rule are summarized below. More 
detailed discussions of these provisions are in Sections III and IV of 
this preamble.

Summary of the Major Provisions of the Regulatory Action

Applicable Clinical Trial

    This final rule clarifies which clinical trials of FDA-regulated 
drug products (including biological products) and device products and 
which pediatric postmarket surveillances of a device product, are 
applicable clinical trials for which information must be submitted to 
ClinicalTrials.gov. The final rule considers all interventional 
clinical trials with one or more arms and with one or more pre-
specified outcome measures to be controlled clinical trials. The final 
rule does not consider any expanded access use (e.g., access under 
treatment INDs or treatment protocols, which provide widespread access, 
access for intermediate-sized patient populations, or access for 
individual patients) to be an applicable clinical trial. The final rule 
also describes an approach for evaluating, prior to registration, 
whether a particular clinical trial or study is an applicable clinical 
trial (see Section IV.A.5 and Section IV.B.2).

Responsible Party

    This final rule specifies that there must be one (and only one) 
responsible party for purposes of submitting information about an 
applicable clinical trial. The sponsor of an applicable clinical trial 
will be considered the responsible party, unless and until the sponsor 
designates a qualified principal investigator as the responsible party. 
This final rule specifies the approach for determining who will be 
considered the sponsor of an applicable clinical trial under various 
conditions, what qualifies a principal investigator to be designated a 
responsible party by a sponsor, and how responsibility reverts to the 
sponsor if a designated principal investigator is unable to fulfill the 
requirements for submitting information to ClinicalTrials.gov unless 
and until the sponsor designates another principal investigator as the 
responsible party (see Section IV.A.2).

Registration

    This final rule specifies requirements for registering applicable 
clinical trials at ClinicalTrials.gov. It requires that the responsible 
party register an applicable clinical trial not later than 21 calendar 
days after enrolling the first human subject (also referred to as 
participant or subject), and it specifies the data elements of clinical 
trial information that must be submitted at the time of registration. 
These data elements include the descriptive information, recruitment 
information, location and contact information, and administrative data 
elements listed in section 402(j) of the PHS Act, as well as additional 
required data elements under the Secretary's authority to modify the 
registration information requirements by

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rulemaking as long as such modifications improve, and do not reduce, 
the clinical trial information available to the public in 
ClinicalTrials.gov. We consider these additional required registration 
data elements necessary to enable the NIH to implement other statutory 
provisions, indicate the status of human subjects protection review of 
the trial, facilitate the public's ability to search and retrieve 
information from ClinicalTrials.gov, and help ensure that entries are 
meaningful and unambiguous. We note that some of these additional data 
elements required under this rule were included in ClinicalTrials.gov 
before FDAAA was enacted or have been implemented since 2007 as 
optional data elements (see Section IV.B).
    Although section 402(j) of the PHS Act includes a provision 
delaying public posting of registration information for applicable 
clinical trials of unapproved or uncleared device products until the 
device product is approved or cleared, the final rule includes a 
provision under which the responsible party for an applicable device 
clinical trial can indicate to the Agency that it is authorizing the 
public posting of clinical trial registration information that would 
otherwise fall under the delayed posting provision prior to approval or 
clearance of the product (see Section IV.B.5).

Expanded Access Information

    Section 402(j) of the PHS Act requires the submission of 
information regarding whether, for an applicable drug clinical trial of 
an unapproved drug product (including an unlicensed biological 
product), expanded access to the investigational product being studied 
in the applicable clinical trial is available under section 561 of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act). If the responsible 
party for an applicable clinical trial of an unapproved drug product 
(including an unlicensed biological product) is both the sponsor of the 
applicable clinical trial being registered and the manufacturer of the 
unapproved product, this rule requires the submission of a separate 
expanded access record containing details about how to obtain access to 
the investigational product. Once an expanded access record has been 
created for a particular investigational product and a National 
Clinical Trial (NCT) number has been assigned to it, the responsible 
party must update the applicable clinical trial(s) with that NCT number 
and provide that NCT number when submitting clinical trial registration 
information for any future applicable clinical trial(s) studying the 
same investigational product. The NCT number for the expanded access 
record allows ClinicalTrials.gov to link the existing expanded access 
record to the study record for the clinical trial (see Section IV.B.5 
and Section IV.D.3).

Results Information Submission

    This final rule addresses the statutory requirement for the 
submission of summary results information for applicable clinical 
trials of drug products (including biological products) and device 
products that are approved, licensed, or cleared by FDA. It also 
extends the requirement for results information submission to 
applicable clinical trials of drug products (including biological 
products) and device products that are not approved, licensed, or 
cleared by FDA. The rule requires the submission of data in a tabular 
format summarizing participant flow; demographic and baseline 
characteristics; primary and secondary outcomes, as well as results of 
any scientifically appropriate statistical tests; and adverse event 
information. In addition, the rule requires the submission of the full 
protocol and statistical analysis plan (if a separate document) (see 
Section III.D).
    In general, this rule requires the submission of results 
information not later than 1 year after the completion date (referred 
to as the ``primary completion date'') of the clinical trial, which is 
defined as the date of final data collection for the primary outcome 
measure. Results information submission could be delayed for up to 2 
additional years from the date of submission of a certification that 
either an unapproved, unlicensed, or uncleared product studied in the 
trial is still under development by the manufacturer or that approval 
will be sought within 1 year after the primary completion date of the 
trial for a new use of an approved, licensed, or cleared product that 
is being studied in the trial. This rule also permits responsible 
parties to request extensions to the results information submission 
deadlines for ``good cause'' as well as a permanent waiver of results 
information submission requirements for extraordinary circumstances 
(see Section IV.C.3 and Section IV.C.6).

Adverse Events Information

    This final rule requires the responsible party to submit 
information summarizing the number and frequency of adverse events 
experienced by participants enrolled in a clinical trial, by arm or 
comparison group, as well as a brief description of each arm or group 
as a component of clinical trial results information. It also requires 
submission of three tables of adverse event information: One 
summarizing all serious adverse events; another one summarizing other 
adverse events that occurred with a frequency of 5 percent or more in 
any arm of the clinical trial; and finally, one summarizing all-cause 
mortality data by arm or group. This final rule clarifies that these 
adverse event tables must include information about events that 
occurred, regardless of whether or not they were anticipated or 
unanticipated. In addition, this rule requires responsible parties to 
provide the time frame for adverse event data collection and specify 
whether the collection approach for adverse events was systematic or 
non-systematic. The final rule does not require a responsible party to 
collect adverse event information that is not specified in the protocol 
(see Section IV.C.4).

Updates and Other Required Information

    This final rule requires that all submitted information be updated 
at least annually if there are changes to report. More rapid updating 
is required for several data elements to help ensure that users of 
ClinicalTrials.gov have access to accurate, up-to-date information 
about important aspects of an applicable clinical trial or other 
clinical trial. The final rule also requires timely corrections to any 
errors discovered by the responsible party or the Agency during quality 
control review of submissions or after the information has been posted. 
The rule clarifies that the responsible party's obligation to submit 
updates and correction of errors ends on the date on which the required 
data elements for clinical trial results information have been 
submitted for all primary and secondary outcomes and all adverse events 
that were collected in accordance with the protocol, and the quality 
control review process has concluded (see Section IV.D.3).

Effective Date and Compliance Date

    This final rule will be effective January 18, 2017. As of that 
date, the ClinicalTrials.gov system will allow responsible parties to 
comply with the rule. Responsible parties will have 90 calendar days 
after the effective date to come into compliance with the requirements 
of this rule (see Section IV.F).

Legal Consequences of Non-Compliance

    This final rule outlines the potential civil or criminal actions, 
civil monetary penalty actions, and grant funding

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actions that may be taken if responsible parties fail to comply with 
the rule's requirements. It does not outline all potential legal 
consequences, e.g., laws governing the veracity of information 
submitted to the federal government, however, and should not be 
understood as describing the exclusive means of enforcement that the 
government might undertake with respect to compliance with the 
provisions of section 402(j) of the PHS Act, including these 
regulations (see Section IV. E).

Costs and Benefits

    Based on our cost estimates, this regulatory action is expected to 
result in $59.6 million in annual costs, and it is not expected to have 
a significant impact on the economy. The costs consist primarily of the 
time needed to organize, format, and submit to ClinicalTrials.gov 
information that was prepared for or collected during the clinical 
trial (e.g., summary of key protocol details and clinical trial results 
information). The potential benefits include greater public access to 
information about ongoing and completed applicable clinical trials. 
Such information may help potential clinical trial participants to 
better understand their options for participating in new trials; to 
better enable funders and clinical researchers to determine the need 
for new trials; to provide more complete information for those who use 
evidence from clinical trials to inform medical and other decisions; 
and to better enable the scientific community to examine the overall 
state of clinical research as a basis for engaging in quality 
improvement (e.g., with regard to research methods). The rule is also 
expected to provide greater clarity about what is required for those 
who are subject to the legal mandate to submit information to 
ClinicalTrials.gov (see Section V).

Commonly Used Abbreviations

ANDA Abbreviated New Drug Application
API Application Program Interface
BLA Biologics License Application
CBER Center for Biologics Evaluation and Research, FDA
CDER Center for Drug Evaluation and Research, FDA
CDISC Clinical Data Interchange Standards Consortium
CDRH Center for Devices and Radiological Health, FDA
CFR Code of Federal Regulations
CONSORT Consolidated Standards of Reporting Trials
CSR Clinical Study Report
CTRP Clinical Trial Reporting Program, NCI
EMA European Medicines Agency
EU European Union
EudraCT European Clinical Trials Database
FDA Food and Drug Administration, HHS
FDAAA Food and Drug Administration Amendments Act of 2007
FDAMA Food and Drug Administration Modernization Act of 1997
FD&C Act Federal Food, Drug, and Cosmetic Act
FOIA Freedom of Information Act
FR Federal Register
HDE Humanitarian Device Exemption
HHS Department of Health and Human Services
ICH International Conference on Harmonization of Technical 
Requirements of Pharmaceuticals for Human Use
ICMJE International Committee of Medical Journal Editors
IDE Investigational Device Exemption
IND Investigational New Drug Application
IOM Institute of Medicine (now the Health and Medicine Division of 
the National Academies of Sciences, Engineering, and Medicine)
IPD Individual Participant Data
IRB Institutional Review Board
IVD In Vitro Diagnostic
LPLV Last Patient Last Visit
MedDRA Medical Dictionary for Regulatory Affairs
MeSH[supreg] Medical Subject Headings
NCI National Cancer Institute, NIH
NCT National Clinical Trial
NDA New Drug Application
NIH National Institutes of Health, HHS
NLM National Library of Medicine, NIH
NPRM Notice of Proposed Rulemaking
OHRP Office for Human Research Protections, HHS
PCORI Patient-Centered Outcomes Research Institute
PDF Portable Document Format
PHS Act Public Health Service Act
PMA Premarket Approval
PRS Protocol Registration and Results System, ClinicalTrials.gov
RFA Regulatory Flexibility Act
SAP Statistical Analysis Plan
SNOMED CT[supreg] Systematized Nomenclature of Medicine--Clinical 
Terms[supreg]
UMLS Unified Medical Language System
U.S. United States
U.S.C. United States Code
U.S. TSA U.S. Trade Secrets Act
UTSA Uniform Trade Secrets Act, Uniform Law Commission
WHO World Health Organization
XML Extensible Markup Language

Table of Contents

I. Background
II. Overview of Statutory Provisions
III. Discussion of Public Comments on Selected Key Issues
    A. Scope and Applicability
    B. Submission of Results Information for Applicable Clinical 
Trials of Unapproved, Unlicensed, or Uncleared Products for Any Use
    C. Submission of Technical and Non-technical Summaries
    D. Submission of Protocols and Statistical Analysis Plans
IV. Discussion of Public Comments Related to Specific Provisions of 
the Regulations
    A. Subpart A--General Provisions
    1. What is the purpose of this part?--Sec.  11.2
    2. To whom does this part apply?--Sec.  11.4
    3. What are the requirements for the submission of truthful 
information?--Sec.  11.6
    4. In what format must clinical trial information be 
submitted?--Sec.  11.8
    5. What definitions apply to this part?--Sec.  11.10
    B. Subpart B--Registration
    1. Who must submit clinical trial registration information?--
Sec.  11.20
    2. Which applicable clinical trials must be registered?--Sec.  
11.22
    3. When must clinical trial registration information be 
submitted?--Sec.  11.24
    4. What constitutes clinical trial registration information?--
Sec.  11.28
    5. By when will the NIH Director post clinical trial 
registration information submitted under Sec.  11.28?--Sec.  11.35
    C. Subpart C--Results Information Submission
    1. Who must submit clinical trial results information?--Sec.  
11.40
    2. For which applicable clinical trials must clinical trial 
results information be submitted?--Sec.  11.42
    3. When must clinical trial results information be submitted for 
applicable clinical trials subject to Sec.  11.42?--Sec.  11.44
    4. What constitutes clinical trial results information?--Sec.  
11.48
    5. By when will the NIH Director post clinical trial results 
information submitted under Sec.  11.48?--Sec.  11.52
    6. What are the procedures for requesting and obtaining a waiver 
of the requirements clinical trial results information submission?--
Sec.  11.54
    D. Subpart D--Additional Submissions of Clinical Trial 
Information
    1. What requirements apply to the voluntary submission of 
clinical trial information for clinical trials of FDA-regulated drug 
products (including biological products) and device products?--Sec.  
11.60
    2. What requirements apply to applicable clinical trials for 
which submission of clinical trial information has been determined 
by the NIH Director to be necessary to protect the public health?--
Sec.  11.62
    3. When must clinical trial information submitted to 
ClinicalTrials.gov be updated or corrected?--Sec.  11.64
    E. Subpart E--Potential Legal Consequences of Non-compliance
    1. What are potential legal consequences of not complying with 
the requirements of this part?--Sec.  11.66
    F. Effective Date, Compliance Date, and Applicability of 
Requirements in This Part
    V. Regulatory Impact Statement
    A. Comments and Response
    B. The Final Rule
    C. Need for the Final Rule
    D. Benefits of the Final Rule
    E. Costs Associated With the Final Rule
    1. Registration of Applicable Clinical Trials
    2. Results Information Submission
    3. Delayed Submission of Results Information via Certification 
or Extension Request

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    4. Triggered Submission of Clinical Trial Information Following 
a Voluntary Submission
    5. Expanded Access Records
    6. Institutional Compliance Costs
    F. Alternatives to the Final Rule
    G. Regulatory Flexibility Act
    H. Unfunded Mandates Reform Act of 1995
    I. Federalism
VI. Paperwork Reduction Act of 1995
VII. Legal Authority
VIII. References
Regulatory Text

I. Background

    This final rule implements requirements for submitting registration 
and summary results information for specified clinical trials of drug 
products (including biological products) and device products to 
ClinicalTrials.gov, the clinical trial registry and results data bank 
operated by the NLM, NIH, since 2000. This final rule provides for the 
expanded registry and results data bank specified in 402(j) of the PHS 
Act (42 U.S.C. 282(j)), as amended by Title VIII of FDAAA and including 
technical corrections made to FDAAA under Public Law 110-316. These 
provisions are intended to enhance patient enrollment, provide a 
mechanism to track subsequent progress of clinical trials, provide more 
complete results information, and enhance patient access to and 
understanding of the results of clinical trials (see 42 U.S.C. 282(j), 
section 402(j) of the PHS Act).
    The requirements apply to the responsible party (the sponsor or 
designated principal investigator) for certain clinical trials of drug 
products (including biological products) and device products regulated 
by the FDA under designated sections of the FD&C Act.
    The Notice of Proposed Rulemaking (NPRM) for Clinical Trials 
Registration and Results Submission was published on November 21, 2014, 
in the FR (79 FR 69566). We received nearly 900 comments during the 120 
day public comment period, which closed on March 23, 2015. Of the total 
comments received, about 60 percent were nearly identical in content, 
expressing support for clinical trial transparency efforts and the 
goals of the NPRM and provided specific perspectives on a number of the 
proposals. Another large subset of comments also expressed support for 
clinical trial transparency and the NPRM goals, but did not comment on 
specific proposals. There were about 100 distinct comments that 
addressed specific NPRM proposals. As reflected below, all of the 
comments were reviewed and all points and perspectives were carefully 
considered. Section III includes discussion of comments on several key 
issues in the final rule, and Section IV includes discussion of 
comments related to each specific provision in the final rule. For each 
key issue and specific provision, we outline the statutory basis, the 
NPRM proposal, the relevant public comments, our response to the 
comments, and the approach taken in the final rule. The NPRM provided a 
comprehensive review of the legislative background and history that led 
to its development and, by extension, to this final rule. We review it 
again here in brief.
    NLM initially developed the database, known as ClinicalTrials.gov, 
in response to the statutory mandate of section 113 of the Food and 
Drug Administration Modernization Act of 1997 (FDAMA) to establish, 
maintain, and operate a data bank of information on certain clinical 
trials (these requirements currently are codified at 42 U.S.C. 282(i), 
PHS Act 402(i)), and in support of NLM's statutory mission to improve 
access to information to facilitate biomedical research and the public 
health (see 42 U.S.C. 286(a)). The registry became publicly available 
in February 2000. Since the establishment of ClinicalTrials.gov, the 
scientific community, general public, and others have called for many 
new measures to improve access to and transparency of information about 
clinical trials. In addition, various parties have developed and 
implemented trial registration policies including, for example, journal 
editors (through the International Committee of Medical Journal Editors 
(ICMJE)) [Ref. 1, 2] and industry (through the International Federation 
of Pharmaceutical Manufacturers and Associations) [Ref. 3]. 
ClinicalTrials.gov accepts information on trials other than those 
legally required to be registered in support of the mission of the NLM 
and other policies such as those from the ICMJE [Ref. 1, 2]. With the 
enactment of Title VIII of FDAAA, the legal mandate for 
ClinicalTrials.gov reporting was expanded to include more registration 
information for a broader set of clinical trials, as well as results 
information.
    As discussed in the proposed rule, there are significant public 
health benefits to requiring the disclosure of the information required 
under this rule. Enhancements to the scope of ClinicalTrials.gov 
improve its utility in assisting individuals in finding trials for 
which they may be eligible to enroll, and then ensuring that their 
participation is honored and trust is enhanced by creating a public 
record of the trial and its results. In addition, access to more 
complete information about clinical trials has both scientific and 
other public health benefits. The scientific benefits relate to the 
prevention of incomplete and biased reporting of individual trials, and 
the provision of information about a more complete and unbiased set of 
trials; the resulting set of data about clinical trials can form a more 
robust basis for current medical decision making and future research 
planning. In addition, ClinicalTrials.gov provides an overview of the 
clinical trials enterprise, facilitating quality improvement in study 
focus, design, and reporting. The rule should also provide greater 
clarity about what is required for those who are subject to the legal 
mandate to submit information to ClinicalTrials.gov.
    For many years, members of the scientific community, general 
public, industry, and others have been in active discussions about the 
need for increased access to information about clinical trials [Ref. 
4]. Communities have expressed concern about the lack of publications 
from clinical trials [Ref. 5] (regardless of outcomes) and bias in the 
literature, [Ref. 6, 7] which may be due to selective reporting by 
trial sponsors or by journals in response to manuscripts that they deem 
less interesting. Interested parties have highlighted the importance of 
filling this gap because of missed opportunities to share knowledge 
that could have had implications for research participants who took 
part in these trials, future research participants who may benefit from 
this missing knowledge in the design of studies in which they will 
participate, and patients who may have benefited from the missing 
information in terms of a more robust understanding of their diseases, 
conditions, and potential treatments.
    Even before this rulemaking, extensive research had been conducted 
using the clinical trial information that is publicly available on 
ClinicalTrials.gov. The published literature relying on 
ClinicalTrials.gov data includes:
     Studies characterizing the clinical research for specific 
conditions, such as acute kidney injury and the assessment of endpoints 
and sample size in prevention trials [Ref. 8];
     studies identifying research gaps in a domain, such as for 
pediatric studies [Ref. 9];
     studies assessing data mining methods, such as the 
systematic identification of pharmacogenomics information from clinical 
trials [Ref. 10];
     studies characterizing the overall clinical research 
landscape, such as the characteristics of clinical trials registered in 
ClinicalTrials.gov [Ref. 11];

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     studies evaluating publication bias or selective 
reporting, such as the lack of publication for trials registered on 
ClinicalTrials.gov [Ref. 12];
     studies of research reporting, for example, by examining 
discrepancies between the ClinicalTrials.gov results database and peer-
reviewed publications [Ref. 13]; and
     studies assessing specific research-related methods and 
issues, such as the reporting of non-inferiority trials in 
ClinicalTrials.gov [Ref. 14] and the use of ClinicalTrials.gov to 
estimate condition-specific nocebo effects and other factors affecting 
outcomes of analgesic trials [Ref. 15].
    Many commenters identified the issues noted above, and supported 
the need for greater access to information about clinical trials. A 
large majority of comments in response to the NPRM expressed support 
for the rule, with many noting the value of transparency of clinical 
trials, in general. Commenters highlighted that accessible information 
about trials is critical for the public, including patients, and will 
contribute to better science in various ways. For example, one 
commented that the proposed rule promotes transparency, benefitting 
patients in the long run. Another asserted that doctors work with 
uncertainty and that access to all results information, regardless of 
statistical significance, can be important. Others argued that 
requiring more trials to be registered and reported will allow science 
to progress more quickly because scientists will be able to learn from 
trials that they otherwise would not have had access to, helping them 
to avoid ``reinventing the wheel.''
    On the other hand, we recognize that the posting of results 
information from applicable clinical trials of unapproved, unlicensed, 
and uncleared products, as well as unapproved, unlicensed, or uncleared 
uses of approved/licensed/cleared medical products, presents special 
challenges. Despite the concerns raised by opponents to the rule (such 
as concerns from device manufacturers and the pharmaceutical industry 
about disclosure of what they view to be proprietary, confidential 
information and its impact on innovation and investment incentives, and 
concerns that the delay for submission of results information is 
insufficient given the length and cost of drug development), it is 
important that results information for each such clinical trial of an 
unapproved, unlicensed, and uncleared product be presented in an 
unbiased manner, but with the understanding that the evaluation of the 
overall benefit and risk profile of each such product, or each use of 
an already approved product, be determined by an assessment of the full 
evidence base for that product (i.e., not from the results of any one 
trial in isolation). Under the FD&C Act, the PHS Act, and their 
implementing regulations, firms that market medical products are 
generally required to submit an application to FDA for premarket 
review, and provide robust scientific evidence that demonstrates that 
the product is safe and effective for each of its intended uses, before 
the firm distributes the product for each such use. During FDA 
premarket review of medical products, FDA also generally reviews 
proposed labeling for the intended use(s) of the product to ensure that 
the labeling provides adequate information for the safe and effective 
use of the product. Real harms have been associated with use of medical 
products for unapproved uses--harms to health as well as the diversion 
of resources to ineffective treatments [Ref. 16, 17].

A. Review of Scientific Benefits Related to Specific Provisions of the 
Rule

Registration Information
    A public registry of trials enables interested parties, including 
patients, to find trials in which they might want to participate and 
facilitates the discovery of trials for academic research centers with 
experts studying particular diseases or conditions [Ref. 18]. The 
highly structured data, along with the search engine, enable members of 
the public to search for trials that might meet their needs by using a 
variety of technical and non-technical terms [Ref. 19]. This is of 
particular importance for trials that involve unapproved, uncleared, or 
unlicensed medical products that might not have a generic name [Ref. 
20]. These trials tend to use company-specific code names that 
ClinicalTrials.gov links to their eventual generic name (if one is 
assigned). As a result, a user of the system can find all trials 
associated with a given product, even if they use different names (or 
codes) at different stages of the product development cycle. Without 
such a registry, there would be no single, centralized way to identify 
trials studying any intervention for any disease regardless of sponsor 
or funding for which an individual may be eligible (e.g., previous 
Federal trial registries established under the Health Omnibus Extension 
of 1988 for trials for human immunodeficiency virus infection and 
acquired immune deficiency syndrome, commonly referred to as HIV/AIDS, 
and FDAMA 113 for effectiveness studies for serious or life-threatening 
diseases or conditions conducted under investigational new drug 
applications (INDs) were limited to certain conditions and one 
intervention type, i.e., drugs).
    The public record also ensures that each individual's participation 
in a trial is appropriately respected by preventing the conduct of 
``secret'' trials, for which their existence is not publicly known 
(and/or their results are never publicly reported after completion or 
misreported--i.e., reporting bias) [Ref. 21, 22]. The unique identifier 
assigned to each record (NCT number) also permits, for the first time, 
a way to identify each clinical trial unambiguously [Ref. 23] and link 
information about a single clinical trial from different resources/
databases [Ref. 24].
    The searchable, structured listing of trials also enables 
Institutional Review Boards (IRBs) [Ref. 25], researchers, funding 
agencies, systematic reviewers [Ref. 26, 27], and other groups, 
including the Presidential Commission for the Study of Bioethics Issues 
[Ref. 28], and the National Academies of Science workshops [Ref. 29], 
to see the landscape of trials on a given topic, by a particular 
funder, by geography [Ref. 30], by population [Ref. 9], or other 
relevant criteria. Providing these users with such a capability informs 
their judgments about the potential value of new trials, scientific and 
financial accountability of sponsors, as well as helping to ensure that 
assessments of the risks and benefits of a potential intervention for a 
particular use account for the totality of evidence from all prior 
trials. Such analyses of the clinical research also provide feedback 
and insights for the clinical research community itself, by informing 
the design and analysis of future trials [Ref. 11, 31, 32].
    The information that describes the clinical trial in the registry 
records also facilitates assessments of the quality and appropriateness 
of trial reporting by enabling journal editors, researchers, and other 
readers of the medical literature to assess the degree to which the 
disclosed results (e.g., journal articles, scientific conferences) 
accurately reflect the prespecified protocol and have accounted for all 
prespecified outcome measures. This helps to (1) prevent the type of 
incomplete results reporting that has been documented in conference and 
journal abstracts, as well as in full journal articles [Ref. 33] and 
(2) allow the members of the public to assess fidelity to the protocol, 
which is essential to understanding the validity of disclosed results 
[Ref. 34].

[[Page 64987]]

    The freely downloadable registry data enable third parties to use 
the information that describes the clinical trial to meet other 
specific needs [Ref. 35], such as reformatting the data for 
constituents of various patient advocacy groups (e.g., patients with 
breast cancer) [Ref. 36], data mining for associations among 
interventions and diseases studied worldwide, and for use in semi-
automated data collection for conducting critical appraisals and 
systematic reviews to support evidence-based medicine. For example, 
while ClinicalTrials.gov does not itself match potential participants 
with relevant trials, the rule ensures the timely posting of 
registration information about trials currently enrolling participants. 
This information is used by third parties to provide matching services 
that help patients find trials that might be appropriate for them.
Summary Results Information
    The public availability of results information helps investigators 
design trials and IRBs review proposed trials, by allowing them to 
weigh the proposed study's risks and benefits against a more complete 
evidence base than is currently available through the scientific 
literature [Ref. 37]. The rule facilitates better science through 
aiding in the identification of knowledge gaps for trials of all types 
of products, whether unapproved or approved and marketed. Mandatory 
submission and posting of results information will also help 
investigators avoid repeating trials on drug and device products 
(including biological products) that have been found to be unsafe or 
unsuccessful while also providing access to information that may help 
verify findings.
    While the registry information at ClinicalTrials.gov can be used to 
determine where information might be missing from the literature (e.g., 
missing trials, missing outcome measures) [Ref. 13, 38, 39], the 
results database fills many gaps in the medical evidence base by 
providing tabular objective data that summarize findings from trials. 
These data can be used by systematic reviewers and others who analyze 
the literature to develop evidence-based treatment and policy 
recommendations [Ref. 26].
    FDAAA has led to the development of a minimum reporting set that 
provides key facts about the aggregate analyses for each trial without 
the accompanying narrative interpretations found in journal 
articles[Ref. 40]. In this way, results are made available in a timely 
manner for all prespecified primary and secondary outcome measures, and 
all serious and frequent adverse events, and complement the published 
literature [Ref. 41].
    The submission and posting of results information on 
ClinicalTrials.gov may occur before, simultaneously with, or after 
journal publication, but is independent of journal submission and 
publication. The legal requirements help to fill substantial gaps in 
the database left by the non-publication (or very delayed publication) 
of a substantial portion of clinical trials in the medical literature 
[Ref. 42, 43]. In addition, the complete set of results information for 
all primary and secondary outcome measures that were specified in a 
study protocol supplements the more limited set of results data found 
in the published literature [Ref. 44]. The availability of results 
information from applicable clinical trials will help to prevent 
skewing of the evidence base that is the foundation of systematic 
reviews and clinical practice guidelines. In addition, if information 
were to be presented publicly about the safety profile of an approved 
drug product, the availability of clinical trial results information 
through ClinicalTrials.gov could help inform the public record about 
the drug product's safety [Ref. 45].
Review of Public Health Benefits Related to Specific Provisions of the 
Rule
    Results information for trials of unapproved products may inform 
the assessment of risks and benefits that potential participants might 
face in subsequent studies of those same or similar products; they may 
also contribute to the overall assessments that are made of similar 
marketed products [Ref. 46]. Trials of products that are unapproved, 
unlicensed, and uncleared are unlikely to be published if the results 
of these trials are insufficient to support applications for product 
approvals (e.g., because the study resulted in negative findings or was 
inadequately designed or executed). This rule's requirements that 
responsible parties submit results information from clinical trials of 
unapproved, uncleared, or unlicensed products regardless of whether 
approval, clearance, or licensure is sought, as well as the public 
posting of this information, are expected to alleviate the concerns 
regarding bias in the literature and selective publication. Frequently 
cited economic benefits of sharing clinical trial data generally 
include avoiding a suboptimal return on the financial resources 
invested by study funders and sponsors [Ref. 47], while the submission 
and posting of results information from trials of unapproved, 
uncleared, or unlicensed products in particular is expected to reduce 
costs by minimizing the number of redundant trials. Overall, the rule's 
requirement ensures the public availability and accessibility of 
information that likely would not otherwise have been in the public 
domain.
    The reporting of an unambiguous accounting for all deaths, as 
required by the final rule, within each trial enables researchers and 
others to understand the most basic elements of the study in a way that 
was not previously possible in many cases [Ref. 48].
    Mandatory submission and posting of the protocol and statistical 
analysis plan (SAP) for each reported trial provides a resource for 
researchers and others interested in understanding the detailed methods 
used to conduct a particular trial and analyze the collected data [Ref. 
49, 50, 51]. Our reasoning behind their inclusion is more fully 
explained in Section III.D on Submission of Protocols and Statistical 
Analysis Plans, but we wish to emphasize that availability of the 
protocol and SAP is expected to provide users of ClinicalTrials.gov 
with a fuller picture of the trial. One of the aims of the statute and 
of the rule is to ``provide more complete results information'' 
(section 402(j)(3)(D)(i) of the PHS Act), which we believe complements 
the goals of increased transparency and accountability. As such, the 
addition of the protocol as clinical trial results information to be 
submitted and posted on ClinicalTrials.gov furthers this statutory 
purpose and significantly enhances the understanding of the trial and 
the context of the data fields and results information provided. It 
also enables readers to conduct a more complete evaluation of results 
[Ref. 47, 52, 53]. Although protocols are sometimes provided along with 
published articles, they are currently distributed among different 
journal Web sites and cannot be reliably found for most trials. 
Protocols also help to provide a more nuanced understanding of key 
trial methods, including, for example, the detailed eligibility 
criteria; how information was collected for key outcome measures and 
adverse events; and how data were handled, including detailed methods 
of statistical analyses. Such details of trial methods can affect the 
interpretation of a study's findings [Ref. 52, 53, 54, 55]. SAPs 
describe the analyses to be conducted and the statistical methods to be 
used, including ``plans for analysis of baseline descriptive data and 
adherence to the intervention, prespecified primary and

[[Page 64988]]

secondary outcomes, definitions of adverse and serious adverse events, 
and comparison of these outcomes across interventions for prespecified 
subgroups. The full SAP describes how each data element was analyzed, 
what specific statistical method was used for each analysis, and how 
adjustments were made for testing multiple variables. If some analysis 
methods require critical assumptions, data users will need to 
understand how those assumptions were verified.'' [Ref. 47].
Limiting ClinicalTrials.gov to Objective Data
    As described in greater detail in Section III.C on Submission of 
Technical and Non-technical Summaries, the final rule does not require 
the submission of technical or non-technical narrative summaries of 
study results due to a lack of evidence that such summaries would 
always meet the statutory standard of not being misleading or 
promotional (section 402(j)(3)(D)(iii)(I) and section 
402(j)(3)(D)(iii)(II) of the PHS Act). In fact, experts suggest that 
such summaries can lead to biased reporting, whether because of 
omission or commission [Ref. 56]. Presenting results information in a 
tabular format leads to a more objective database. We believe that 
actively avoiding the introduction of bias serves an important public 
health interest--one that Congress foresaw--and prevents 
ClinicalTrials.gov from being a platform in which data are conflated 
with opinions or interpretation.
    In this regard, it should be noted that nothing in this rule 
authorizes a firm to use information posted in, or links to, other Web 
sites available on ClinicalTrials.gov to promote unapproved, 
unlicensed, or uncleared medical products or unapproved, unlicensed, or 
uncleared uses of approved or cleared medical products, or supersedes 
or alters other statutory and regulatory provisions related to such 
communications. For example, under the FD&C Act, the PHS Act, and their 
implementing regulations, firms that market medical products are 
generally required to submit an application to FDA for premarket 
review, and provide robust scientific evidence that demonstrates that 
the product is safe and effective for each of its intended uses, before 
the firm distributes the product for each such use. To the extent firms 
make a product available for one use (whether as a medical product or 
not), but make express or implied claims regarding the safety or 
efficacy of that product for another medical product use, for which it 
lacks the applicable approval, licensure or clearance, they are 
effectively evading the premarket review requirements of the applicable 
law and undermining the public health interests advanced by these 
requirements.
    In addition, where emerging and developing scientific data are not 
yet sufficiently complete or robust to demonstrate safety and efficacy 
of the product for an initial or additional intended use, 
representations of safety and effectiveness can be misleading, 
particularly if addressed to health care providers and/or patients 
[Ref. 57, 58]. Marketing activities and communications can also be 
designed to persuade, promote, and influence prescribing and use in 
ways that are not based on valid scientific evidence, to the extent 
such evidence exists [Ref. 59, 60].
    It is important to note that even though we are limiting the 
submissions to objective data elements, the government does not 
independently verify the scientific validity or relevance of the 
information submitted to ClinicalTrials.gov beyond the limited quality 
control review by NIH, which is focused on the clarity and completeness 
of the information submitted, not the quality, validity, meaning or 
relevance of the trial itself. Accordingly, the inclusion of data and 
information in the ClinicalTrials.gov platform, the links to other 
studies and Web sites, and the conduct of the limited quality control 
review by NIH, do not constitute a government affirmation or 
verification that the information within or referenced in the database, 
or communications that rely on that information, are truthful and non-
misleading.
Other Benefits
    Other benefits relate to the role in assisting individuals in 
finding trials in which to enroll, and then ensuring that their 
participation is honored and trust is enhanced by creating a public 
record of the trial and its results. It also fulfills an obligation to 
trial participants that is established between them and the research 
team. Individuals participate in clinical trials with the understanding 
that the research will contribute to the expansion of knowledge 
pertaining to human health. When trial information is withheld from 
public scrutiny and evaluation, the interpretation of the data and the 
public's trust in the research may be compromised. The rule helps to 
further the goal of ensuring that participation in research leads to 
accountability via the public reporting of information. Much has been 
written about the importance of trust in clinical research, and 
although many factors promote the development of trust, ensuring a 
public record of the trials in which people participate contributes 
significantly to this goal [Ref. 47, 61].
    Finally, the availability of results information is expected to 
assist people in making more informed decisions about participating in 
a clinical trial by providing them and their care providers with access 
to information about the results of a broader set of clinical trials of 
various interventions that have been studied for a disease or condition 
of interest.

B. Anticipated Long-Term Benefits of ClinicalTrials.gov Beyond the 
Final Rule

    ClinicalTrials.gov provides the scaffolding on which individual 
participant data (IPD (the next frontier in transparency) and other 
trial ``meta-data'' can be organized in the future. This is 
particularly important to catalyze the enormous potential value of data 
sharing. Such IPD (and, for example, associated biospecimens) are most 
valuable if their availability is identified in a searchable system and 
associated with key trial meta-data so that they can be used in a 
scientifically appropriate manner. ClinicalTrials.gov provides 
mechanisms for linking the trial records with sources of IPD and meta-
data about each trial as recommended by the Institute of Medicine 
(IOM)in a 2015 report entitled Sharing Clinical Trial Data: Maximizing 
Benefits, Minimizing Risks and ICMJE [Ref. 47, 62]; the search 
interface allows for the easy identification of such data so that 
researchers can identify data for their secondary use.

II. Overview of Statutory Provisions

    The final rule clarifies and establishes additional procedures and 
requirements for registering and submitting results information, 
including adverse event information, for certain clinical trials of 
drug products (including biological products) and device products, as 
well as for pediatric postmarket surveillances of a device product that 
are required by FDA under section 522 of the FD&C Act; the final rule 
requirements implement section 402(j) of the PHS Act.
    Title VIII of FDAAA, enacted on September 27, 2007, section 801(a), 
amended the PHS Act by directing the Secretary of the Department of 
Health and Human Services (HHS), acting through the Director of the NIH 
(or the Agency) to expand the existing clinical trial registry data 
bank known as ClinicalTrials.gov and to ensure that the data bank is 
publicly available through the Internet. Among other duties, NIH is

[[Page 64989]]

directed to expand the data bank to include registration information 
for a broader set of clinical trials than were required to register 
under FDAMA. Section 402(j) of the PHS Act specifies that identified 
entities or individuals, called responsible parties, are to submit 
registration information for certain applicable clinical trials of 
drugs (defined by section 402(j)(1)(A)(vii) of the PHS Act to include 
biological products) and devices, including any pediatric postmarket 
surveillance of a device required by FDA under section 522 of the FD&C 
Act (21 U.S.C. 360l). Section 402(j)(2)(A)(iii) of the PHS Act 
authorizes the Secretary of HHS to modify by regulation the data 
elements required for registration, provided that the Secretary 
provides a rationale for why such modification ``improves and does not 
reduce'' the information included in the data bank. The statute 
specifies certain deadlines by which registration information is to be 
submitted to the data bank.
    Section 402(j)(3) of the PHS Act further directs the Agency to 
augment the registry data bank to include summary results information 
through a multistep process, as follows:
    First, for those clinical trials that form the primary basis of an 
efficacy claim or are conducted after a product is approved, licensed, 
or cleared, the registry data bank is to be linked to selected existing 
results information available from the NIH and FDA (section 
402(j)(3)(A) of the PHS Act). Such information includes citations to 
published journal articles focused on the results of applicable 
clinical trials, posted FDA summaries of FDA advisory committee 
meetings at which applicable clinical trials were considered, and 
posted FDA assessments of the results of any applicable drug clinical 
trials that were conducted under section 505A or 505B of the FD&C Act 
(21 U.S.C. 355a, 21 U.S.C. 355c).
    Second, for each applicable clinical trial subject to section 
402(j) of the PHS Act, the responsible party must submit to the data 
bank results information required under section 402(j)(3)(C) of the PHS 
Act. Such information is to include tables of demographic and baseline 
characteristics of the ``patients who participated in the clinical 
trial'' (section 402(j)(3)(C)(i) of the PHS Act), i.e., the enrolled 
human subjects, and the primary and secondary outcome measures for each 
arm of the clinical trial, as well as a point of contact for scientific 
information about the clinical trial results and information on whether 
certain agreements exist between the sponsor and the principal 
investigator that limit the ability of the principal investigator to 
discuss or publish the results of an applicable clinical trial after it 
is completed. The ClinicalTrials.gov basic results component was 
launched on September 27, 2008.
    In addition, section 402(j)(3)(I)(i) of the PHS Act directs the 
Secretary to issue regulations to ``determine the best method for 
including in the registry and results data bank appropriate results 
information on serious adverse and frequent adverse events for 
applicable clinical trials (required to submit results information 
under section 402(j)(3)(C) of the PHS Act) in a manner and form that is 
useful and not misleading to patients, physicians, and scientists.'' If 
regulations are not issued by September 27, 2009, then section 
402(j)(3)(I)(ii) of the PHS Act specifies that the statutorily mandated 
adverse event reporting provisions specified in section 
402(j)(3)(I)(iii) of the PHS Act shall take effect, requiring the 
submission of certain information summarizing serious and frequent 
adverse events observed during an applicable clinical trial. 
Regulations were not issued by the deadline, so the statutorily 
mandated adverse event reporting provisions required by sections 
402(j)(3)(I)(ii) and (iii) of the PHS Act took effect on September 27, 
2009, at which time the ClinicalTrials.gov basic results database was 
updated accordingly. Section 402(j)(3)(I)(v) of the PHS Act indicates 
that adverse event information is ``deemed to be'' clinical trial 
information that is included in the data bank pursuant to the 
requirements for results information submission under section 
402(j)(3)(C) of the PHS Act.
    Third, section 402(j)(3)(D) of the PHS Act requires the Secretary 
to further expand the data bank by regulation ``to provide more 
complete results information and to enhance patient access to and 
understanding of the results of clinical trials.'' It requires 
consideration of specific issues in developing the regulations, in 
particular:
    (1) Whether to require submission of results information for 
applicable clinical trials of products that are not approved, licensed, 
or cleared (whether approval, licensure, or clearance was sought) (see 
section 402(j)(3)(D)(ii)(II) of the PHS Act.); and if submission of 
clinical trial results information is required for such applicable 
clinical trials, the date by which that information is required to be 
submitted. (See section 402(j)(3)(D)(iv)(III) of the PHS Act.);
    (2) Whether non-technical written summaries of the clinical trial 
and its results can be included in the data bank without being 
misleading or promotional. (See section 402(j)(3)(D)(iii)(I) of the PHS 
Act.);
    (3) Whether technical written summaries of the clinical trial and 
its results can be included in the data bank without being misleading 
or promotional. (See section 402(j)(3)(D)(iii)(II) of the PHS Act.);
    (4) Whether to require submission of the full clinical trial 
protocol or only such information on the protocol as may be necessary 
to help evaluate the results of the trial. (See section 
402(j)(3)(D)(iii)(III) of the PHS Act.);
    (5) Whether the 1 year period for submission of results information 
should be increased to a period not to exceed 18 months. (See section 
402(j)(3)(D)(iv)(I) of the PHS Act.); and
    (6) Whether requirements for results information submission as set 
forth in the regulations should apply to applicable clinical trials for 
which results information required under section 402(j)(3)(C) of the 
PHS Act is submitted before the effective date of such regulations. 
(See section 402(j)(3)(D)(iv)(II) of the PHS Act.).
    Section 402(j)(3)(D)(v) of the PHS Act further requires that the 
regulations shall establish:
    (1) A standard format for the submission of clinical trial 
information. (See section 402(j)(3)(D)(v)(I) of the PHS Act.);
    (2) Additional information on clinical trials and results written 
in nontechnical, understandable language for patients. (See section 
402(j)(3)(D)(v)(II) of the PHS Act.);
    (3) Procedures for quality control, with respect to completeness 
and content of clinical trial information, to help ensure that data 
elements are not false or misleading and are non-promotional. (See 
section 402(j)(3)(D)(v)(III) of the PHS Act.);
    (4) Appropriate timing and requirements for updates of clinical 
trial information and whether and how such updates should be tracked. 
(See section 402(j)(3)(D)(v)(IV) of the PHS Act.);
    (5) A statement to accompany the entry for an applicable clinical 
trial when primary and secondary outcome measures for such applicable 
clinical trial are submitted as a voluntary submissions after the date 
specified in section 402(j)(2)(C) of the PHS Act. (See section 
402(j)(3)(D)(v)(V) of the PHS Act.); and
    (6) Additions or modifications to the manner of reporting the data 
elements established under the results information submission 
provisions of section 402(j)(3)(C) of the PHS Act. (See section 
402(j)(3)(D)(v)(VI) of the PHS Act.).

[[Page 64990]]

    Section 402(j)(3)(D)(vii) of the PHS Act requires the Secretary to 
convene a public meeting to solicit input from interested parties on 
those issues. The public meeting was convened on April 20, 2009, on the 
NIH campus. The public meeting attracted more than 200 registered 
participants and 60 written comments. All of the comments received 
prior to, during, and after the public meeting are available in the 
Clinical Trials Public Meeting Docket, ID: NIH-2009-0002, at the 
www.regulations.gov Web site [Ref. 63]. We carefully reviewed the 
comments received in developing the proposed provisions to address the 
considerations enumerated in section 402(j)(3)(D) of the PHS Act. Many 
of the comments helped inform development of the proposed rule, which 
was issued on November 21, 2014, for public comment. For purposes of 
this rulemaking, we prepared a memorandum summarizing these comments 
from the public meeting and the issues commented upon [Ref. 64].
    Furthermore, section 402(j)(4)(A) of the PHS Act directs that the 
data bank accept ``voluntary submissions'' of complete registration or 
complete results information for certain clinical trials for which such 
information would not otherwise be required to be submitted, provided 
that the responsible party complies with requirements that could 
involve submission of information on additional clinical trials.
    Section 402(j)(5) of the PHS Act specifies certain procedures and 
penalties related to non-compliance. Among other things, it directs NIH 
to publicly post notices of noncompliance in the data bank; requires 
report forms under certain HHS grants to include a certification that 
required registration and results information submission under section 
402(j) of the PHS Act are complete; requires federal agencies to verify 
compliance before future funding or continuation of funding under 
section 402(j) of the PHS Act; and grants FDA the authority to sanction 
responsible parties who fail to comply with section 402(j) of the PHS 
Act.
    Section 801(b) of FDAAA includes certain conforming amendments to 
the FD&C Act, which make failure to comply with specified requirements 
of section 402(j) of the PHS Act, and the submission of false or 
misleading clinical trial information under section 402(j) of the PHS 
Act, prohibited acts under the FD&C Act (see 21 U.S.C. 331(jj)(1)-(3)). 
Committing any such prohibited act could subject the violator to 
criminal and/or civil penalties, including civil money penalties.
    Section 801(c) of FDAAA requires the Secretary to issue guidance on 
how the requirements of section 402(j) of the PHS Act apply to a 
pediatric postmarket surveillance of a device, where that pediatric 
postmarket surveillance is not a clinical trial. The preamble of this 
final rule addresses this topic and is intended to serve as the 
required guidance.
    Section 801(d) of FDAAA includes a preemption provision, which 
states that ``[u]pon the expansion of the registry and results data 
bank under section 402(j)(3)(D) of the PHS Act, as added by this 
section, no State or political subdivision of a State may establish or 
continue in effect any requirement for the registration of clinical 
trials or for the inclusion of information relating to the results of 
clinical trials in a database.''

III. Discussion of Public Comments on Selected Key Issues

A. Scope and Applicability

    The final rule covers requirements for the submission of clinical 
trial registration and results information to the ClinicalTrials.gov 
database. It includes expanded requirements for the submission of 
clinical trial registration and results information, as authorized by 
section 402(j) of the PHS Act, to improve public access to information 
about certain clinical trials of FDA-regulated drug products (including 
biological products) and device products. However, the rule does not 
impose requirements on the design or conduct of clinical trials or on 
the data that must be collected during clinical trials. Instead it 
specifies how data that were collected and analyzed in accordance with 
a clinical trial's protocol are to be submitted to ClinicalTrials.gov.
    Following the public comment period, we received comments on a 
variety of the NPRM's sections and key issues, which are discussed in 
detail in the other subsections of Section III and in Section IV of 
this preamble. We also received comments from approximately 115 
commenters on topics that, while important, are outside of the scope of 
the NPRM and the rule. Although we are not responding to these 
comments, the types of topics raised by these comments are described 
below.
    We received comments suggesting that the rule should establish 
requirements for the conduct of clinical trials and that compliance 
with the rule should affect whether future clinical trials may proceed. 
For example, it was suggested that the rule should not permit trials 
with placebo groups to be conducted where there is no benefit to the 
participant and the condition studied is life-threatening. It was also 
suggested that studies should not be allowed to proceed to the next 
phase until all information submission requirements of the rule are 
met. We emphasize neither section 402(j) of the PHS Act nor this rule 
establishes requirements for clinical trial design or progress.
    Commenters also provided input on the role of human subjects review 
boards, suggesting that the rule should require all proposed studies to 
be subject to their review, and that the rule should clarify HHS' 
position on human subjects protection. The role of human subjects 
review boards in the course of research is outside of the scope of this 
rule, but Human Subjects Protection Review Board Status is a required 
registration data element (see Sec. Sec.  11.10(b)(35) and 
11.28(a)(2)(iv)(D)).
    Commenters also provided input on how they see the role of the rule 
with respect to FDA action. For example, it was suggested that the rule 
should prohibit the approval of a product application submitted to FDA 
unless results information submission requirements have been met. While 
the rule's results information submission requirements are connected to 
FDA approval, licensure, or clearance in terms of triggers for results 
information submission in certain cases, the rule does not affect, 
direct, or prohibit FDA from acting on a particular application or 
submission. Although FDA's actions with respect to approval, licensure, 
or clearance are outside the scope of this rule, FDA enforces FDAAA's 
registration and results information submission requirements and the 
requirement that a responsible party not submit false and/or misleading 
information. As described in more detail in Section IV.E, if FDA 
identifies a violation, the Agency may notify the responsible party 
and, as appropriate, initiate administrative proceedings for civil 
monetary penalties or the process for civil or criminal judicial 
actions.
    We received comments about enforcement of the rule, suggesting that 
NIH and FDA should be enforcing the current requirements (i.e., before 
the rule's effective date) as well as the additional results 
information reporting requirements in the final rule. We have addressed 
the applicability of the requirements of section 402(j) of the PHS Act 
and final rule throughout this preamble, including in the Effective 
Date, Compliance Date, and Applicability of Requirements in this Part 
discussion in Section IV.F. A few commenters suggested that FDA should 
enforce results information reporting requirements and that it should 
cancel

[[Page 64991]]

marketing approvals ``in cases of egregious misrepresentations.'' 
Commenters also proposed specific penalty structures, such as only 
penalizing the responsible party and not the institution and making all 
intentional violations criminal with mandatory prison sentences. They 
also proposed incentives, such as providing easier submission 
mechanisms and citable credit for shared data sets. The specifics of 
how and under what circumstances FDA will seek to enforce section 
402(j) of the PHS Act are beyond the scope of the rule, as are issues 
relating to the marketing of FDA-regulated products. FDA may issue 
guidance regarding enforcement in the future. FDA enforces FDAAA's 
registration and results information submission requirements and the 
requirement that a responsible party not submit false and/or misleading 
information. As described in more detail in Section IV.E, if FDA 
identifies a violation, the Agency may may notify the responsible party 
and, as appropriate, initiate administrative proceedings for civil 
monetary penalties or the process for civil or criminal actions.
    Although we did include in the preamble to the proposed rule a 
general discussion of the statutory procedures and penalties related to 
non-compliance (79 FR 69570), we did not otherwise discuss in detail 
the legal ramifications of failure to comply with the requirements of 
section 402(j) of the PHS Act, including these regulations. Other than 
the requirement that a responsible party not submit false or misleading 
information and the associated notice of potential liabilities for 
doing so (see Sec.  11.6), the proposed codified text did not describe 
the potential legal consequences of failing to comply with the 
requirements of the rule. However, as discussed in Section IV. E below, 
we are adding a new Sec.  11.66 that describes potential legal 
consequences provided for in the FDAAA enforcement provisions for 
failure to comply with the requirements in these regulations.
    Some commenters suggested that the rule should require registered 
trials to make IPD datasets available to qualified researchers and some 
suggested that the rule should require the submission and disclosure of 
de-identified IPD datasets to ClinicalTrials.gov. The sharing or 
submission of de-identified IPD is not required or authorized in 
section 402(j) of the PHS Act, and is, thus, not included in this rule. 
In addition, ClinicalTrials.gov does not currently have a mechanism to 
directly collect datasets containing de-identified IPD. As discussed in 
Section I, however, ClinicalTrials.gov provides optional registration 
data elements that allow responsible parties to specify whether there 
is a plan to share the IPD or associated documents from the trial. 
Providing such meta-data about IPD in a searchable system facilitates 
identification of such data for use in a scientifically appropriate 
manner. In this way, we anticipate that ClinicalTrials.gov can be used 
in the future to catalyze IPD sharing.
    Some commenters expressed concern about whether posting results 
information might be considered ``prior publication'' by journal 
editors thereby precluding subsequent publication of a journal article, 
while others suggested that posting of results information could be 
delayed an additional 12 months while papers undergo peer review. The 
rule implements the directives of section 402(j) of the PHS Act and is 
independent of the ICMJE clinical trial registration policy [Ref. 1, 
2]. However, we note that the ICMJE has stated that submission of 
summary results to ClinicalTrials.gov will not be considered prior 
publication and will, thus, not interfere with journal publication 
[Ref. 2]. Interested parties are encouraged to explore the policies of 
the ICMJE and of the journals to which they seek to submit papers.
    Some commenters also requested that NIH publish guidance clarifying 
the rule's requirements and provide training to clinical investigators 
about them. The Agency intends to continue making guidance documents 
and other materials available, including examples, case studies, and, 
as discussed below, a publicly-accessible checklist-based tool 
available at https://prsinfo.clinicaltrials.gov (or successor site) 
consisting of the relevant data elements and detailed explanation of 
each criterion. One commenter also suggested that one of the reasons 
for poor compliance with current law is the difficulty in 
interpretation and complexities around results reporting. We expect 
that the clarifications in this rule will help to address this concern.
    Commenters provided suggestions regarding the usability of 
ClinicalTrials.gov. Comments regarding technical changes to the Web 
site are discussed in Section IV.A.4 (``In what format must clinical 
trial information be submitted?--Sec.  11.8''). While the details of 
the usability of ClinicalTrials.gov were not outlined in the NPRM or 
codified in this rule, we do wish to address these comments. Some 
commenters were dissatisfied with the process for entering data into 
the Protocol Registration and Results System (PRS), noting it is 
difficult to navigate, cumbersome, and complex. The PRS is the 
electronic system maintained by ClinicalTrials.gov that responsible 
parties use to register and submit results information for their 
studies, described at https://prsinfo.clinicaltrials.gov. They pointed 
to limitations of the PRS in sorting, filtering, and building queries, 
and some had specific suggestions on elements by which the site should 
be able to search, filter, and sort. We note that the PRS user 
interface has been updated incrementally over time with significant 
changes being made between 2014 and 2016, including the implementation 
of features to help streamline the results data entry process. In 
addition, based on usability study findings and expert evaluation, we 
further streamlined the data submission process for registration and 
results information, improved the reporting and portfolio management 
functions (with this series of enhancements, including one made in 
March 2016, addressing many of the concerns expressed by commenters), 
and provided enhanced resource materials for data submitters. We have 
also been providing 1-on-1 assistance to investigators submitting 
results in the PRS. While we continue our efforts to enhance the 
usability of the PRS and train personnel at academic institutions to 
provide centralized support to their investigators, the 1-on-1 
assistance initiative has proven to be effective for providing 
customized support to investigators in fulfilling their requirements--
especially for the many investigators who are using the PRS to submit 
results information for the first time. We will also expand the options 
in the PRS to accommodate the requirements of the final rule.
    Commenters wanted the site to be user-friendly and allow for 
feedback, suggesting the NIH consult with experts to develop tools and 
with members of the public to ensure a user-friendly interface. We have 
conducted usability studies with a wide user audience and continue to 
obtain valuable feedback from a survey implemented on the public site. 
An example of a change that was made using this feedback was adding an 
option to search for trials based on the specific age of the potential 
participant (previously only age groups were easily searchable). We 
note that users may continue to provide feedback by using the ``Contact 
NLM Help Desk'' link on the bottom of every page on the 
ClinicalTrials.gov public Web site and by responding to the survey, 
when prompted. We intend to further consider this valuable input and 
collect

[[Page 64992]]

additional input as we continue to refine the site and optimize it to 
support provider and patient needs and to improve its scientific 
utility. Our goal is for clinical researchers, data scientists, health 
care providers, patients, and the public users of the site to have a 
more positive experience and for the site to be functional for these 
diverse audiences.
    Other commenters wanted to be sure the Agency has sufficient 
resources to carry out NLM's mission. Commenters also requested better 
communication between the ClinicalTrials.gov staff that operate the PRS 
and responsible parties, particularly via email, and suggested that the 
NIH reinstate in-person training sessions. Over the last year, we have 
expanded both the customer service and reviewer staff and provided 
comprehensive training to help ensure communications with responsible 
parties are as prompt, clear, and helpful as possible. We will continue 
to ensure staff are well-trained and monitor the satisfaction of 
responsible parties with the communications they receive. We will 
continue to offer PRS training to responsible parties. In addition, we 
will be launching a series of activities, such as webinars and 
presentations at selected conferences, to educate the biomedical 
research community about their obligations and to ensure that patients 
and care providers are aware of the information available at 
ClinicalTrials.gov. All such information will be available from https://prsinfo.clinicaltrials.gov. Overall, we are taking steps to improve 
the usability of the resource for all users of ClinicalTrials.gov, data 
submitters and data users alike.
    Finally, a few commenters suggested that the law and the final rule 
should apply to all researchers conducting clinical trials with NIH 
funds. A number of commenters also took note of the proposed NIH Policy 
on Dissemination of NIH-Funded Clinical Trial Information, which was 
issued by NIH on November 19, 2014, in tandem with the publication of 
the NPRM [Ref. 65]. The policy proposed that all NIH-funded awardees 
and investigators conducting clinical trials should be expected to 
register their clinical trials and submit results information to 
ClinicalTrials.gov. NIH proposed that the policy would apply to 
awardees and investigators conducting clinical trials, funded in whole 
or in part by NIH, whether or not they are subject to section 402(j) of 
the PHS Act. The policy would, thereby, also apply to NIH-funded phase 
1 clinical trials of FDA regulated drugs, small feasibility studies of 
devices, and trials of interventions not regulated by FDA, including 
surgical and behavioral interventions.
    The draft policy proposed that the same registration and results 
information submission elements and reporting timeframes that would be 
required under the final rule would also apply to those clinical trials 
subject to the NIH policy, through the terms and conditions of the NIH 
funding awards. Most of the NPRM commenters who also commented on the 
draft NIH policy were supportive of it and of its application to a 
wider range of clinical trials [Ref. 66]. NIH considered those comments 
and comments received on the policy itself in developing the final 
policy. The final policy is substantively the same as the proposed 
draft policy in terms of scope, applicability, and the content and 
timing of registration and results information submission. It requires 
NIH-funded applicants and offerors to submit a plan for the 
dissemination of NIH-funded clinical trial information that will 
address how the policy's expectations for registration and results 
information submission will be met. NIH-funded awardees and 
investigators conducting clinical trials funded in whole or in part by 
NIH will be required to comply with all terms and conditions of award, 
including following their plan for the dissemination of NIH-funded 
clinical trial information. The final NIH policy, NIH Policy on 
Dissemination of NIH-Funded Clinical Trial Information, appears 
elsewhere in this FR [FR OFFICE, PLEASE CROSS-REFERENCE NIH POLICY] and 
includes a preamble discussing the public comments on the draft policy.

B. Submission of Results Information for Applicable Clinical Trials of 
Unapproved, Unlicensed, or Uncleared Products for Any Use

Overview of Proposal
    Section 402(j) of the PHS Act requires the submission and posting 
of registration information and results information for applicable 
clinical trials of approved, licensed, or cleared products, as well as 
submission of registration information and posting requirements for 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products. The statute provides the Secretary with the discretion 
through rulemaking to require the submission of results information 
from applicable clinical trials of products that are unapproved, 
unlicensed, or uncleared, whether or not approval, licensure, or 
clearance was sought. In particular, section 402(j)(3)(D)(ii)(II) of 
the PHS Act specifies that the Secretary, through regulation, shall 
establish whether results information should be required for ``(aa) an 
applicable drug clinical trial for a drug that is not approved under 
section [505 of the FD&C Act] and not licensed under section [351 of 
the PHS Act] (whether approval or licensure was sought or not); and 
(bb) an applicable device clinical trial for a device that is not 
cleared under [section 510(k) of the FD&C Act] and not approved under 
section [515 or section 520(m) of the FD&C Act] (whether clearance or 
approval was sought or not).'' Given this authority and various factors 
discussed in the NPRM (79 FR 69633), we proposed to require submission 
of results information from applicable clinical trials of FDA-regulated 
drugs (including biological products) and devices that are unapproved, 
unlicensed, or uncleared for any use as of the completion date, whether 
or not approval, licensure, or clearance was sought.
    Regarding the scope of trials for which submission of results 
information in accordance with subpart C of the proposed rule is 
required, Sec.  11.42(a) proposed to require submission of results 
information for all applicable clinical trials (i.e., regardless of 
whether the product being studied was approved, licensed, or cleared) 
for which submission of registration information was required under 
proposed Sec.  11.22 and for which the completion date was on or after 
the effective date of the rule. Section 11.42(b) proposed to require 
submission of results information for those applicable clinical trials 
for which submission of registration information was required under 
proposed Sec.  11.22 and for which the completion date was before the 
effective date of the rule, but for which the relevant results 
information submission deadline in proposed Sec.  11.44 was on or after 
the effective date of the rule and results information was submitted on 
or after the effective date, consistent with the applicable deadline 
established by proposed Sec.  11.44.
    With respect to the proposed results information submission 
deadlines for applicable clinical trials of drugs and devices that are 
not approved, licensed, or cleared by FDA for any use as of the 
completion date of the trial (where the completion date occurs prior to 
the effective date of the final rule), but are subsequently approved on 
or after the effective date, proposed Sec.  11.44(a)(2) would require 
results information to be submitted by the earlier of (i) 1 year after 
the primary completion date or (ii) 30 calendar days after FDA 
approval,

[[Page 64993]]

licensure, or clearance, except as otherwise provided under Sec.  
11.44(c), (d), or (e). Under proposed Sec.  11.44(c), results 
information submission for applicable clinical trials studying FDA-
regulated drugs (including biological products) or devices that were 
not approved, licensed, or cleared by the FDA for any use before the 
completion date of the trial may be delayed for up to 2 additional 
years (i.e., up to 3 years after the primary completion date) if the 
responsible party certifies before the results information submission 
deadline that initial approval, licensure, or clearance of the studied 
product is being sought or may be sought by the sponsor at a future 
date. If the responsible party so certifies, all required clinical 
trial results information must be submitted by the earlier of (1) 30 
calendar days after FDA approves, licenses, or clears the drug or 
device for any indication studied in the applicable clinical trial, (2) 
30 calendar days after a marketing application or premarket 
notification is withdrawn and not resubmitted within 210 calendar days, 
or (3) 2 years from the date of certification (proposed Sec.  
11.44(c)(2)). Proposed Sec.  11.44(d) addressed the submission 
requirements in situations where clinical trial results information has 
not been collected for a secondary outcome measure by the completion 
date.
    The NPRM also addressed the situation in which results information 
for an applicable clinical trial of a device not previously approved or 
cleared is required to be submitted. Proposed Sec.  11.35(b)(2) 
implemented section 402(j)(2)(D)(ii)(I) of the PHS Act, which prohibits 
the Director from posting submitted registration information prior to 
the date on which FDA approves or clears the device studied in the 
applicable clinical trial. Therefore, the timelines for submitting and 
posting clinical trial results information for applicable device 
clinical trials for unapproved or uncleared devices in proposed 
Sec. Sec.  11.44 and 11.52, respectively, could result in the public 
availability of clinical trial results information for such trials 
before the information submitted during registration is posted in 
accordance with proposed Sec.  11.35(b)(2) for these same trials, and 
for devices that are never approved or cleared, without such 
registration information ever being posted.
    As we explained in the NPRM, posting clinical trial results 
information without sufficient corresponding public availability of 
certain descriptive information about the trial (that is similar to the 
type of information included as part of registration) would fail to 
provide the necessary context for understanding clinical trial results 
information, thereby significantly limiting understanding of posted 
results information (79 FR 69580). Section 402(j)(3)(D)(ii)(II) of the 
PHS Act authorizes the Secretary to require, through rulemaking, the 
submission of clinical trial results information for applicable 
clinical trials of products that have not been approved, licensed or 
cleared, whether or not approval, licensure or clearance had been 
sought. Specifically, it authorizes the Secretary to require, for an 
applicable device clinical trial of a device that has not been 
previously approved or cleared, the submission of the results 
information that is described in section 402(j)(3)(D)(iii) of the PHS 
Act. Section 402(j)(3)(D)(iii) of the PHS Act states that the 
regulations ``shall require, in addition to the elements described in 
[section 402(j)(3)(C) of the PHS Act] . . . [s]uch other categories as 
the Secretary determines appropriate.'' Thus, for applicable device 
clinical trials of unapproved or uncleared devices, the Secretary can 
require, through rulemaking, submission of ``such other categories'' of 
results information as the Secretary determines appropriate in addition 
to the information required under section 402(j)(3)(C) of the PHS Act. 
As discussed in the NPRM, in order to ``enhance patient access to and 
understanding of the results of clinical trials'' as required by 
section 402(j)(3)(D)(i) of the PHS Act, we interpreted ``such other 
categories'' of results information for applicable device clinical 
trials of unapproved or uncleared devices subject to proposed Sec.  
11.35(b)(2) and for which posting of registration information continues 
to be delayed to include, among other things, certain descriptive 
information that is similar to the type of information that is required 
to be submitted under section 402(j)(2)(A)(ii) of the PHS Act (79 FR 
69581). Accordingly, proposed Sec.  11.48(a)(6) required responsible 
parties for applicable device clinical trials of unapproved or 
uncleared devices, for which the device remained unapproved or 
uncleared at the time of results information submission to submit this 
descriptive information as part of clinical trial results information.
Comments and Response
    A number of commenters addressed the topic of results information 
submission for applicable clinical trials of unapproved, unlicensed, or 
uncleared products. Commenters who supported the proposal stated that 
public availability of results information from trials of unapproved, 
unlicensed, and uncleared drugs (including biological products) and 
devices is expected to have public health benefits, as it helps protect 
the safety of participants who volunteer to be in clinical trials by 
reducing the likelihood that people will unknowingly design, approve, 
or participate in clinical trials that are duplicative and unnecessary 
(e.g., because similar clinical trials have already been conducted but 
not published), or that are potentially ineffective or harmful (e.g., 
because similar interventions have been shown to be harmful or 
ineffective in previous, unpublished clinical trials). Commenters also 
stated that results information from trials of unapproved, unlicensed, 
or uncleared products will reduce costs by minimizing the number of 
redundant trials.
    Commenters expected that public availability of results information 
will assist potential human subjects in making more informed decisions 
about participating in a clinical trial by providing them and their 
care providers with information about the results of a broader set of 
clinical trials of various interventions that have been studied for a 
disease or condition of interest. Investigators and human subjects 
protection review boards that already have access to unpublished 
information from the sponsor of a clinical trial or the manufacturer of 
a drug or device will have access via ClinicalTrials.gov to information 
about other clinical trials of similar unapproved, unlicensed, or 
uncleared products that might help them in designing or considering the 
potential risks and benefits of participation in a clinical trial.
    Commenters highlighted that results should be put to the broadest 
use because participants in research often put themselves at risk to 
participate and they deserve to have their participation contribute to 
the advancement of medical science, so that future patients may benefit 
from the knowledge gained. Commenters also indicated that increased 
transparency could help researchers learn from failed trials, verify 
findings, advance research, and improve overall understanding of 
disease. Commenters stated that trial results that are never published 
distort the evidence base for systematic reviews conducted to support 
development of clinical practice guidelines, which increases the time 
and effort needed to develop such guidelines. One commenter suggested 
that because it is common for products to be used outside of their 
approved marketing authorization in medical practice, information on 
trials of unapproved, unlicensed, or uncleared products

[[Page 64994]]

should comply with robust reporting requirements in order to minimize 
potential risk to the public.
    A couple of commenters mentioned that the requirement to submit 
results information from trials of unapproved products is consistent 
with the 2014 European Union (EU) clinical trial regulations. We agree 
with this point and note the ongoing regulatory efforts by the European 
Medicines Agency (EMA) to make results information from clinical trials 
of drugs conducted within the EU available in a publicly accessible 
data bank, regardless of the approval status of the drug [Ref. 67, 68, 
69]. As discussed in the NPRM, all clinical trials of drugs performed 
within the EU are registered in EMA's European Clinical Trials Database 
(EudraCT) database, with information on phase 2, 3, and 4 clinical 
trials and all pediatric clinical trials made public through the EU 
Clinical Trials Register (79 FR 69578) [Ref. 70]. In October 2013, EMA 
released a new version of the EudraCT database to support the 
submission and public posting of summary clinical trial results on the 
EU Clinical Trials Register (EU CTR). The specified summary results 
information differs from the detailed information that would be 
submitted to EMA as part of a Marketing Authorization Application. As 
noted in the EMA's announcement, the EudraCT summary results data 
requirements are ``substantially aligned'' with those of the 
ClinicalTrials.gov results database [Ref. 71].
    Commenters who were opposed to the proposal suggested that 
submission (and public posting) of results information for trials of 
products still under development may curtail incentives to invest in 
innovative research. Regarding devices in particular, it was suggested 
that requiring results information submission for trials of uncleared 
devices will have a negative effect on the development of new and 
innovative devices. Comments suggested that the risk of disclosing such 
results information would outweigh the benefit to the public, who 
cannot use a product that is not approved, licensed, or cleared. See 
the discussion of Sec.  11.44 in Section IV.C.3 of this preamble for 
comments and the Agency response regarding the timeline for submission 
of results information for trials of unapproved, unlicensed, or 
uncleared products.
    Several commenters raised legal challenges, citing the FD&C Act, 
the Freedom of Information Act (FOIA), and the U.S. Trade Secrets Act 
(U.S. TSA). We disagree with these comments. As an initial matter, we 
would like to clarify that FDA's disclosure laws and regulations do not 
apply to information submitted to ClinicalTrials.gov. FDA's statutory 
provisions apply to information obtained by the FDA pursuant to the 
enumerated statutory provisions of the FD&C Act, (see sections 301(j) 
and 520(c) of the FD&C Act) and FDA's general and product-specific 
disclosure regulations for drug products (including biological 
products) and device products apply to FDA records. (See 21 CFR part 20 
and 21 CFR 312.120, 314.430, 807.95, 812.38, and 814.9). Information 
submitted to ClinicalTrials.gov is submitted to NIH pursuant to section 
402(j) of the PHS Act and the regulations promulgated under it. 
Registration and results information submitted to ClinicalTrials.gov is 
not obtained pursuant to the FD&C Act, nor is it maintained as an FDA 
record.
    With respect to the FOIA (5 U.S.C. 552), although the FOIA provides 
a general right to obtain information in Federal Agency records, it 
also establishes certain exemptions from disclosure; thus, while the 
FOIA is, broadly speaking, a disclosure statute, it also states that 
the disclosure requirements do not apply to information in Agency 
records if that information falls within one of the enumerated 
exemptions (see 5 U.S.C. 552(b)). In other words, an Agency is not 
required to release information under FOIA if that information falls 
within one of the enumerated exemptions. One of the categories of 
information that is exempted from disclosure is ``trade secrets and 
commercial or financial information obtained from a person [that is] 
privileged and confidential.'' (5 U.S.C. 552(b)(4)). In contrast, the 
U.S. TSA (18 U.S.C. 1905) explicitly prohibits the release of such 
information by an Agency employee from Agency records. However, the 
U.S. TSA prohibitions do not apply when the disclosure of information 
is authorized by law. As established by the Supreme Court in Chrysler 
Corp. v. Brown, 441 U.S. 281 (1979), a statute or validly promulgated 
regulation requiring disclosure constitutes ``authorization by law'' 
for purposes of the U.S. TSA. Section 402(j) of the PHS Act requires 
that the Agency post certain registration and results information from 
applicable clinical trials, and further requires the Secretary to 
determine via rulemaking whether to require the submission and posting 
of results information from applicable clinical trials of unapproved, 
unlicensed, or uncleared drugs and devices (see section 402(j)(3)(D)(i) 
and (ii)(II) of the PHS Act), as well as to determine what results 
information must be submitted (see section 402(j)(3)(D)(iii)(IV) of the 
PHS Act). Accordingly, to the extent that clinical trial information, 
including but not limited to results information from applicable 
clinical trials of unapproved, unlicensed, or uncleared drugs and 
devices, described in section 402(j) of the PHS Act and this final rule 
may contain trade secret and/or confidential commercial information, 
the requirement that such information be posted on ClinicalTrials.gov 
is authorized by law for the purposes of the U.S. TSA.
    It was also suggested that the provision in section 
402(j)(2)(D)(ii)(I) of the PHS Act for delayed disclosure of 
registration information prohibits the posting of results information 
for applicable clinical trials of unapproved or uncleared devices. We 
believe the authority to require submission of results information for 
applicable clinical trials of unapproved and uncleared devices is clear 
from the language in section 402(j)(3)(D)(ii)(II)(bb) of the PHS Act. 
We have explained above the reasoning for requiring responsible parties 
to submit certain descriptive information as part of clinical trial 
results information for certain applicable device clinical trials of 
unapproved or uncleared device products, which is maintained in the 
final rule at Sec.  11.48(a)(7).
    One commenter also suggested that disclosure would be a forced 
release of trade secrets and confidential commercial information in 
violation of common law applicable to trade secrets. Another commenter 
raised a constitutional challenge, suggesting that the Agency would be 
disclosing trade secrets through this requirement, which they argued 
would constitute a regulatory taking of property without just 
compensation, in violation of the Fifth Amendment of the U.S. 
Constitution. We disagree.
    The Supreme Court found in Ruckelshaus v. Monsanto (467 U.S. 986 
(1984)) that trade secrets are property for purposes of the application 
of the Takings Clause of the Fifth Amendment. Most states have adopted 
the Uniform Trade Secrets Act (UTSA) and its definition of ``protected 
trade secret interests'': ``[I]nformation, including a formula, 
pattern, compilation, program, device, method, technique, or process 
that: (i) Derives independent economic value, actual or potential, from 
not being generally known to, and not being readily ascertainable by 
proper means by, other persons who can obtain economic value from its 
disclosure or

[[Page 64995]]

use, and (ii) is the subject of efforts that are reasonable under the 
circumstances to maintain its secrecy.'' (See UTSA with 1985 Amendments 
Sec.  1(4)).
    However, even if there is a protected trade secret interest, the 
question of whether the government's proposed regulation amounts to a 
taking under the Fifth Amendment requires additional analysis. In Penn 
Cent. Transp. Co. v. City of New York (438 U.S. 104 (1978)), the 
Supreme Court set forth a three-factor analysis for determining whether 
a regulatory taking had occurred. Specifically, the Court identified 
(1) The extent to which an Agency's regulation interferes with distinct 
investment-backed expectations, (2) The economic impact of the 
regulation on the claimant, and (3) The character of the governmental 
action.
    As an initial matter, none of the commenters identified any 
specific information that they assert constitutes trade secret 
information for purposes of a takings analysis, and that would be taken 
as a result of the statutory and regulatory requirements regarding 
submission to and posting on ClinicalTrials.gov. With respect to the 
factors outlined by the Supreme Court in Penn Central, we do not 
believe that drug and medical device manufacturers have a reasonable 
expectation at this time that the results information described in the 
final rule will be kept confidential. This is because (1) the field of 
drug and device development is highly regulated, (2) there has been 
robust public debate over the need for greater transparency of clinical 
trial results, and (3) it has been clear since the proposed rule was 
issued in 2014 (and in our view since the enactment of FDAAA, with its 
requirement that the rulemaking address the issue of results 
information submission and posting for applicable clinical trials of 
unapproved, unlicensed, and uncleared products), that such information 
can and may be made available to the public. None of the commenters 
have identified specific information required under the regulations 
that they believe would be of value to competitors, or that would allow 
competitors to benefit from innovators' scientific and technical 
advancements. Nor, as stated above, have they identified specific 
clinical trial results information that would be required to be 
submitted and that would meet the definition of a protected trade 
secret property interest for purposes of a takings analysis.
    Regarding the final factor under Penn Central, we reiterate that, 
as discussed at length in this preamble, as well as in the proposed 
rule, there are significant public health benefits to requiring the 
disclosure of the information posted on ClinicalTrials.gov, including 
for applicable clinical trials of unapproved, unlicensed, and uncleared 
products. For many years the scientific community, general public, 
industry and others have engaged in high-profile public discussions 
about the need for increased access to information about clinical 
trials. Potential societal harms associated with having an incomplete 
medical evidence base have been reviewed; for example, studies have 
revealed that selective publication of clinical trial results could 
give a misleading picture about serious adverse effects of widely 
marketed drugs and about increased risks of such effects in certain 
segments of the population [Ref. 45].
    As noted previously, the requirements for submission to and posting 
on ClinicalTrials.gov have the additional public health benefit of 
supporting international standards and norms (e.g., Declaration of 
Helsinki, World Health Organization (WHO) Statement on Public 
Disclosure of Clinical Trials Results) and with industry, governmental, 
and other policies. The requirements under section 402(j) of the PHS 
Act, including those in this final rule, reflect our careful 
consideration and balancing of the burdens and benefits of the 
disclosure of this information for the drug and medical device industry 
and the public. These requirements further the important public health 
goals of enhancing patient enrollment in clinical trials, providing a 
mechanism to track the progress of clinical trials, and enhancing 
patient access to and understanding of the results of clinical trials.
    The final rule maintains the proposal to require the submission of 
results information for applicable clinical trials of unapproved, 
unlicensed, or uncleared products, regardless of whether FDA approval, 
licensure, or clearance is or will be sought or obtained. We conclude 
that this requirement is in furtherance of the express statutory 
purpose of section 402(j)(3)(D)(i) of the PHS Act, which states that 
the Secretary shall expand the registry and results data bank ``[t]o 
provide more complete results information and to enhance patient access 
to and understanding of the results of clinical trials.'' We considered 
a number of factors, notably the potential public health benefits of 
timely disclosure of results information for applicable clinical trials 
of unapproved, unlicensed, or uncleared products; the potential effects 
of disclosure on the competitive advantage of drug and device 
manufacturers, including incentives to invest in the development of new 
products intended to improve public health; and other results 
information submission requirements and policies (e.g., those of the 
EMA). Other considerations include the relative burden on the 
responsible party of submitting results information for an applicable 
clinical trial of an unapproved, unlicensed, or uncleared product, the 
date by which results information must be submitted and practical 
issues of implementation and compliance.
    As discussed in the NPRM (79 FR 69578), we recognize that the 
posting of results information about applicable clinical trials of 
unapproved, unlicensed, and uncleared products presents special 
challenges. Such information would be accessible to care providers and 
their patients but describe products that are not approved, licensed, 
or cleared, and thus may not be available outside of clinical trials. 
Further, even for approved, licensed, or cleared products, the posted 
results information might contain information about unapproved, 
unlicensed, or uncleared uses and further information may be helpful in 
understanding potential risks and benefits. We believe that the results 
information from any individual applicable clinical trial should be 
considered in the context of the broader set of information available 
about the product and alternative products. In keeping with current 
practice, we intend to establish links from clinical trial records in 
ClinicalTrials.gov to additional sources of information, including but 
not limited to the FDA and NIH information specified in section 
402(j)(3)(A)(ii) of the PHS Act (we intend to indicate that the links 
were added by the Agency and not by the responsible party for the 
applicable clinical trial). We intend to provide information to assist 
users in better understanding and interpreting the information 
available in ClinicalTrials.gov, including materials that describe the 
general purpose and content of the data bank, a general description of 
the limitations of the results information presented, and cautions that 
the information should be used in conjunction with advice from 
healthcare professionals.
    In this regard, it bears repeating that nothing in this rule 
authorizes a firm to use information posted in, or links to other Web 
sites available on, ClinicalTrials.gov, to promote unapproved, 
unlicensed, or uncleared medical products or unapproved, unlicensed, or 
uncleared uses of approved, licensed, or cleared medical products, or 
supersedes or alters other statutory and regulatory provisions

[[Page 64996]]

related to such communications. In addition, the government does not 
independently verify the scientific validity or relevance of the 
information submitted to ClinicalTrials.gov beyond the limited quality 
control review by NIH. As discussed in Section III.C.12 of the NPRM, 
since responsible parties have been submitting results, the NIH has 
used a two-step process for quality control, starting with an automated 
system-based check prior to submission followed by a detailed, manual 
review after submission. This detailed review is based on quality 
review criteria for identifying apparent errors, deficiencies, or 
inconsistencies that are not detected by the automated checks. If any 
such problems are identified in the detailed, manual review, the 
proposed rule stated, the Director would send an electronic 
notification to the responsible party, indicating that the submission 
contains apparent errors, deficiencies, and/or inconsistencies listing 
such issues and requesting that they be addressed. Accordingly, the 
inclusion of data and information in the ClinicalTrials.gov platform, 
the links to other studies and Web sites, and the conduct of the 
limited quality control review by NIH, do not constitute a government 
affirmation or verification that the information within or referenced 
in the database, or communications that rely on that information, are 
truthful and non-misleading, particularly where they are being pointed 
to in the context of treatment decisions relating to the use of a 
product for an unapproved use.
    The final rule does make a modification to the NPRM regarding 
applicable clinical trials that are completed before the effective date 
of the final rule and that study a product that is not approved, 
licensed, or cleared as of the effective date of the final rule. 
Proposed Sec.  11.44(a)(2) would have required that for: (1) Applicable 
clinical trials that reach their completion date prior to the rule's 
effective date, (2) of products that are unapproved, unlicensed, or 
uncleared as of the completion date, and (3) for which the studied 
product is approved, licensed, or cleared by FDA on or after the 
effective date, if not otherwise subject to other deadlines specified 
in proposed Sec.  11.44, results information must be submitted by the 
earlier of one year after the completion date or 30 calendar days after 
FDA approval, licensure, or clearance. A commenter suggested this could 
result in a situation in which a trial ends shortly before FDA approval 
or clearance and is not given a full year to submit results information 
after the trial's primary completion date. This provision has been 
removed from the final rule. As discussed in more detail below, an 
applicable clinical trial of an unapproved, unlicensed, or uncleared 
product that reaches its primary completion date before the effective 
date of the final rule is not subject either to the results information 
submission requirements in the final rule or the results information 
submission requirements specified in section 402(j)(3)(C) and section 
402(j)(3)(I) of the PHS Act.
    Commenters also suggested changes to the scope of the results 
information submission requirement for applicable clinical trials of 
unapproved, unlicensed, or uncleared products and addressed the 
statutory charge to the Secretary to determine whether the rule should 
require the submission of results information from applicable clinical 
trials of unapproved, unlicensed, or uncleared products, whether or not 
approval, licensure, or clearance will be sought (section 
402(j)(3)(D)(ii)(II) of the PHS Act). Commenters suggested various 
options on the subject of the abandonment of product development, 
including that abandoned products should be identified, but submission 
of results information from applicable clinical trials of such products 
should not be required; commenters also suggested that the rule should 
only apply to applicable clinical trials of unapproved, unlicensed, or 
uncleared products that have been declared abandoned by the sponsor.
    As explained in the proposed rule and above, while limiting results 
submission to those applicable clinical trials of unapproved, 
unlicensed, or uncleared products for which product development has 
been abandoned by industry would mitigate industry concerns about 
disclosing potentially valuable information to competitors, it would do 
little to address concerns about bias in the disclosure of information 
(79 FR 69577). Considerable information of potential scientific, 
clinical, and public significance would still be hidden from public 
view and would continue to be unavailable for consideration by human 
subjects protection review boards in assessing proposed clinical 
trials, by individuals considering participation in them, or by other 
researchers who are planning similar clinical trials or clinical trials 
of similar products. In addition, limiting results information 
submission and posting to applicable clinical trials of products for 
which product development has been abandoned would be difficult to 
administer because only the sponsor and/or manufacturer are in a 
position to determine that product development has been abandoned for 
all potential uses. Moreover, product development is often suspended 
for periods of time before being resumed when company priorities change 
or an investigational product is transferred to another company. 
Information about unapproved, unlicensed, or uncleared products for 
which product development may have been suspended might therefore 
remain undisclosed for long periods of time, depriving the public of 
the benefits that could result from disclosure.
    A few commenters suggested that if the proposal is adopted, only a 
limited number of primary or key secondary outcomes prior to regulatory 
approval should be required to be submitted, or the final rule should 
allow the submission of redacted results information, especially when 
the product has not been approved, licensed, or cleared by FDA. The 
Agency disagrees; we believe that results information submission for 
all pre-specified primary and secondary outcomes, as required in the 
statute, is necessary to serve the public interest in having access to 
full and complete information. Selective reporting of results 
information would produce an incomplete and potentially skewed 
submission that ultimately would not serve the interests of the public 
and users of ClinicalTrials.gov.
    Finally, it was suggested that device manufacturers be permitted to 
withhold proprietary information from the public as long as doing so 
does not pose a risk to patients. As discussed in Section IV.B. 5, 
trials of unapproved or uncleared device products qualify for a delay 
in the disclosure of registration information. However, based on the 
evidence available in the published literature as described in Section 
I of this preamble, we have concluded that selectively withholding of 
clinical trial information, including results information, at the 
discretion of the responsible party does not best serve the public 
interest. In addition, section 402(j) of the PHS Act requires the trial 
results in summary form (rather than individual participant-level 
form), which we believe can be provided without disclosing trade secret 
or confidential commercial information. Commenters did not indicate how 
such results information is or could be considered proprietary (or how 
it could contain proprietary information). Furthermore, even if the 
summary results information required to be submitted and posted does 
include such proprietary information, as discussed above, section 
402(j) of the PHS Act and

[[Page 64997]]

this final rule constitute authorization by law to disclose this 
information.
Final Rule
    Based on the comments received and the statutory requirements, this 
final rule maintains the requirement to submit results information from 
applicable clinical trials of unapproved, unlicensed, and uncleared 
products consistent with the timelines outlined in Sec.  11.44. The 
timely disclosure of results information, along with options for 
limited delays in results information submission deadlines with 
certification when seeking initial approval, licensure, or clearance, 
or approval, licensure, or clearance of a new use, takes into 
consideration the various interests at stake, including the public 
health benefits of disclosure and the commercial interests of sponsors.
    Registration information must be submitted by the deadlines 
outlined in Sec.  11.24, which do not distinguish between the 
submission of information from applicable clinical trials of approved, 
licensed, or cleared products and information from applicable clinical 
trials of unapproved, unlicensed, or uncleared products. Section 11.35 
specifies (see Section IV.B.5) the timelines for posting of 
registration information for applicable drug clinical trials 
(regardless of product approval status), applicable clinical trials of 
device products that previously were approved or cleared, and 
applicable clinical trials of device products that have not been 
previously approved or cleared (which qualify for delayed posting in 
Sec.  11.35(b)(2)(i)). Section IV.B.5 also describes new Sec.  
11.35(b)(2)(ii) that provides a process for a responsible party to 
indicate to the Director that it is authorizing the Director to 
publicly post its clinical trial registration information at 
ClinicalTrials.gov prior to the date of FDA approval or clearance of 
its device product. If the responsible party submits the Post Prior to 
U.S. FDA Approval or Clearance data element under Sec.  
11.28(a)(2)(i)(Q), the Director will post publicly the registration 
information that would otherwise be subject to delayed posting as 
specified in Sec.  11.35(b)(2)(i), except for certain administrative 
data, as soon as practicable.
    Under Sec.  11.44, delayed submission of results information for 
applicable clinical trials involving products that are unapproved, 
unlicensed, or uncleared for any use is permitted only if the 
responsible party certifies as set forth in Sec.  11.44 (c) (and prior 
to the standard results information submission deadlines as specified 
in Sec.  11.44(a)) that the sponsor or manufacturer intends to continue 
with product development, meaning that it is either seeking, or may at 
a future date seek, initial approval, licensure, or clearance of the 
product under study in the applicable clinical trial. For the purposes 
of this final rule only, we interpret ``use'' to include 
``indication.'' For the purposes of this final rule, ``indication'' 
means ``the disease or condition the product is intended to diagnose, 
treat, prevent, cure, or mitigate.''
    Section 402(j)(3)(D)(iv)(III) of the PHS Act directs that, in 
determining the timeline for submission of results information from 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products, the Secretary take into account both the certification 
process under section 402(j)(3)(E)(iii) of the PHS Act ``when approval, 
licensure, or clearance is sought'' and ``whether there should be a 
delay of submission when approval, licensure, or clearance will not be 
sought.'' Specifically with regard to applicable clinical trials of 
unapproved, unlicensed, or uncleared products for which approval, 
licensure, or clearance will not be sought, we interpret the phrase 
``will not be sought'' in section 402(j)(3)D)(iv)(III)(bb) of the PHS 
Act to mean that the sponsor or manufacturer has no intention of 
continuing with commercial development of the product. For these 
trials, as with the disclosure of clinical trial results information 
from applicable clinical trials of all unapproved, unlicensed, or 
uncleared products, we believe that the public benefits of disclosure 
of results information outweigh any private, commercial interests (see 
discussion in Section II, Overview of Statutory Provisions). With 
respect to products for which initial approval, licensure, or clearance 
is, or may at a future date be sought, we recognize that, in many 
cases, this is information that will be known only to the sponsor or 
manufacturer of the drug product (including biological product) or 
device product and may not even be known to them at the time a clinical 
trial is completed, especially for an earlier stage trial, such as a 
phase 2 applicable drug clinical trial. Instead, the sponsor or 
manufacturer may know only that it intends to continue with product 
development, such as through the conduct of a subsequent clinical 
trial. Therefore, as a condition of delaying results information 
submission for unapproved, unlicensed, or uncleared products for any 
use, Sec.  11.44(c) requires the responsible party to certify that the 
sponsor intends to continue with product development and either is 
seeking, or may at a future date, seek approval, licensure, or 
clearance. If the responsible party elects to submit a certification 
for delayed submission, it is the responsible party's obligation to 
verify that the particular applicable clinical trial meets the Sec.  
11.44(c) criteria, as explained in this preamble.
    If, after submission of a certification under Sec.  11.44(c), the 
drug product (including biological product) or device product studied 
in the applicable clinical trial becomes approved, licensed, or cleared 
for the use studied in the applicable clinical trial, results 
information will be due 30 calendar days after the date of product 
approval, licensure, or clearance. If, after submission of such a 
certification, initial approval is no longer being sought (e.g., 
product development is abandoned), any continued delay in results 
information submission is not warranted, and the responsible party 
should submit results information as soon as practicable, but not later 
than 30 calendar days after the application or premarket notification 
is withdrawn without resubmission for no less than 210 calendar days 
(i.e., 240 calendar days after submission of the withdrawal request). 
We limit the allowable delay period for results information submission 
for applicable clinical trials of unapproved, unlicensed, or uncleared 
products for any use to 2 years after the submission of a certification 
(i.e., up to a total of 3 years after the primary completion date) for 
delayed results information submission, which parallels the 
statutorily-mandated 2 year limitation in Sec.  11.44(b). The 
certification must be submitted prior to the date on which results 
information would otherwise be due under the standard submission 
deadline in Sec.  11.44(a) (i.e., 12 months after the primary 
completion date), and we permit only one certification to be submitted 
for each clinical trial.
    In addition, the final rule maintains Sec.  11.48(a)(6) as proposed 
in final Sec.  11.48(a)(7), which requires responsible parties to 
submit additional descriptive results information for applicable device 
clinical trials of unapproved or uncleared devices for which 
registration information is not posted at the time of results 
information submission. In such situations, posting clinical trial 
results information with certain descriptive information that is 
similar to the type of information that is included as part of 
registration, provides the necessary context for understanding clinical 
trial results information and improves the understanding of posted 
results information. As explained in the proposed rule, facilitating 
this

[[Page 64998]]

understanding is why journal articles and other reports of the results 
of clinical trials routinely include information about the disease or 
condition and interventions under study, the inclusion and exclusion 
criteria for participants, the location(s) of the trial, etc. Without 
such information, results data about patient demographics, outcomes, 
and adverse events could be uninterpretable and inaccessible. For 
example, patients and other users typically access clinical trial 
results by searching for (and retrieving) clinical trials with specific 
characteristics that involve a particular intervention or type of 
intervention, study a particular disease or condition, recruit certain 
types of subjects, take place during a particular time period, are 
conducted in a specific location or particular facility, are sponsored 
by a particular organization, or match a title or identification number 
they have found in other public sources.
    Similarly, consistent with section 402(j)(3)(D)(i) of the PHS Act, 
providing information about the purpose of the study, its design, the 
intervention(s) studied, the types of subjects eligible to participate, 
the duration of the study, and the outcome measures will enhance the 
understanding of clinical trial results by researchers, healthcare 
providers, patients and other users of ClinicalTrials.gov. Users can 
benefit from knowing whether the clinical trial is completed, if data 
are still being collected for other outcome measures, or if the 
clinical trial was prematurely terminated. They can benefit from 
understanding whether information has been submitted for all 
anticipated outcome measures and corresponds to the outcome measures 
that the clinical trial was designed to achieve or whether the outcome 
measures changed during the course of the study. They can also benefit 
from information to assist in comparing results with the results of 
other clinical trials and with other publicly available information 
about a clinical trial of interest and other trials. Whether the 
clinical trial was reviewed for human subjects protection and who had 
authority over the conduct of the trial can also be useful. In 
addition, users may benefit from knowing who submitted the information 
and when it was last verified (i.e., to indicate whether it might be 
out of date). Such information is not readily available from 
information submitted under Sec.  11.48(a)(1)-(5), but is similar to 
the descriptive information provided during registration (e.g., Primary 
Purpose, Primary Outcome Measure(s), Overall Recruitment Status) (see 
Sec.  11.28(a)).
    In addition, requiring responsible parties for applicable device 
clinical trials of unapproved, unlicensed, or uncleared device products 
to resubmit information submitted previously to the data bank during 
registration under Sec.  11.28(a), in order to comply with Sec.  
11.48(a)(7), would be inefficient and impose an unnecessary burden on 
responsible parties. It would also introduce the possibility that the 
additional information provided at the time of results information 
submission would be inconsistent with the registration information and 
require the Agency to perform an additional quality review of the 
registration information. To promote efficiency, responsible parties 
must fulfill the requirement under Sec.  11.48(a)(7) by affirming in 
the data bank when submitting clinical trial results information that 
they are submitting information that is already contained in the data 
bank and that such information has been updated as specified in Sec.  
11.64(a)(iii) and that it will be included as clinical trial results 
information. Once this affirmation is made, any information listed in 
Sec.  11.48(a)(7) that was previously submitted to the data bank will 
automatically populate the results information data fields and be 
posted when results information is posted.
    As discussed in Section IV.B.5 of this preamble, we also note that 
under final Sec.  11.35(b)(2)(ii), a responsible party can indicate to 
the Director that it is authorizing the Director to publicly post its 
clinical trial registration information, that would otherwise be 
subject to delayed posting, as specified in Sec.  11.35(b)(2)(i), prior 
to the date of FDA approval or clearance. For an applicable device 
clinical trial for which registration information described in Sec.  
11.28 has been posted in accordance with Sec.  11.35(b)(2)(ii) before 
the submission of results information described in Sec.  11.48, the 
requirement of Sec.  11.48(a)(7) will not apply.

C. Submission of Technical and Non-technical Summaries

Overview of Proposal
    Sections 402(j)(3)(D)(iii)(I) and (II) of the PHS Act specify that 
the regulations shall require ``[a] summary of the clinical trial and 
its results that is written in non-technical, understandable language 
for patients'' and ``[a] summary . . . that is technical in nature,'' 
respectively, ``if the Secretary determines that such types of summary 
[both non-technical and technical] can be included without being 
misleading or promotional.'' We interpreted this statutory condition to 
mean that such summaries should be required only if the summaries can 
be consistently produced by responsible parties in a way that is not 
misleading or promotional.
    In the NPRM, we acknowledged that if non-technical and technical 
summaries could be consistently produced without being misleading or 
promotional, patients, members of the general public, clinicians, and 
researchers might benefit from brief, well-written, accurate, and 
objective summaries of the results of individual clinical trials (79 FR 
69581). We discussed considerations related to the optimal format for 
narrative non-technical summaries and the question of whether a single, 
brief summary of an individual trial can provide sufficient background 
and context to avoid being potentially misleading to a clinician or 
patient interested in the clinical significance of the results. We 
described the challenges of producing summaries of trials with many 
outcome measures and adverse events without being selective. In 
addition to reviewing the relevant literature on the matter, we 
consulted with the FDA Risk Communication Advisory Committee [Ref. 72] 
and considered prior public comments from a public meeting held in 2009 
[Ref. 63]. We indicated that, until further research could be conducted 
to assess the value of these summaries to the public and whether they 
can consistently be provided in a manner that is objective and not 
misleading, we would defer the decision about whether or not to require 
the submission of narrative summaries. We indicated that we would 
continue to provide links, where possible, from individual clinical 
trials in ClinicalTrials.gov to related peer reviewed literature and 
other information about the intervention, disease, or condition 
studied. The NPRM invited public comment pertaining to whether the 
inclusion of technical and non-technical summaries should be required 
in clinical trial data submission on ClinicalTrials.gov and what 
methodologies could be employed to ensure non-misleading, non-
promotional, accurate, and consistent summaries (79 FR 69582).
Comments and Response
    Comments addressed the question of whether the submission of 
technical and non-technical narrative results summaries should be 
required. Commenters noted that preparing both technical and non-
technical summaries would be burdensome (e.g., a commenter estimated 
that providing a non-technical summary would add 4 hours to the overall 
time to complete the

[[Page 64999]]

submission of the results information for a clinical trial) and raised 
concerns regarding the ability of trial sponsors to write accurate, 
non-promotional, and non-misleading summaries. Commenters suggested 
that if results summaries were to be required, the Secretary would need 
to develop and issue guidelines or templates regarding their 
appropriate authorship, content, evaluation, and format to ensure 
consistency across summaries. No comments addressed the methods that 
might be employed to help answer the questions about whether narrative 
summaries could be consistently produced in a non-promotional and non-
misleading manner. However, several commenters suggested external 
organizations with whom the Secretary might collaborate on narrative 
summary issues, namely the ICMJE to ensure that narrative summaries 
would not preclude future journal publications; the Multi-Regional 
Clinical Trials Center of Brigham and Women's Hospital and Harvard to 
investigate the format they are using for summaries; the FDA regarding 
Drug Trials Snapshots; and the Patient-Centered Outcomes Research 
Institute (PCORI) regarding peer review and public release of research 
findings. One commenter suggested that the summaries could be subject 
to a peer review process or prepared by independent medical writers. 
For both technical and non-technical summary results submission, there 
were commenters who supported deferral of a decision pending further 
exploration and the development of guidelines for preparing such 
documents.
    With regard to technical summaries specifically, some commenters 
suggested that such summaries would be redundant to the required trial 
results information proposed in the NPRM. Other commenters expressed 
concerns regarding disclosure of proprietary information, particularly 
if such summaries were to be posted prior to FDA product approval. One 
commenter supported requiring technical summaries of results because 
they would suit the needs of professionals, manufacturers, and others 
in the industry. Several commenters suggested that as an alternative to 
technical summaries, ClinicalTrials.gov could systematically link to 
published reviews and/or clinical study reports (CSRs) submitted to 
FDA.
    With regard to non-technical summaries specifically, commenters 
pointed out that it may be difficult for members of the public to 
understand study results provided in a technical summary and that the 
provision of lay summaries would enhance public understanding of the 
results. Others highlighted the difficulty inherent in writing a simple 
summary that presents the nuances of complex research findings, noting 
that systematic reviews, which synthesize all available evidence, are 
better sources of information for the lay public than brief summaries 
of a single trial. One commenter suggested that the informed consent 
document could be required in lieu of a lay summary because it provides 
important basic information in non-technical terms and has been 
reviewed by an independent party, i.e., an IRB.
    Taking the public comments into consideration, and given concerns 
about the potential for harm to public health from the promotion of 
medical products for unapproved uses, the Secretary is declining at 
this time to require narrative results summaries until further research 
is conducted to determine whether and, if so, how, summaries can be 
reliably and consistently produced without being promotional or 
misleading. Current approaches in the dissemination of trial summaries, 
such as FDA's Drug Trials Snapshots, PCORI's summary reports, and 
industry efforts to return summary results to participants, may be 
informative and will be reviewed and considered as part of any further 
research.
    To provide additional information to the general public about a 
registered clinical trial, we will accept optional submission of the 
final version of the informed consent document to be posted on the 
associated record. Although the informed consent document does not 
provide information on interpreting the results of the trial, the 
document is written in lay language and its description of the trial's 
purpose, procedures, risks and potential benefits may help put the 
trial results into clearer context.
Final Rule
    The final rule does not require the submission of technical or non-
technical summaries of results to ClinicalTrials.gov because we have 
not identified evidence on the basis of which to conclude that there is 
a feasible way to ensure that the information contained in such 
summaries will be consistently produced without being misleading or 
promotional. We will continue to explore automated ways to consistently 
produce result summaries in a non-promotional, non-misleading way as 
well as mechanisms for linking results to information that might assist 
users in interpreting the results of clinical trials, such as 
systematic reviews and summary outcome information that sponsors and 
investigators provide to participants following the trial's completion. 
Should we determine in the future that narrative summaries can be 
consistently produced in a non-promotional, non-misleading way, a 
separate rulemaking process with notice and public comment will be 
undertaken.

D. Submission of Protocols and Statistical Analysis Plans

Overview of Proposal
    Section 402(j)(3)(D)(iii)(III) of the PHS Act stipulates that 
regulations for an expanded registry and results data bank shall 
require at the time of results information submission, in addition to 
basic results information, the submission of ``[t]he full protocol or 
such information on the protocol for the trial as may be necessary to 
help to evaluate the results of the trial'' (emphasis added).
    The NPRM noted that this statutory requirement could be satisfied 
in several ways, such as ``(1) [r]equiring submission of additional 
structured data elements derived from, or describing, the protocol; (2) 
requiring submission of portions of the final protocol or other 
narrative information about the conduct of the study that is associated 
with the protocol (e.g., a SAP, if not part of the protocol); or (3) 
requiring submission of the full protocol at the time of results 
submission, meaning the final version of the protocol, including all 
protocol amendments, in a format such as Portable Document Format 
(PDF)'' (79 FR 69582). As we explained in the NPRM, given the proposals 
for submission of additional registration and results information, we 
did not propose to require submission of the protocol or other 
``information on the protocol.'' We did, however, solicit public 
comment on whether the registration and results information proposed 
for submission was sufficient to meet the statutory requirement. We 
asked for perspectives on the relative benefits and burdens of 
preparing and submitting any additional information and how such 
information would help evaluate the results of the clinical trial.
Comments and Response
    Commenters supportive of a requirement for protocol submission 
maintained that it improves transparency and quality of reporting by 
providing information to the public about inclusion and exclusion 
criteria, the interventions studied, and trial outcomes. They suggested 
that the availability of the protocol allows users to compare reported 
outcomes and

[[Page 65000]]

analyses against those pre-specified in the protocol. Some commenters 
asserted that a full understanding of the trial results is not possible 
without having access to the protocol and the trial's procedural 
details, details they stated permit the study to be replicated or built 
upon and that are pivotal to improving the design of future trials.
    Some commenters pointed to an IOM recommendation that called for 
sharing of the protocol and SAP not only to help other investigators 
understand the original analysis, replicate or reproduce the study, and 
carry out additional analyses, but also because it complements trial 
registration in identifying trials that were initiated, allows future 
auditing of data sharing, facilitates meta-analyses and systematic 
reviews, promotes greater standardization of protocol elements (e.g., 
interventions, outcomes), and may help reduce unnecessary duplication 
of studies [Ref. 47].
    Another commenter maintained that an added benefit of making 
protocols available through ClinicalTrials.gov was that it would help 
journal editors, reviewers, and readers verify the a priori or post hoc 
nature of trial outcomes. They noted that journal editors encounter 
situations where outcomes reported in manuscripts do not match those 
listed on ClinicalTrials.gov and that posting of study protocols would 
be an important additional safeguard against reporting bias. Another 
commenter pointed out that a central archive for protocols would 
alleviate the burden on clinical trial investigators in addressing 
multiple requests for a copy of their protocols.
    Commenters in support of a requirement for protocol submission also 
noted that, unless a standardized protocol format were required, the 
burden would be minimal because the document already exists. One 
commenter suggested that because the requirement is virtually burden-
free and the benefits are so great, the requirement should be 
retroactive as far back as possible.
    Commenters opposed to requiring protocol submission offered a 
number of reasons for this position. They suggested that the proposed 
registration and results elements provide sufficient information to 
understand the results of a clinical trial. Some thought the protocols 
should not be required because they will be confusing to the public and 
detrimental to recruitment, noting that they are technical, not 
standardized, and may have multiple amendments. Some asserted that 
protocols contain personally identifiable information, proprietary 
information, or other information that, if publicly disclosed, could be 
damaging to business interests. They suggested that a submission 
requirement would conflict with protections under the FD&C Act, FDA 
regulations, and FOIA. Commenters in support of protocol submission 
suggested redaction of such information was an appropriate remedy that 
should be allowed before submission. Finally, other commenters opposed 
redaction of information based on concerns it would be too burdensome 
and time consuming, with one commenter suggesting that allowing 
responsible parties to redact proprietary information might result in 
the exclusion of essential details needed for others to understand the 
results of the trial. No specific burden estimates associated with 
protocol redaction and submission were provided.
    We appreciate that the data elements proposed in the NPRM are 
helpful to those reviewing and analyzing entries in ClinicalTrials.gov, 
and it was due to these additional elements that we did not propose the 
submission of the protocol in the NPRM. However, we found compelling 
and persuasive the arguments that protocols provide information in a 
context that is not captured by these elements alone and that the 
protocol will improve transparency and the quality of reporting by 
providing a more complete picture of the trial. We understand that 
although the registration data elements include descriptors of key 
features of the protocol, there are times when this additional detail 
may be helpful to researchers and others with an interest in the 
clinical trial's results and the ability to assess those results. For 
example, the protocol provides more detail than the registry and 
results data elements about methods of participant selection, 
randomization, masking, and assignment to arms; methods of collecting 
clinical trial data; specific information about clinical trial 
interventions (e.g., other elements of care that were provided in 
addition to the specified interventions); and assessment of adverse 
events. The protocol may also contain information on the statistical 
techniques used to analyze collected results information, which helps 
others in interpreting the submitted results of a clinical trial. The 
protocol's description of the approach and circumstances that led to 
data collection may be helpful in contextualizing the submitted results 
information. We agree that this picture will help users of 
ClinicalTrials.gov to interpret the data elements that are required by 
this rule and that the protocol will be an important part of results 
information reporting for those wishing to fully understand the trial 
and its reported outcome measures.
    We were also persuaded by the rationale for protocol submission 
discussed in the 2015 IOM report on sharing clinical trial data [Ref. 
47], which described the value it would have for journal editors, 
reviewers, and readers in helping to verify trial outcomes and 
safeguard against reporting bias, and that it would help investigators 
in addressing multiple individual requests for a copy of their 
protocols. Further, it would allow for access to this information long 
after any prevailing document retention requirements have lapsed.
    We did not find the argument that some might not understand the 
protocol to be a sufficient reason to not require its submission. 
Rather, although we acknowledge that there may be some individuals who 
may not understand the protocol, we believe that in general it will 
enhance understanding through its detail, content, and context. 
Regarding the suggestion that its posting could be detrimental to 
recruitment, we require the protocol at the time of results information 
submission, thereby eliminating the concern that posting the protocol 
will affect a trial's recruitment.
    With regard to the argument that the protocol contains proprietary 
information, section 402(j)(3)(D)(iii)(III) of the PHS Act specifically 
requires the Agency to determine via this rulemaking whether to require 
the submission of the protocol. As discussed above in Section III.B, a 
statute or validly promulgated regulation requiring disclosure 
constitutes authorization by law to disclose information that might 
otherwise be considered to be trade secret and/or confidential 
commercial information as those terms are defined in the FOIA and the 
TSA. However, notwithstanding this authorization, if there is a case in 
which a responsible party believes that a protocol does contain trade 
secret and/or confidential commercial information, the responsible 
party may redact that information, so long as the redaction does not 
include any specific information that is otherwise required to be 
submitted under this rule. For example, the Intervention Name(s) for 
each intervention studied must be submitted under Sec.  
11.28(a)(2)(i)(J); therefore, this information may not be redacted from 
the protocol for that trial.
    The burden of redacting protocols prior to submission is on the 
responsible party; the Agency does not intend to review protocols to 
assess

[[Page 65001]]

whether they contain trade secret and/or confidential commercial 
information. Regarding the concern that redaction might result in a 
protocol lacking in essential details necessary to understand the 
results, we emphasize that responsible parties must comply with all 
other applicable results information submission requirements of this 
rule. The Agency may contact a responsible party if it appears that the 
responsible party has redacted information that is otherwise required 
to be submitted under these regulations. More specific guidance 
regarding redaction will be considered in the future.
    In addition, we believe that concerns that might exist about a loss 
of competitive advantage are mitigated because the submission of the 
protocol is not required until after the trial is completed and 
clinical trial results information is submitted in accordance with the 
deadlines specified in Sec.  11.44. We also note that Sec.  11.44(c) 
provides for delays in submitting clinical trial results information 
for an applicable clinical trial that studies a product that is not yet 
approved by the FDA, thereby allowing for additional time before the 
protocol is required to be submitted.
    Moreover, in our experience, protocols do not contain proprietary 
information or manufacturer details. However, as noted above, should 
there be a case in which a protocol does contain such information, 
redaction of such information will be allowed as long as the redaction 
does not encompass the information that is otherwise required to be 
submitted under this rule.
    While some commenters were concerned about posting of personal 
information contained in protocols, in our experience, protocols 
generally do not contain information about individual clinical trial 
participants. However, if such information were to be included in a 
protocol, it should be redacted. Again, the burden of doing so is on 
the responsible party; the Agency does not intend to review protocols 
to assess whether they include personal information about trial 
participants. However, if it comes to the Agency's attention that 
personal information about trial participants has been included in a 
protocol, the Agency may contact the responsible party regarding the 
matter.
    Protocols can include information about principal investigators and 
other individuals associated with conducting a clinical trial. In 
response to the concerns expressed by the commenters, responsible 
parties may redact personally identifying information about individuals 
who are involved in conducting the clinical trial if that information 
is not otherwise required to be submitted as part of clinical trial 
information. The Agency anticipates that because information such as 
work email addresses and contact information related to the clinical 
trial is likely available through other public sources (e.g., a medical 
center's Web site), in many cases this information will not need to be 
redacted and, therefore, the burden associated with redaction will be 
minimal.
    Because the protocol document already exists, we do not foresee 
this additional submission requirement to be burdensome. Rather, 
submission of the protocol itself is expected to be a minimally 
burdensome requirement that would involve an upload of an existing 
electronic document. We also expect that it will be less burdensome for 
a responsible party to submit the protocol than to extract and submit 
specified portions or selected information from a protocol. Similarly, 
as mentioned above, we do not expect redactions of any proprietary or 
personal information to be burdensome. The submission of the protocol 
at the time of the submission of clinical trial results information, 
rather than at the time of clinical trial registration information, 
also minimizes the burden on responsible parties in that any amendments 
that occurred over the course of the trial would already be 
incorporated into the document.
    We also agree with the commenters who urged requiring submission of 
the SAP if it is not included in the protocol document. Many of the 
benefits of the protocol that were cited by commenters (summarized 
above) derived from the statistical analysis section of the protocol. 
If that section were written as a separate document (the SAP), then 
that document would be necessary to derive those same benefits (e.g., 
better understanding of how data were collected and analyzed). As noted 
by commenters, the IOM recommended that both the full protocol and the 
SAP, including all versions and amendments, ``should be shared to help 
other investigators understand the original analysis, replicate or 
reproduce the study, and carry out additional analysis'' [Ref. 47]. 
SAPs describe the analyses to be conducted and the statistical methods 
to be used, including ``plans for analysis of baseline descriptive data 
and adherence to the intervention, prespecified primary and secondary 
outcomes, definitions of adverse and serious adverse events, and 
comparison of these outcomes across interventions for prespecified 
subgroups. The full SAP describes how each data element was analyzed, 
what specific statistical method was used for each analysis, and how 
adjustments were made for testing multiple variables . . . if some 
analysis methods require critical assumptions, data users will need to 
understand how those assumptions were verified'' [Ref. 47]. Some 
commenters objected to requiring the submission of both the protocol 
and the SAP, for the reasons described above; other commenters raised 
similar objections specifically with respect to the submission of SAPs. 
We find these objections unpersuasive for the reasons described above 
related to protocols. Therefore, we are requiring submission of the SAP 
as part of clinical trial results information.
    If the SAP is submitted as part of the protocol, it need not be 
separately submitted. Some commenters objected to submission of SAPs 
because the SAPs might contain proprietary information. Although we 
think it unlikely that SAPs will contain proprietary information, we 
will accept redacted SAPs under the same terms as redacted protocols. 
We wish to emphasize that neither this requirement nor anything in this 
rule sets standards or creates requirements for the substantive content 
of protocols or SAPs.
Final Rule
    The final rule requires submission of the full version of the 
protocol and the SAP (if a separate document) as part of clinical trial 
results information, as specified in Sec.  11.48(a)(5). Submission of 
the protocol and SAP allows interested users of ClinicalTrials.gov to 
contextualize the reported clinical trial results information. We 
emphasize that this rule does not create requirements for the 
substantive content of protocols or SAPs. However, to allow for 
unambiguous identification of the submitted document(s), the protocol 
and SAP (if submitted as separate document) must contain a cover page 
that lists the Official Title (as defined in Sec.  11.10(b)(2)), NCT 
number (as defined in Sec.  11.10(a), if available), and the date of 
each document. We are requiring the inclusion of this additional 
information pursuant to our authority in section 402(j)(3)(D)(iii)(IV) 
of the PHS Act.
    The requirements for submission of the protocol and the SAP are 
detailed in Sec.  11.48(a)(5) of the final rule, which stipulates that 
``[a] copy of the protocol and the statistical analysis plan (if not 
included in the protocol), including all amendments approved by a human 
subjects protection review board (if applicable), before the time of 
submission under this subsection and that apply to all clinical trial 
Facility

[[Page 65002]]

Locations'' must be submitted. It further indicates that ``[t]he 
responsible party must include the Official Title (as defined in Sec.  
11.10(b)(2)), NCT number (as defined in Sec.  11.10(a)) (if available), 
and date of the protocol and the statistical analysis plan on the cover 
page of each document.'' In addition, ``[t]he responsible party may 
redact names, addresses, and other personally identifiable information, 
as well as any trade secret and/or confidential commercial information 
(as those terms are defined in the Freedom of Information Act (5 U.S.C. 
552) and the Trade Secrets Act (18 U.S.C. 1905)) contained in the 
protocol or statistical analysis plan prior to submission, unless such 
information is otherwise required to be submitted under this part. The 
protocol and statistical analysis plan must be submitted in a common 
electronic document format specified at https://prsinfo.clinicaltrials.gov.''
    The protocol and, if separate, the SAP, will be posted with other 
clinical trial results information, in accordance with Sec.  11.52. If 
amendments are made to the protocol between the initial submission of 
partial clinical trial results information and later submission of 
additional partial results information, the responsible party must 
submit a copy of the revised protocol at the time of the later 
submission of partial results information, in accordance with Sec.  
11.44(d)(3)(i). However, the Protocol and Statistical Analysis Plan 
results data element in Sec.  11.48(a)(5) are excluded from the 
updating requirements in Sec.  11.64(a)(2)(i). Each submitted version 
of the protocol and SAP will continue to be available through the 
ClinicalTrials.gov archive site.

IV. Discussion of Public Comments Related to Specific Provisions of the 
Regulations

A. Subpart A--General Provisions

1. 11.2--What is the purpose of this part?
Overview of Proposal
    The NPRM described in Sec.  11.2 the overall purpose of the 
regulations. Implementing section 402(j) of the PHS Act (42 U.S.C. 
282(j)), the rule provides the requirements and procedures for the 
submission of clinical trial information for certain applicable 
clinical trials and other clinical trials to the Director of the NIH to 
be made publicly available through ClinicalTrials.gov.
Comments and Response
    As noted earlier, more than half of the submitted comments were 
identical in content. These commenters addressed proposed Sec.  11.2 by 
recommending that the final rule be expanded to require registration 
and results information submission for all clinical trials. They 
reasoned that it was important and in the public interest for data on 
all clinical trials of drugs, biological products, and devices, and not 
only ``certain applicable clinical trials,'' to be posted before the 
trial moves from one phase to the next. These commenters also suggested 
replacing the phrase ``certain applicable clinical trials'' in proposed 
Sec.  11.2 with ``all clinical trials.''
    The statute required the Agency to make a number of decisions 
through rulemaking, including whether to expand the requirement to 
report results information to applicable clinical trials of unapproved, 
unlicensed, or uncleared products, but it did not call for 
consideration of whether all clinical trials should be subject to 
registration and reporting requirements. Since the statute limits the 
applicability to applicable clinical trials as defined, these comments 
are outside the scope of the current rulemaking. Comments on the scope 
of the rule are further discussed in Section III.A of this preamble, 
Scope and Applicability, and in Section IV.B.2 in the discussion of 
Sec.  11.22.
Final Rule
    No changes are made in Sec.  11.2 of the final rule.
2. 11.4--To whom does this part apply?
Overview of Proposal
    Proposed Sec.  11.4(a) specified that the regulations would apply 
to any person or entity that is considered to be the ``responsible 
party,'' defined in section 402(j)(1)(A)(ix) of the PHS Act, for an 
applicable clinical trial that is required to be registered under Sec.  
11.22 or a clinical trial for which clinical trial information is 
submitted voluntarily under Sec.  11.60. Proposed Sec.  11.4(b), which 
would implement section 402(j)(1)(B) of the PHS Act, required the 
responsible party to communicate their identity and contact information 
to the Director by submitting the Responsible Party Contact Information 
data element during registration. Proposed Sec.  11.4(c) outlined 
procedures for determining the responsible party for each applicable 
clinical trial or other clinical trial subject to this part. In 
particular, Sec.  11.4(c)(1) specified who would be considered the 
sponsor and required that each applicable clinical trial or other 
clinical trial must have one sponsor. Furthermore, Sec.  11.4(c)(2) 
established the requirements and procedures for a sponsor to designate 
a principal investigator to be the responsible party. If and when a 
designated principal investigator becomes unable to meet all of the 
requirements for being designated as a responsible party, proposed 
Sec.  11.4(c)(3) outlined the mechanisms by which the sponsor would 
become the responsible party.
Comments and Response
    Commenters suggested replacing the phrase ``applicable clinical 
trial'' in proposed Sec.  11.4 with ``all clinical trials.'' Commenters 
also expressed their opinions regarding proposed Sec.  11.4 which 
focused on the designation of a responsible party. While commenters 
expressed support for assigning one responsible party per applicable 
clinical trial, they sought clarification regarding procedures for when 
a designated responsible party becomes unable to meet all of the 
requirements under Sec.  11.4(c)(2)(i) (e.g., principal investigator 
leaves the institution, principal investigator dies). Furthermore, a 
commenter suggested that the responsible party remain responsible for 
clinical trial information submission requirements even after leaving 
his/her institution and another suggested that the responsible party be 
able to change the sponsor, for example, when the principal 
investigator changes institutions.
    As explained in the response to comments for Sec.  11.2, section 
402(j) of the PHS Act did not call for consideration of whether all 
clinical trials should be subject to registration and results 
information reporting requirements, and it limits the applicability to 
applicable clinical trials as defined. The Agency outlines in Sec.  
11.4(c)(2) and (3) of the final rule the procedures on the designation 
of a responsible party. These procedures specify that in the event a 
principal investigator who has been designated the responsible party no 
longer meets or is no longer able to meet all the requirements of Sec.  
11.4(c)(2)(i), the sponsor must withdraw the designation in the format 
specified at https://prsinfo.clinicaltrials.gov (or successor site), at 
which time the sponsor will be considered the responsible party unless 
and until the sponsor makes a new designation. These procedures, 
however, do not allow for a principal investigator who has been 
designated as the responsible party to change the sponsor because Sec.  
11.4(c) defines the sponsor as the default responsible party. 
Consistent with the statute, the sponsor is permitted to designate a 
principal

[[Page 65003]]

investigator as the responsible party. However, if the designated 
principal investigator no longer meets or is no longer able to meet the 
criteria for being designated a responsible party (e.g., due to 
changing institutions), the role of responsible party reverts back to 
the original sponsor.
    Commenters also suggested that it would be more helpful if the 
electronic ClinicalTrials.gov system, i.e., PRS, used by responsible 
parties to register and submit results information for their trials 
included a way for sponsors to designate a principal investigator as 
the responsible party. Commenters also suggested that PRS 
administrators should be allowed to control the settings in the 
Responsible Party field so they can set the ``default'' according to 
policies or preferences established by an institution.
    Sponsors are not only responsible for assigning the role of 
responsible party, but they must also ensure that a designated 
principal investigator knows that he/she has been assigned the 
responsibility and has accepted the role and designation. Given the 
legal ramifications of the responsible party role, we do not believe it 
is appropriate for the assignment to be set through a default mechanism 
controlled through the PRS. We note that tools are available in the PRS 
to help remind responsible parties, including principal investigators 
designated as a responsible party, when a study record requires 
attention (see https://prsinfo.clinicaltrials.gov or successor site). 
We will continue to evaluate and develop tools in the PRS to help 
ensure that responsible parties understand their reporting obligations.
Final Rule
    Final Sec.  11.4 maintains the proposed approach of the NPRM, and 
clarifies in Sec.  11.4(a) that the rule also applies to any 
responsible party required by the Director to register under Sec.  
11.62 to protect the public health (discussed in more detail in Section 
IV.D.2). Thus, final Sec.  11.4(a) specifies that the rule applies to 
the responsible party for an applicable clinical trial that is required 
to be registered under Sec.  11.22, for which clinical trial 
information is voluntarily submitted under Sec.  11.60 (discussed in 
more detail in in Section IV.D.1), or for which the Director has 
determined, consistent with Sec.  11.62, that clinical trial 
information must be submitted in order to protect the public health. 
The responsible party is either the sponsor of the clinical trial or a 
principal investigator who meets the criteria specified in Sec.  
11.4(c)(2) and has been so designated by the sponsor. In no case will 
this rule apply to the sponsor or principal investigator or other 
individual or entity associated with a clinical trial of drug or device 
not subject to FDA jurisdiction. Although section 402(j)(4)(A) of the 
PHS Act directs the Secretary to permit ``[v]oluntary submissions'' of 
clinical trial information for ``a clinical trial that is not an 
applicable clinical trial or that is an applicable clinical trial that 
is not subject to'' the registration provisions of section 402(j)(2) of 
the PHS Act, we interpret section 402(j) of the PHS Act and, thus, the 
final rule as not applying to anyone who submits information to 
ClinicalTrials.gov about trials of interventions that are not subject 
to FDA jurisdiction under sections 505, 510(k), 515, 520(m), or 522 of 
the FD&C Act, or section 351 of the PHS Act. Moreover, we interpret 
section 402(j) of the PHS Act as not applying to anyone who submits 
information to ClinicalTrials.gov for a study that is neither an 
applicable clinical trial (including a pediatric postmarket 
surveillance of a device product as defined in this part) nor a 
clinical trial as defined in Sec.  11.10(a), even if it involves a drug 
or device subject to sections 505, 510(k), 515, 520(m), or 522 of the 
FD&C Act, or section 351 of the PHS Act. For example, section 402(j) of 
the PHS Act would not apply to information submitted for a study using 
a diagnostic tool that is a device product subject to section 510(k) of 
the FD&C Act, such as a magnetic resonance imaging scanner, that is not 
studying the device product and is not otherwise an applicable clinical 
trial, clinical trial as defined in Sec.  11.10(a), or pediatric 
postmarket surveillance of a device product as defined in this part. 
(See the discussion of ``Studies a U.S. FDA-regulated Device Product'' 
in Section IV.B.4) Consistent with other statutory authorities of the 
Agency and long-standing practice, however, ClinicalTrials.gov may, and 
does, accept registration and results information on clinical studies, 
as defined in Sec.  11.10(a), that are not subject to the requirements 
of section 402(j) of the PHS Act (including under this rule).
    Section 11.4(b) of the final rule implements section 402(j)(1)(B) 
of the PHS Act, which provides that the Secretary ``shall develop a 
mechanism by which the responsible party for each applicable clinical 
trial shall submit the identity and contact information of such 
responsible party to the Secretary at the time of submission of 
clinical trial [registration] information.'' Section 11.4(b) provides 
that the responsible party's identity and contact information must be 
included as part of the clinical trial information that is submitted in 
accordance with Sec.  11.28(a)(2)(iii)(B) and Sec.  11.28(a)(2)(iv)(F) 
and updated in accordance with Sec.  11.64(a). Responsible party 
contact information must be provided under the data element entitled 
Responsible Party Contact Information (Sec.  11.28(a)(2)(iv)(F)) that, 
as specified in Sec.  11.10(b)(37) includes the name, official title, 
organizational affiliation, physical address (i.e., street address), 
mailing address, phone number, and email address of the responsible 
party or of a designated employee of the organization that is the 
responsible party.
    Section 11.4(c) outlines procedures for determining the responsible 
party for each clinical trial subject to this part. The Agency believes 
that there must be one (and only one) responsible party for each 
clinical trial subject to this part for which clinical trial 
information is submitted. Having only one responsible party for each 
clinical trial facilitates procedural requirements during registration 
and results information submission and prevents situations in which 
both a sponsor and a principal investigator consider themselves the 
responsible party and submit information for the same clinical trial. 
Absent a responsible party, the objectives of registration and results 
information submission cannot be met. The definition of responsible 
party under section 402(j)(1)(A)(ix) of the PHS Act specifies, first, 
that the sponsor will be the responsible party and, second, that the 
principal investigator is the responsible party if delegated this role 
through a designation ``by a sponsor, grantee, contractor, or 
awardee.'' With regard to clinical trials, the Agency looks first to 
determine who is the sponsor of the clinical trial, consistent with the 
definition in this part, and assumes that such individual or entity is 
the responsible party, unless the principal investigator has been 
designated the responsible party in accordance with the procedure in 
Sec.  11.4(c)(2). For a pediatric postmarket surveillance of a device 
product that is not a clinical trial, the responsible party would be 
considered the entity FDA, under section 522 of the FD&C Act, orders to 
conduct the pediatric postmarket surveillance of a device product. In 
the final rule, Sec.  11.4(c) clarifies that ``device'' means ``device 
product.''
    Section 11.4(c)(1) specifies who will be considered the sponsor. 
The Agency believes that there must be a sponsor as that term is used 
in section 402(j)(1)(A)(ix) of the PHS Act for each clinical trial and 
that (as stated above)

[[Page 65004]]

there can be only one sponsor. Without a defined sponsor, there cannot 
be a responsible party for a clinical trial because the responsible 
party is defined as either the sponsor or the principal investigator 
who has been so designated by the sponsor. The definition of sponsor in 
Sec.  11.10(a) includes both a ``sponsor'' and a ``sponsor-
investigator'' as those terms are defined in 21 Code of Federal 
Regulations (CFR) 50.3. or any successor regulation. Both definitions 
in 21 CFR 50.3 refer to the sponsor as, in part, the person or entity 
who ``initiates'' the clinical investigation. For purposes of this 
rule, if a clinical trial is being conducted under an IND or 
investigational device exemption (IDE), the IND/IDE holder is 
considered to be the individual or entity who initiated the clinical 
trial and, therefore, the sponsor, regardless of how the clinical trial 
is being funded. For clinical trials not conducted under an IND or IDE, 
the sponsor is considered to be the person or entity who initiated the 
trial and would be identified as follows:
    (1) Where the clinical trial is being conducted by an entity under 
a research assistance funding agreement such as a grant or sponsored 
research agreement, the funding recipient generally is considered to be 
the initiator of the clinical trial, and therefore, the sponsor. This 
is because, as a general rule, when a clinical trial is funded in this 
manner, the funding recipient ``initiates'' the clinical trial process 
by, for example, submitting a funding proposal and designing the 
clinical trial.
    (2) Where the clinical trial is being conducted by an entity under 
a procurement funding agreement such as a contract, the party obtaining 
the goods or services for its direct benefit or use (the funder) 
generally is considered to be the initiator of the trial, and 
therefore, the sponsor. This is because, as a general rule, when a 
clinical trial is funded in this manner, it is the funder of the 
clinical trial that initiates the clinical trial process by, for 
example, contracting with another entity for that entity to conduct a 
clinical trial meeting the specifications of the funder.
    (3) Where there is no funding agreement supporting the clinical 
trial, the person or entity who initiated the clinical trial by 
preparing and/or planning the clinical trial, and who has appropriate 
authority and control over the clinical trial to carry out the 
responsibilities under section 402(j) of the PHS Act (including this 
part) is the sponsor.
    Furthermore, Sec.  11.4(c)(2) establishes the procedures for 
designation of a principal investigator as the responsible party. 
Section 402(j)(1)(A)(ix) of the PHS Act defines the responsible party, 
as either ``the sponsor of the clinical trial'' (as defined in [21 CFR 
50.3] (or any successor regulation)); or the principal investigator of 
such clinical trial if so designated by a sponsor, grantee, contractor, 
or awardee,'' so long as such person meets certain criteria. In order 
to give practical effect to this provision, we conclude that, for any 
given applicable clinical trial or other clinical trial subject to this 
part, only one entity--the sponsor--can designate the principal 
investigator as the responsible party. We believe this interpretation 
is consistent with section 402(j) of the PHS Act because in many 
situations the sponsor of the clinical trial will also be a grantee, 
contractor, or awardee. In addition, interpreting this provision in a 
different manner could result in situations in which both a sponsor 
(e.g., an IND/IDE holder) and a principal investigator (designated by a 
separate grantee, contractor, or awardee) consider themselves the 
responsible party and submit information for the same clinical trial. 
This would not only increase the overall burden associated with 
registration, but more importantly would undermine the integrity of the 
data bank and potentially cause confusion to users of the system.
    Section 402(j)(1)(A)(ix) of the PHS Act permits a principal 
investigator to serve as a responsible party only if he or she ``is 
responsible for conducting the trial, has access to and control over 
the data from the clinical trial, has the right to publish the results 
of the trial, and has the ability to meet all of the requirements under 
[section 402(j) of the PHS Act] for the submission of clinical trial 
information.'' Accordingly, if the principal investigator does not meet 
the specified conditions for serving as the responsible party, the 
sponsor cannot designate the principal investigator as the responsible 
party, and the sponsor must remain the responsible party. In Sec.  
11.10(a) we define, for purposes of this part, the term principal 
investigator to mean ``the individual who is responsible for the 
overall scientific and technical direction of the study.'' We note that 
under section 402(j)(1)(A)(ix) of the PHS Act, in order to be 
designated the responsible party, the principal investigator must be 
responsible for ``conducting the trial'' and must have ``access to and 
control over the data from the clinical trial.'' We interpret ``the 
trial'' to refer to the ``clinical investigation'' as defined in 21 CFR 
312.3 and this part, and to mean ``the entire clinical investigation.'' 
Similarly, we interpret ``the data'' to mean ``all of the data,'' 
including data collected at all sites of a multi-site trial.
    To clarify our understanding of section 402(j)(3)(C)(iv) of the PHS 
Act as it relates to whether a principal investigator would be eligible 
to serve as the responsible party, this section requires the 
responsible party to indicate, as an element of clinical trial results 
information, whether there exist ``certain agreements,'' which are 
described, with certain exceptions, as ``an agreement . . . that 
restricts in any manner the ability of the principal investigator, 
after the completion date of the trial, to discuss the results of the 
trial at a scientific meeting or any other public or private forum, or 
to publish in a scientific or academic journal information concerning 
the results of the trial.'' We do not view the presence of such an 
agreement as necessarily disqualifying a principal investigator from 
serving as the responsible party. Rather, we view only those agreements 
that prevent the principal investigator from performing the functions 
described in section 402(j)(1)(A)(ix)(II) of the PHS Act and Sec.  
11.4(c)(2)(i) of this part or from submitting clinical trial 
information or any updates to such information required by section 
402(j) of the PHS Act and this part as preventing the principal 
investigator from serving as the responsible party.
    To provide for the orderly implementation of section 
402(j)(1)(A)(ix)(II) of the PHS Act, pursuant to which the sponsor may 
designate a principal investigator as the responsible party, and ensure 
that the principal investigator has notice of the designation, we have 
detailed the process in Sec.  11.4(c)(2)(ii) for designating a 
principal investigator. It indicates that the sponsor shall provide 
notice of the designation to the principal investigator and obtain 
acknowledgement of the principal investigator's understanding of their 
responsibilities under this part. We intend to continue to provide 
mechanisms in the PRS for the sponsor and the principal investigator to 
indicate the designation and the acknowledgement, respectively. The 
designation by the sponsor is currently reflected in ClinicalTrials.gov 
by having the principal investigator submit clinical trial information 
via the sponsor's organizational account (the sponsor must provide an 
account for the principal investigator within the sponsor's PRS 
organizational account). The acknowledgement is reflected by having the 
principal investigator list their name as the responsible party and 
indicate that they were designated as the responsible party by the 
sponsor.

[[Page 65005]]

This approach has been available in ClinicalTrials.gov since 2011.
    If and when a designated principal investigator no longer meets or 
is no longer able to meet all of the requirements of a responsible 
party, Sec.  11.4(c)(3) outlines the mechanisms by which, if the 
withdrawal of such designation occurs, the sponsor would become the 
responsible party. This might occur if, for example, a principal 
investigator dies, retires, changes jobs, or turns control of the 
clinical trial data over to the sponsor. Final Sec.  11.4 modifies the 
NPRM approach by clarifying in Sec.  11.4(c)(3) that the sponsor, and 
not the clinical investigator, must withdraw the designation of a 
principal investigator as the responsible party. Because of this 
clarification, proposed Sec.  11.4(c)(3)(ii) is no longer necessary, so 
Sec.  11.4(c)(3)(i) is designated as Sec.  11.4(c)(3).
    We note that even if a sponsor designates a principal investigator 
as the responsible party for an applicable clinical trial registered 
under Sec.  11.22, there may be times when the sponsor would need to 
provide the principal investigator with certain information in order 
for the principal investigator to meet the obligations of the 
responsible party. For example, in order for a principal investigator 
who has been designated as the responsible party to satisfy the 
conditions for submitting a certification for delayed submission of 
results information under Sec.  11.44(b) or (c), the sponsor would 
likely have to provide the investigator with information about the 
conditions involving FDA action on a product application or submission, 
such as approval, that would require the responsible party to submit 
clinical trial results information as set forth in Sec.  11.44(b) or 
(c).
    Although we expect that a principal investigator who has been 
designated as the responsible party to request such information from 
the sponsor, we also expect a sponsor who has designated a principal 
investigator as the responsible party to provide appropriate 
information in a timely fashion. A principal investigator who is not 
provided the information necessary to enable him or her to meet all of 
the requirements for submitting and updating clinical trial information 
does not meet the criteria set forth in Sec.  11.4(c)(2)(i) to serve as 
the responsible party. If the sponsor does not provide the principal 
investigator with the requisite information to meet the criteria under 
Sec.  11.4(c)(2)(i), the principal investigator cannot be designated, 
or continue to act, as a responsible party and the responsible party 
would be, or would revert to, the sponsor.
3. 11.6--What are the requirements for the submission of truthful 
information?
Overview of Proposal
    Section 402(j)(5)(D) of the PHS Act specifies that ``clinical trial 
information submitted by a responsible party under this subsection 
shall not be false or misleading in any particular.'' In addition, the 
NPRM described other federal laws that address the submission of false 
or misleading information to the Federal Government (79 FR 69597). 
Specifically, it is a prohibited act under section 301(jj)(3) of the 
FD&C Act to submit clinical trial information under section 402(j) of 
the PHS Act that is false or misleading in any particular. In addition, 
other federal laws govern the veracity of information submitted to the 
Federal Government, such as 18 U.S.C. 1001 (making it a crime to make 
certain false statements to the executive, legislative, or judicial 
branch of the U.S. Government).
    Proposed Sec.  11.6 set out the requirements for the submission of 
truthful information. Proposed Sec.  11.6(a) stated that submitted 
clinical trial information must not be false or misleading and that 
submission of such information may subject the responsible party to 
civil or criminal liability. Proposed Sec.  11.6(b) required the 
responsible party to certify that submitted information is truthful and 
not misleading and that the responsible party is aware of the potential 
consequences of submitting such information. The certification was 
intended to ensure that responsible parties are aware of these 
statutory requirements and to provide an opportunity for them to attest 
to the veracity of the information at the time of submission.
Comments and Response
    Commenters addressed proposed Sec.  11.6. While no commenters 
disagreed with the proposal to include an explicit requirement that 
submitted clinical trial information must not be false or misleading 
and that a warning that submission of such information would subject 
the responsible party to civil, criminal, and/or administrative 
liability, commenters did address the proposal to require responsible 
parties to certify that submitted information is truthful and not 
misleading and that the responsible party is aware of the potential 
consequences of submitting such information. Several commenters noted 
that Title VIII of FDAAA did not stipulate that the Agency should 
require such a certification in the context of submissions to 
ClinicalTrials.gov. They also suggested that the requirement 
effectively duplicated three other statutory requirements beginning 
with two provisions in Title VIII of FDAAA that require the information 
submitted to ClinicalTrials.gov to not be false or misleading (section 
282(j)(5)(D) of the PHS Act), which is reflected in proposed Sec.  
11.6(a) and the requirement that sponsors submit a certification to 
accompany the product applications or submission to FDA stating that 
the sponsor is in compliance with Title VIII of FDAAA (section 
282(j)(5)(B) of the PHS Act), and reflected in the prohibited acts 
provisions (21 U.S.C. 331(jj)(3). They also pointed to the statutory 
prohibition on making false statements to the Federal Government at 18 
U.S.C. 1001, which carries criminal penalties.
    One commenter questioned the appropriateness of requiring 
responsible parties to certify that information submitted is not 
misleading due to a concern about how members of the public might react 
to the information. The concern was related to the fact that the 
structured nature of the database limited the responsible party's 
ability to provide clarifying contextual information, which if allowed 
to be provided, in the view of the commenter, would minimize the 
possibility of misleading a reader about some aspect of the clinical 
trial. The commenter also suggested that the proposed certification 
requirement would require a responsible party to evaluate whether 
providing the submitted information could ``mislead'' a member of the 
public and that, if the responsible party concluded that such a result 
were even remotely possible, they would be in an untenable position of 
having to reconcile conflicting legal obligations (i.e., the 
responsible party could not satisfy its legal obligation to submit the 
clinical trial information under the PHS Act without certifying 
otherwise).
    Commenters suggested alternatives to the certification requirement. 
One suggested that the requirement be reworked to focus on assuring 
that the submitted information is ``truthful and complete'' rather than 
the subjective ``not misleading.'' Another suggested that it would be 
more appropriate to require the responsible party to certify that ``the 
information contained in this submission is accurate to the best of the 
sponsor's knowledge.'' Notwithstanding the general support expressed 
for Sec.  11.6, and although we do not agree that providing structured 
data entry in standard data formats could lead to misinterpretations of 
the data, we

[[Page 65006]]

conclude that the commenters who addressed proposed Sec.  11.6(b) 
specifically raised some valid concerns. The commenters suggested that 
responsible parties are well aware that they are legally bound to 
submit truthful information to the Federal Government and that a 
specific attestation to the veracity of the information at the time of 
information submission to ClinicalTrials.gov is unnecessary. As such, 
and given the other provisions in section 402(j) of the PHS Act that 
protect against the submission of false or misleading information, we 
have decided to drop the requirement that the responsible party certify 
that submitted information is truthful and not misleading and that the 
responsible party is aware of the potential consequences of submitting 
such information. With regard to the hypothetical concern that 
providing structured data entry in standard data formats could lead to 
misinterpretations of the data, it is important to note that we are not 
aware that such misunderstandings have occurred nor did any comments 
identify a specific example. Section 11.6(a) will be retained as a 
stand-alone provision of the final rule.
Final Rule
    The final rule eliminates proposed Sec.  11.6(b) and retains the 
requirement that submitted clinical trial information must not be false 
or misleading. The final rule also clarifies in Sec.  11.6 that a 
responsible party who submits false and/or misleading information may 
be subject to civil monetary penalties and/or to other civil or 
criminal remedies available under U.S. law. Eliminating proposed Sec.  
11.6(b) does not change the responsible party's obligation to be 
truthful and not misleading in submissions to ClinicalTrials.gov.
4. 11.8--In what format must clinical trial information be submitted?
Overview of Proposal
    Section 402(j)(3)(D)(v)(I) of the PHS Act requires the 
establishment of a ``standard format'' for the submission of clinical 
trial information. Section 402(j)(2)(B) of the PHS Act also requires 
that clinical trial information be submitted in such a way that is 
searchable by the public. Proposed Sec.  11.8 set forth the required 
format for submitting clinical trial information to ClinicalTrials.gov. 
The proposal specified that information must be submitted 
electronically to ClinicalTrials.gov in the format specified at http://prsinfo.clinicaltrials.gov and explained that no other format would be 
accepted. Although the proposal used the phrase ``form and manner'' 
instead of ``format,'' we are using ``format'' in the final rule to be 
consistent with the language of the statute in section 
402(j)(3)(D)(v)(I). As discussed in sections II.B and III.C.10 of the 
NPRM, NLM is adopting a tabular, structured data entry system to 
promote objective reporting, optimize data display, permit effective 
searching of ClinicalTrials.gov, and facilitate cross-trial 
comparisons.
    Proposed Sec. Sec.  11.10, 11.28, and 11.48 specified the 
individual data elements of clinical trial information that must be 
submitted to ClinicalTrials.gov at the time of registration and results 
information submission (and updated in accordance with proposed Sec.  
11.64), including the subelements that are considered to be part of a 
data element (e.g., proposed Sec.  11.10(b)(5) specifies that the Study 
Design data element includes the subelements Interventional Study 
Model, Number of Arms, Arm Information, Allocation, Masking, and Single 
Arm Controlled).
    In sections IV.B.4 and IV.C.4 of the NPRM, we described the 
specific format in which data elements and subelements would be 
required to be submitted to ClinicalTrials.gov. For some data elements 
and subelements, responsible parties would be required to submit 
information in free-text form. For other data elements and subelements, 
responsible parties would be required to select the best response from 
menus of options presented in ClinicalTrials.gov. The Agency also 
developed a mechanism for uploading registration and results data in an 
automated electronic fashion using eXtensible Markup Language (XML) 
files.
    We explained in the NPRM preamble that the Agency might make minor 
changes from time to time to the specific format in which responsible 
parties would be required to submit individual data elements and 
subelements to ClinicalTrials.gov (79 FR 69598). We indicated that we 
would provide prior notice and seek public comment on any proposed 
changes to the format of submitting clinical trial information and that 
any changes would ultimately be reflected in the PRS.
    We invited comment on the specific format described in the proposed 
rule for submitting data elements and subelements of proposed clinical 
trial information, including comments on the benefits and burden 
associated with providing proposed data elements and subelements, 
whether proposed menu options are sufficient to accommodate the range 
of potential entries (e.g., for different trial designs), and whether 
an ``other'' option is needed in additional data elements (79 FR 
69598). We also invited comment on the proposed approach described in 
this section for modifying the format of submitting clinical trial 
information over time.
Comments and Response
    Commenters addressed the proposed format of submission. Some 
comments explicitly supported the proposed rule requirements for 
information to be submitted in a structured format. Other comments 
addressed data formatting issues in the PRS. Some of these commenters 
recommended that the PRS allow submissions in Microsoft Excel[supreg] 
files, such as for adverse events, particularly because academic 
medical centers are generally not familiar with XML. We note that the 
PRS system has allowed for the submission of adverse event information 
in spreadsheet format, including Excel, since 2013 and will continue to 
allow this format.
    Other commenters requested that the PRS accept submissions in the 
same electronic formats as required by the Agency and other federal 
funders for submissions to their own databases (e.g., Clinical Trial 
Reporting Program (CTRP) for the National Cancer Institute (NCI)). This 
approach of broadly accepting the same electronic format as other 
systems is not feasible. Any single standard data format adopted by 
ClinicalTrials.gov must provide sufficient generality and flexibility 
to accommodate accurate reporting of the mandated clinical trial 
information for a wide range of clinical trial designs, research areas/
domains, and funder/sponsor classes covered by the law. While the 
Agency appreciates that accepting a variety of submission formats from 
other federal databases may be less burdensome for responsible parties, 
the PHS Act requires the final rule to establish a standard format for 
the submission of clinical trial information. This standard format 
will, in turn, facilitate search and comparison of entries in the 
registry data bank, as is also required under the statute. Furthermore, 
it is possible for other systems to map their content to the standard 
data format at ClinicalTrials.gov. For example, because the data 
elements used to describe a clinical trial in the NCI's CTRP are 
designed to be compatible with the standard format required for 
submitting clinical trial registration information to 
ClinicalTrials.gov, responsible parties who have previously submitted 
trial information to CTRP can submit that same information directly 
into the PRS at ClinicalTrials.gov. NCI intends to continue to ensure 
that the information

[[Page 65007]]

collected in CTRP is compatible with the requirements of the final 
rule, while continuing to collect and maintain other information that 
meets distinct CTRP purposes. NIH is also taking steps to bring more 
standardization to the information obtained from clinical trial 
applicants and awardees in order to enhance its stewardship of clinical 
trials. These efforts will also take into consideration the data 
elements in ClinicalTrials.gov.
    ClinicalTrials.gov supports this information exchange by making 
available to all organizations the specific data elements and their 
definitions, an XML schema, an application program interface (API), and 
information about validation messages. We, therefore, retain the PRS 
submission format in the final rule in order to meet the requirements 
of the law, but will continue to allow responsible parties who have 
previously submitted clinical trial data elements to a number of other 
databases that are compatible with the PRS standard format to transfer 
clinical trial information automatically from those databases into 
ClinicalTrials.gov.
    Some commenters recommended the use of the Clinical Data 
Interchange Standards Consortium (CDISC) data format to ensure 
harmonization for registration and results information reporting. To 
our knowledge, there is no existing standard data format that supports 
the entirety of the requirements in the final rule. However, if such a 
standard data format is developed and adopted by a significant number 
of responsible parties, the Agency will work to provide appropriate 
interfaces for providing information in that format. In general, the 
PRS will accept XMLs that meet the requirements of the PRS and that 
include information that satisfies the elements and subelements 
required in this regulation.
    A number of commenters also stressed the importance of 
harmonization with international and other standard data formats for 
uniformity in registration and results information submissions. Some 
commenters requested that data formats be made consistent and be 
harmonized with databases such as the EU EudraCT database administered 
by the EMA [Ref. 70], or the WHO International Clinical Trial Registry 
Platform Trial Registration Data Set (Version 1.2.1) [Ref. 73]. One 
commenter requested specifically that any new data technologies and 
database functionalities should be consistent with the EU and other 
registration databases.
    We note that the NPRM preamble identified data elements that are 
consistent with the WHO Trial Registration Data Set (i.e., brief title, 
official title, study design, primary disease or condition being 
studied in the trial, focus of the study, intervention name, primary 
and secondary outcome measures, eligibility criteria, overall 
recruitment status, and secondary identifications (IDs)) (79 FR 69611 
et al). These data elements are maintained in the final rule. In 
addition, the Agency provided technical assistance to the EMA during 
development of the EudraCT results database so that EudraCT's data 
requirements are substantially aligned with the requirements for 
ClinicalTrials.gov [Ref. 71]. Also, in April 2015, WHO issued a 
Statement on Public Disclosure on Clinical Trial Results [Ref. 74]. 
Although section 402(j)(3)(D)(vi) of the PHS Act requires the Agency to 
consider the status of consensus data elements set of the WHO for 
reporting clinical trial results information, the WHO's April 2015 
statement did not include any consensus data elements. The Agency notes 
that opportunities to incorporate newer data formats in the future will 
be available through the procedures described for format changes in the 
section below.
    One commenter requested that the Systematized Nomenclature of 
Medicine--Clinical Terms (SNOMED CT[supreg]) be used for terminology, 
or in the alternative ICD-10, to ensure the standard's ability to 
``map'' to electronic health records. SNOMED CT[supreg] is a 
comprehensive clinical terminology owned, maintained, and distributed 
by the International Health Terminology Standards Development 
Organization [Ref. 75], which includes NLM as the U.S. member. SNOMED 
CT[supreg] is used in systems of the Federal Government for the 
electronic exchange of clinical health information and is a required 
standard data format in interoperability specifications of the U.S. 
Healthcare Information Technology Standards Panel [Ref. 76]. Since 
SNOMED CT[supreg] provides clinical terminology, it applies most 
directly to the data element of ``primary disease or condition being 
studied in the trial, or focus of the study'' (Sec.  11.10(b)(9)). We 
note that the rule allows the use of SNOMED CT[supreg] for this data 
element or any other vocabulary that has been mapped to Medical Subject 
Headings (MeSH[supreg]) [Ref. 77] with the Unified Medical Language 
System (UMLS) Metathesaurus. The use of ONC-certified or endorsed 
terminologies is encouraged where possible, including, but not limited, 
to SNOMED CT and Logical Observation Identifiers Names and Codes, known 
by its acronym LOINC[supreg].
    Finally, some comments requested that an ``Other'' category option 
be provided for all data elements. We have instead included an 
``Other'' category as menu options only for those data elements where 
we believe it is necessary and appropriate. In some instances, such as 
for Study Phase and Study Type, the menu list is comprehensive and no 
``Other'' category is needed. An advantage of providing a comprehensive 
list of substantive options, when possible, is to mitigate confusion 
and potential errors during data entry. Another key advantage of using 
only controlled terms as menu items is that it increases structure of 
the database, thereby facilitating accurate search and complete 
information retrieval. Allowing the selection of an ``Other'' option 
with additional free-text elaboration can limit the specificity and 
searchability of the database. Thus, we have limited the number of data 
elements that provide an ``Other'' category as an option. As the nature 
of clinical research methodologies and practices evolve and we gain 
more experience with certain data elements, we anticipate that menu 
options will likely change. As described in more detail in the final 
rule discussion for Sec.  11.8, we will use a notice-and-comment 
process before adding any new menu options for a data element.
Final Rule
    The final rule maintains Sec.  11.8, with some modification for 
further clarity, in requiring ``Information submitted under this part 
must be submitted electronically to ClinicalTrials.gov, in the format 
specified at https://prsinfo.clinicaltrials.gov.'' The final rule also 
modifies in the section title the phrase ``form and manner'' to 
``format'' to be consistent with the language used in section 
402(j)(3)(D)(v)(I) of the PHS Act.
    This final rule also specifies the data elements and subelements 
defined in Sec.  11.10 and required by Sec.  11.28 and Sec.  11.48. In 
addition, by describing the registration and results information to be 
submitted to ClinicalTrials.gov, this final rule preamble specifies the 
format in which information will be submitted (such as free text or 
menu selections). The format specified in this final rule preamble will 
be described at https://prsinfo.clinicaltrials.gov (or successor site). 
The choice of providing menu options versus free-text fields and the 
set of menu options offered for specific data elements and subelements 
are

[[Page 65008]]

based on our experience in operating ClinicalTrials.gov and on comments 
received from users of ClinicalTrials.gov, including those who 
commented on the FDA draft and final guidance documents that were 
issued in 2002 and 2004 [Ref. 78, 79] (79 FR 69570) and the preliminary 
version of the results database and adverse event module that were 
available for testing beginning in the spring of 2008 (73 FR 29525). 
Some menus offer a fixed set of options without an ``Other'' option; 
others offer a prespecified set of options plus an ``Other'' option. In 
most cases, responsible parties selecting the ``Other'' option would be 
required to provide a free-text response to elaborate on the ``Other'' 
selections. Some data elements without an ``Other'' option also include 
an optional free-text field in which responsible parties could 
voluntarily provide additional information about the option selected.
    The use of menu options is intended to promote the entry of data in 
a structured format that allows users to search ClinicalTrials.gov and 
retrieve comparable information, consistent with the requirements of 
sections 402(j)(2)(B) and (3)(D)(v)(I) of the PHS Act. Menu options 
have been used in ClinicalTrials.gov since its launch and are routinely 
used to improve the quality and to help ensure the completeness of data 
submitted to information systems. Their use can reduce typographical 
errors in data entry and minimize the data entry burden on responsible 
parties by providing a set of predefined options for common entries. By 
standardizing the set of available responses, they also promote the use 
of consistent terminology across entries and can improve the ability of 
users to search the data bank and compare entries easily across 
clinical trials.
    We further note that to reduce the burden on responsible parties 
related to the submission of information to the data bank, 
ClinicalTrials.gov accommodates both interactive, online entry of 
information for a specific clinical trial and automated uploading of 
information that is prepared in XML format. Responsible parties 
submitting information on multiple clinical trials may upload 
information that is prepared as a batch submission. ClinicalTrials.gov 
also supports uploading of adverse event information using a 
spreadsheet program, such as Microsoft Excel[supreg], so long as it 
conforms to the specified data format of the PRS. Additional 
information about submitting information to ClinicalTrials.gov is 
available at https://prsinfo.clinicaltrials.gov.
    As described in the NPRM, the Agency might periodically make minor 
changes to the specific format in which responsible parties submit 
individual data elements and subelements to ClinicalTrials.gov (79 FR 
69598). Such changes would not require a responsible party to submit 
different or more clinical trial information than is specified in the 
final rule, but would alter the way in which the information is 
entered, with the general aim of making sure the menu options contain 
the most relevant, useful, and convenient options for responsible 
parties and users of the system. For example, if the research community 
develops a new type of clinical trial design, we might expand the list 
of menu options under the Interventional Study Model subelement of the 
Study Design data element to include it. If we find that many of the 
free-text entries for the Why Study Stopped data element fall into a 
small number of categories, we might offer them as menu options (in 
addition to accepting free-text for ``Other'' reasons) to reduce the 
burden of data entry and improve the consistency and comparability of 
responses across registered clinical trials. We will provide prior 
notice and seek public comment on any proposed changes of substantive 
nature to the format of submitting clinical trial information. There 
may be times when changes of a technical nature may be required (e.g., 
updates to the XML, redesign of the user interface, modifications to 
PRS on-screen instructions), for which no public comments will be 
sought.
5. 11.10--What definitions apply to this part?
    Section 11.10 of the NPRM defined certain terms and data elements 
used in the proposed part. The terms defined in proposed Sec.  11.10(a) 
included terms explicitly defined in section 402(j) of the PHS Act 
(e.g., ``applicable clinical trial,'' ``responsible party''); terms 
used but not defined in section 402(j) of the PHS Act (e.g., ``clinical 
trial''); and terms not specifically found in section 402(j) of the PHS 
Act but which are important for implementing the statutory provisions. 
With respect to terms not defined in the statute, we proposed 
definitions to fit within the proposed framework for the expanded data 
bank and for the purposes of satisfying the statutory goals, clarifying 
the application and operation of this proposed rule, in particular as 
related to information to be submitted to ClinicalTrials.gov, and/or 
for convenience. We also referenced some terms defined under the PHS 
Act and the FD&C Act and implementing regulations, as necessary.
    For each term defined in proposed Sec.  11.10(a), we describe below 
the proposed definition, any specific public comment(s) we received and 
our response(s), and the term and definition that is adopted in Sec.  
11.10(a) of the final rule. The list below is alphabetized according to 
the name assigned to the term in the final rule. For example, the term 
``FDA-regulated device'' proposed in the NPRM is ``U.S. FDA-regulated 
device'' in the final rule, so it appears toward the end of the list.
Adverse Event
    In the NPRM, we defined ``adverse event'' in Sec.  11.10(a) as 
``any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with 
the subject's participation in the research, whether or not considered 
related to subject's participation in the research.''
    As we explained in the NPRM, ``adverse event'' is a term used but 
not defined in section 402(j)(3)(I) of the PHS Act to describe a 
certain category of clinical trial results information (79 FR 69598). 
Section 402(j)(3)(I)(iii) of the PHS Act requires the reporting of both 
anticipated and unanticipated adverse events. Current FDA regulations 
define the term ``adverse event'' with respect to drugs, but not to 
devices. (FDA regulations for devices include a different but related 
term, ``suspected adverse device effect,'' that is discussed in the 
definition of the term ``serious adverse event.'') FDA regulations for 
IND safety reporting requirements that were issued on September 29, 
2010 (75 FR 59935), and took effect on March 28, 2011 define an adverse 
event as ``any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related'' (21 CFR 
312.32(a)). In addition to defining the term ``adverse event,'' those 
FDA regulations have the additional purpose of identifying 
circumstances in which certain adverse events (such as those that are 
serious and unexpected and that also meet the definition of a 
``suspected adverse reaction,'' meaning that the adverse event must 
have a reasonable possibility of being caused by the drug) must be 
reported in an expedited fashion while the trial is ongoing.
    The HHS Office for Human Research Protections (OHRP) has a 
definition of adverse event that covers drug, device, and other 
interventions and includes both anticipated and unanticipated

[[Page 65009]]

event(s) regardless of whether they are attributed to the 
intervention(s) studied in the clinical trial. As discussed in OHRP's 
``Guidance on Reviewing and Reporting Unanticipated Problems Involving 
Risks to Subjects or Others and Adverse Events'' (January 2007), an 
adverse event means ``[a]ny untoward or unfavorable medical occurrence 
in a human subject, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject's participation in the research, whether or 
not considered related to the subject's participation in the research'' 
[Ref. 80]. The OHRP definition was adapted from the definition used by 
the International Conference on Harmonization of Technical Requirements 
of Pharmaceuticals for Human Use (ICH) Guideline E6, Good Clinical 
Practice: Consolidated Guidance [Ref. 81] which was published by FDA as 
a guidance document in the FR in 1997 (62 FR 25692). The definition, 
therefore, is consistent with international norms. Although the ICH 
Guidelines are intended to apply to pharmaceutical products, the OHRP 
definition is intended to apply broadly to research in humans that 
involves any type of intervention.
    We received comments on the adverse event definition. The 
commenters asserted that the definition was inconsistent with FDA's 
adverse event definition. One commenter noted that the definition of 
``adverse event'' was vague and requested that the rule define the term 
to be consistent with IRB reporting requirements at continuing review. 
We disagree. The IRB requirements cited by the commenter are described 
in the OHRP guidance from which we derived the adverse event 
definition; this helps ensure consistency in the submission of adverse 
event information for applicable device clinical trials and applicable 
drug clinical trials. As explained above, this definition is consistent 
with, but not identical to, FDA's definition of ``adverse event'' for 
IND safety reporting in 21 CFR 312.32(a). The definition in Sec.  
11.10(a) includes not only those adverse events defined in 21 CFR 
312.32 (which apply to clinical trials of drug products), but also 
adverse events more broadly from research participation subject to this 
part (i.e., including clinical trials of device products) and ensures 
consistency with the international standard. For example, a ``suspected 
adverse event,'' defined by FDA as a subcategory of ``adverse event'' 
that requires a reasonable possibility of being caused by the drug, is 
also included under the definition of ``adverse event'' in Sec.  
11.10(a).
    After considering these comments, we maintain the definition of 
``adverse event'' in Sec.  11.10(a) of the final rule to mean ``any 
untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with 
the subject's participation in the research, whether or not considered 
related to subject's participation in the research.''
    Additionally, this final rule includes a requirement to submit to 
ClinicalTrials.gov summary information about anticipated and 
unanticipated adverse events observed during a clinical trial (as well 
as a requirement to submit information about serious adverse events), 
regardless of attribution (i.e., whether or not the investigator 
believes they are related to the intervention(s)). These requirements 
are consistent with the definition of ``adverse event'' in the final 
rule, which is not limited to adverse events that are anticipated, are 
likely to have been caused by the drug product (including biological 
product) or device product (or other type of intervention used in the 
clinical trial), or have a reasonable possibility of being related to 
the intervention under study. The definition of ``adverse event,'' 
which includes all adverse events regardless of possible attribution 
and regardless of whether they were anticipated, advances the statutory 
goal of providing more information that may be related to medical 
products' potential risks.
Applicable Clinical Trial
    In the NPRM, we defined ``applicable clinical trial'' in Sec.  
11.10(a) to mean ``an applicable device clinical trial or an applicable 
drug clinical trial.'' As we explained, this definition, which is 
identical to the statutory definition in section 402(j)(1)(A)(i) of the 
PHS Act, designates the scope of clinical trials that may be subject to 
the requirements to submit clinical trial registration and results 
information as specified in this part (79 FR 69599). However, not all 
trials meeting the definition of an ``applicable clinical trial'' are 
subject to the clinical trial registration and results information 
submission requirements. For example, an applicable clinical trial that 
reached its primary completion date on or before September 27, 2007 
(i.e., the date of enactment of FDAAA) is not subject to section 402(j) 
of the PHS Act, nor is an applicable clinical trial that was ongoing as 
of September 27, 2007, and reached its primary completion date prior to 
December 26, 2007. In addition, in proposed Sec.  11.22(b), we 
described an approach for determining whether a clinical study or trial 
meets the definition of an ``applicable clinical trial.''
    We received comments on this definition. One commenter supported 
the proposed definition. Other commenters requested that the definition 
include all clinical trials, and one of these commenters further 
requested that the definition be amended in the final rule to include 
any human experiment introducing any form of a drug, device, biologic, 
radiation, or any other form of treatment into the human body. The 
definition of ``applicable clinical trial'' is set forth in section 
402(j) of the PHS Act.
    Based on further review and analysis, we have reconsidered whether 
any expanded access use falls within the definition of ``applicable 
clinical trial.'' For the following reasons, we have determined that no 
expanded access use would be considered an ``applicable clinical 
trial'' under section 402(j) of the PHS Act.
    FDAMA (Pub. L. 105-115) contained two related provisions addressing 
expanded access use. FDAMA added section 561 to the FD&C Act, which 
specifically authorized the Secretary to permit investigational drugs 
and investigational devices to be made available for the diagnosis, 
monitoring, or treatment of serious or life-threatening diseases or 
conditions under certain circumstances. These so-called ``expanded 
access'' provisions were implemented by FDA through its IND and IDE 
regulations (see 21 CFR 312.300-320 and 21 CFR 812.36).
    FDAMA also amended section 402 of the PHS Act to require the 
Secretary to establish a data bank of information on experimental drugs 
for serious or life-threatening diseases and conditions. This FDAMA-
created data bank included two specified aspects: ``(A) A registry of 
clinical trials (whether federally or privately funded) of experimental 
treatments for serious or life-threatening diseases and conditions 
under regulations promulgated pursuant to section 505(i) of the [FD&C 
Act] . . .'' and ``(B) Information pertaining to experimental 
treatments for serious or life-threatening diseases and conditions that 
may be available--(i) under a treatment investigational new drug 
application that has been submitted . . . under section 561(c) of the 
[FD&C Act] . . .'' (currently section 402(i)(3) of the PHS Act). In 
addition, the FDAMA data bank could include information on ``the 
results of clinical trials . . . with the

[[Page 65010]]

consent of the sponsor . . .'' (currently section 402(i)(3) of the PHS 
Act).
    These FDAMA provisions were implemented by NIH through the creation 
of ClinicalTrials.gov. The FDAMA provisions were subsequently amended 
to require information on clinical trials to also include a description 
of whether, and through what procedure, the manufacturer or sponsor 
would make the drug available for expanded access use, particularly in 
children (section 15(c)(2) of Public Law 107-109; 115 Stat. 1420 
(2002)). Thus, there is a distinction reflected in section 402(i) of 
the PHS Act between a clinical trial and expanded access use.
    The FDAAA provision adding current section 402(j) of the PHS Act 
was intended to expand the ClinicalTrials.gov data bank. The structure 
and language of section 402(j) reflect congressional intent to maintain 
in the data bank the same distinction between clinical trials and 
expanded access use. This congressional intent is evident in section 
402(j)(2)(A)(ii)(II)(gg) of the PHS Act, which states that ``in the 
case of an applicable drug clinical trial, if the drug is not approved 
. . . specify whether or not there is expanded access to the drug under 
section 561 of the [FD&C Act] . . .'' This provision implies that 
expanded access use would not itself be considered an ``applicable 
clinical trial.''
    For these reasons, we have concluded that expanded access use under 
section 561 of the FD&C Act does not fall within the definition of 
``applicable clinical trial'' under section 402(j) of the PHS Act. 
However, information on the availability of investigational drug 
products (including biological drug products) for expanded access will 
continue to be required to be submitted to the ClinicalTrials.gov 
database under authority of the section 402(j) registration 
requirements.
    In the final rule, the definition of ``applicable clinical trial'' 
in Sec.  11.10(a) is revised by the addition, at the end of the 
definition, of the following statement: ``Expanded access use under 
section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
360bbb) is not an applicable clinical trial.'' Other than this change, 
we maintain the proposed definition of ``applicable clinical trial'' as 
the first sentence of the definition in the final rule: ``Applicable 
clinical trial means an applicable device clinical trial or an 
applicable drug clinical trial.'' This first sentence of the definition 
is identical to the statutory definition.
    We also received comments specifically on the ``applicable device 
clinical trial'' or ``applicable drug clinical trial'' components of 
the proposed applicable clinical trial definition. These are addressed 
within the definition for each.
Applicable Device Clinical Trial
    In the NPRM, we defined ``applicable device clinical trial'' in 
Sec.  11.10(a) to mean (1) a prospective clinical study of health 
outcomes comparing an intervention with a device subject to section 
510(k), 515, or 520(m) of the FD&C Act against a control in human 
subjects (other than a small clinical trial to determine the 
feasibility of a device, or a clinical trial to test prototype devices 
where the primary outcome measure relates to feasibility and not to 
health outcomes); and (2) a pediatric postmarket surveillance as 
required under section 522 of the FD&C Act.
    As we explained in the NPRM, ``applicable device clinical trial'' 
is the term used in section 402(j)(1)(A) of the PHS Act to designate 
the clinical trial of a device and FDA-ordered pediatric postmarket 
surveillance of a device for which clinical trial information must be 
submitted to ClinicalTrials.gov under section 402(j) of the PHS Act (79 
FR 69599). The proposed rule adopted, in Sec.  11.10, the definition of 
applicable device clinical trial, as provided in section 
402(j)(1)(A)(ii) of the PHS Act: ``(I) a prospective clinical study of 
health outcomes comparing an intervention with a device subject to 
section 510(k), 515, or 520(m) of the [FD&C] Act against a control in 
human subjects (other than a small clinical trial to determine the 
feasibility of a device, or a clinical trial to test prototype devices 
where the primary outcome measure relates to feasibility and not to 
health outcomes); and (II) a pediatric postmarket surveillance as 
required under section 522 of the [FD&C] Act.'' In addition, the 
proposed rule in Sec.  11.10 adopted the definition of ``device'' in 
section 402(j)(1)(A)(vi) of the PHS Act as ``a device as defined in 
section 201(h) of the [FD&C] Act.'' We provided additional elaboration 
of the interpretation of applicable device clinical trial in the NPRM.
    We received several comments on this definition. One commenter 
supported the proposed rule's applicable clinical trial definition with 
respect to devices, particularly that only a ``prospective'' clinical 
study should be considered an ``interventional study,'' and thus an 
applicable clinical trial. Many commenters requested that the 
applicable device clinical trial definition be expanded to include any 
trials in which a device is introduced into the human body, but they 
agreed that the definition should not include observational studies. 
One commenter requested that the definition include small device 
feasibility studies, which are explicitly excluded by the statutory 
definition. Two other commenters requested that the definition include 
all studies conducted under an IDE.
    We have not modified the definition of ``applicable device clinical 
trial'' in the final rule based on these comments. The statutory 
definition explicitly states which trials fall within the definition of 
an applicable clinical trial; it does not include all device clinical 
trials. Section 402(j)(1)(A)(ii) of the PHS Act requires that the 
device must be subject to section 510(k), 515, or 520(m) of the FD&C 
Act. Section 402(j)(1)(A)(ii) of the PHS Act also explicitly excludes 
certain device feasibility studies from the ``applicable device 
clinical trial'' definition. A device is considered to be subject to 
section 510(k), 515, or 520(m) of the FD&C Act if any of the following 
is required before it may be legally marketed in the United States: (1) 
A finding of substantial equivalence under section 510(k) of the FD&C 
Act permitting the device to be marketed, (2) an order under section 
515 of the FD&C Act approving a pre-market approval application for the 
device, or (3) a humanitarian device exemption (HDE) under section 
520(m) of the FD&C Act. Such devices that are considered to be subject 
to section 510(k), 515, or 520(m) of the FD&C Act include significant 
risk devices for which approval of IDE is required under section 520(g) 
of the FD&C Act, non-significant risk devices that are considered to 
have an approved IDE in accordance with 21 CFR 812.2(b), or devices 
that are exempt from the submission requirements of 21 CFR 812 (79 FR 
69600).
    Some commenters also requested clarification of definitional 
elements. One commenter requested that the rule clarify the term 
``health-outcomes'' for making an applicable clinical trial 
determination. We have not provided a definition of ``health outcomes'' 
in the final rule for the applicable device clinical trial definition. 
However, in the NPRM, we explained that a ``prospective clinical study 
of health outcomes'' is a clinical study in which the primary objective 
is to evaluate a defined clinical outcome related to human health (79 
FR 69599). For example, a clinical study of a diagnostic device (such 
as an in vitro diagnostic (IVD)) in which the primary purpose is to 
evaluate the ability of the device to make a diagnosis of a disease or 
condition is related directly to human health and, therefore, would be 
considered a clinical study ``of health outcomes'' for purposes of this 
rule. We

[[Page 65011]]

will consider additional guidance on this term if our experience 
reflects it is needed.
    Another commenter suggested that the term ``feasibility,'' as used 
in the parenthetical exclusion in the definition of ``applicable device 
clinical trial,'' was described in the NPRM in a way that is more 
limited than FDA guidance and requested clarification in the final 
rule. The ``feasibility study'' exclusion in the definition directly 
incorporates the language from section 402(j)(1)(A)(ii)(I) of the PHS 
Act: ``a small clinical trial to determine the feasibility of a device, 
or a clinical trial to test prototype devices where the primary outcome 
measure relates to feasibility and not to health outcomes'' is not an 
``applicable device clinical trial.'' We explained in the NPRM that 
clinical studies designed primarily to determine the feasibility of a 
device or to test a prototype device are considered by the Agency to be 
clinical studies conducted to confirm the design and operating 
specifications of a device before beginning a full clinical trial (79 
FR 69601). Feasibility studies are sometimes referred to as phase 1 
studies, pilot studies, prototype studies, or introductory trials 
(although we note that the use of these terms does not necessarily mean 
that the study is a feasibility study under the definition). Our 
explanation of this exemption is consistent with FDA's regulation of 
devices. FDA published the guidance Investigational Device Exemptions 
(IDEs) for Early Feasibility Medical Device Clinical Studies, Including 
Certain First in Human (FIH) Studies (October 2013) to address the 
development and review of IDE applications for early feasibility 
studies of significant risk devices [Ref. 82]. For the purposes of the 
guidance, the guidance defines an ``early feasibility study'' as a 
limited clinical investigation of a device early in development, 
typically before the device design has been finalized, for a specific 
indication. The guidance further defines a ``traditional feasibility 
study'' as a clinical investigation that is commonly used to capture 
preliminary safety and effectiveness information on a near-final or 
final device design to adequately plan an appropriate pivotal study. 
Section 402(j)(1)(A)(ii)(I) of the PHS Act excludes ``small clinical 
trial[s] to determine the feasibility of a device, or a clinical trial 
to test prototype devices where the primary outcome measure relates to 
feasibility and not to health outcomes'' from the definition of 
``applicable device clinical trial.'' The excluded clinical trials 
described in this statutory definition appear to be consistent with the 
early feasibility study definition in the guidance, but not with that 
of the traditional feasibility study, which evaluates preliminary 
safety and effectiveness information (i.e., for ``health outcomes''). 
Therefore, it is likely that only early feasibility studies would fall 
within this exclusion under the Sec.  11.10 definition of an 
``applicable device clinical trial.''
    Two commenters requested that the rule define ``small,'' which is 
used in the definition's ``feasibility study'' exemption. One of the 
commenters requested that the rule use a ``threshold'' number of 
subjects indicated for the Enrollment data element based on an 
empirical database review, such as not more than 20-30 subjects for a 
study. The other commenter requested clarification of the term 
``small'' and suggested that a device trial with at least 10 subjects 
could not qualify as ``small'' for the ``feasibility study'' exemption. 
We are not including a threshold number in the definition, because some 
studies with an enrolled subject total exceeding a specified threshold 
might be more appropriately considered a ``small feasibility study,'' 
while other studies with an enrolled subject total below the specified 
threshold, depending on the prevalence of the disease or condition, 
might not be considered ``small'' for the purposes of this exemption. 
We note that a trial with at least 10 subjects would generally not be 
considered ``small.''
    To determine whether a device trial is an applicable device 
clinical device, one comment requested clarification as to whether a 
device that is solely packaged and/or labeled in the United States 
would be considered ``manufactured in'' the United States. The 
commenter opposed considering devices that are solely packaged and/or 
labeled in the United States as ``manufacture[d] in the U.S.'' and 
requested clarification in the final rule. Pursuant to section 510 of 
the FD&C Act, FDA's jurisdiction extends to the ``manufacture, 
preparation, propagation, compounding or processing'' of devices, which 
term is defined to include ``repackaging or otherwise changing the 
container, wrapper, or labeling or any . . . device package in 
furtherance of the distribution of the . . . device from the original 
place of manufacture to the person who makes final delivery or sale to 
the ultimate consumer or user.'' The NPRM used the term ``manufacture'' 
as a short-hand for all device activities within FDA's jurisdiction. 
Therefore, a device product that is packaged and/or labeled in the 
United States would be considered ``manufactured'' in the United States 
and subject to section 510(k), 515, or 520(m) of the FD&C Act.
    After considering the comments, we maintain the definition of 
``applicable device clinical trial'' in Sec.  11.10(a), except that we 
have clarified the status of certain clinical trials of combination 
products, made clear that the term ``device'' refers to a particular 
manufacturer's device product, and included the applicable United 
States Code (U.S.C.) statutory citations. In Sec.  11.10(a) of the 
final rule, we define ``applicable device clinical trial'' to mean 
``(1) [a] prospective clinical study of health outcomes comparing an 
intervention with a device product subject to section 510(k), 515, or 
520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 
21 U.S.C. 360e, 21 U.S.C. 360j(m)) against a control in human subjects 
(other than a small clinical trial to determine the feasibility of a 
device product, or a clinical trial to test prototype device products 
where the primary outcome measure relates to feasibility and not to 
health outcomes); (2) [a] pediatric postmarket surveillance of a device 
product as required under section 522 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 3601); or (3) [a] clinical trial of a 
combination product with a device primary mode of action under 21 CFR 
part 3, provided that it meets all other criteria of the definition 
under this part.''
    The first part of the definition in section 402(j)(1)(A)(ii)(I) of 
the PHS Act defines a clinical study as an applicable device clinical 
trial if it meets the following four criteria: (1) It is a prospective 
clinical study of health outcomes; (2) it compares an intervention with 
a device against a control in human subjects; (3) the studied device is 
subject to section 510(k), 515, or 520(m) of the FD&C Act; and (4) it 
is other than a small clinical trial to determine the feasibility of a 
device or a clinical trial to test prototype devices where the primary 
outcome measure relates to feasibility and not to health outcomes. 
Except as described below with regard to pediatric postmarket 
surveillances of a device product, if a clinical investigation fails to 
meet one or more of these criteria, it would not be considered an 
applicable device clinical trial. We have considered the meaning of 
these criteria carefully and our interpretation follows.
    (1) ``Prospective clinical study of health outcomes.'' First, we 
interpret the term ``clinical study,'' with respect to a device 
product. We interpret ``clinical study'' with respect to a device 
product to mean an investigation in which a device product is used in 
one or more human subjects. For the purposes of

[[Page 65012]]

interpreting the term ``clinical study,'' we consider the term ``human 
subject'' to have the same meaning as the term ``subject,'' which is 
defined in FDA regulations as a ``human who participates in an 
investigation, either as an individual on whom or on whose specimen an 
investigational device is used or as a control. A subject may be in 
normal health or may have a medical condition or disease'' (see 21 CFR 
812.3(p)). For the purposes of only the requirements under section 
402(j) of the PHS Act and this rule, the term ``human subject'' does 
not include de-identified human specimens [Ref. 83]. Note that we use 
the term ``participant'' interchangeably with ``human subject'' in this 
document.
    The term ``study'' is often used interchangeably with the term 
``investigation.'' As pertaining to device products, ``investigation'' 
is defined as ``a clinical investigation or research involving one or 
more subjects to determine the safety or effectiveness of a device.'' 
(See 21 CFR 812.3(h).) Although FDA regulations pertaining to device 
products do not specifically define the term ``clinical 
investigation,'' that term is defined in FDA regulations pertaining to 
clinical investigations of drug products (including biological 
products) as ``any experiment in which a drug is administered or 
dispensed to, or used involving, one or more human subjects,'' where 
``experiment'' is defined as ``any use of a drug except for the use of 
a marketed drug in the course of medical practice'' (see 21 CFR 312.3). 
In our view, these definitions can be applied to trials of a device 
product by defining a ``clinical study of a device product'' as ``any 
experiment in which a device product is administered, dispensed to, or 
used involving, one or more human subjects,'' defining an 
``experiment'' as ``any use of a device product except for the use of a 
marketed device product in the course of medical practice,'' and using 
the definition of ``subject'' described above (from 21 CFR 812.3(p)). 
This interpretation helps improve consistency between definitions of 
the terms ``applicable device clinical trial'' and ``applicable drug 
clinical trial.'' In addition, our proposed interpretation of a 
``clinical study'' of a device product would include studies in which 
subjects are assigned to specific interventions according to a study 
protocol. Studies in which a device product is used on a patient as 
part of routine medical care and not because of a study or protocol 
would not be considered clinical studies for the purposes of this rule. 
An example of studies that would not be considered clinical 
investigations include situations in which, after a device product has 
been administered to patients in the course of routine medical practice 
by a healthcare provider, a researcher not associated with the 
administration of the device product reviews the patients' records in 
order to assess certain effects, interviews the patients to assess 
certain impacts, or collects longitudinal data to assess health 
outcomes.
    Second, turning to our interpretation of the term ``prospective,'' 
we consider a prospective clinical study to be any study that is not 
retrospective or, in other words, one in which subjects are followed 
forward in time from a well-defined point (i.e., the baseline of the 
study) or are assessed at the time the study intervention is provided. 
A prospective clinical study may also have non-concurrent (e.g., 
historical) control groups. An example of a retrospective study, and 
therefore not an applicable device clinical trial, is a study in which 
subjects are selected based on the presence or absence of a particular 
event or outcome of interest (e.g., from hospital records or other data 
sources) and their past exposure to a device product is then studied.
    Third, with respect to our interpretation of the phrase ``of health 
outcomes,'' for the purposes of the definition of ``applicable device 
clinical trial,'' we consider a ``prospective clinical study of health 
outcomes'' to be a clinical study in which one or more of the primary 
or secondary outcome measures are biomedical or health-related. For 
example, a clinical study of a diagnostic device (such as an IVD) in 
which the primary outcome measure is the number of subjects with the 
correct diagnosis, would be considered a clinical study of health 
outcomes for the purposes of this proposed rule.
    (2) ``Comparing an intervention with a device against a control in 
human subjects.'' We interpret the phrase an ``intervention with a 
device'' to be an intervention in which a device product is used on a 
human subject in the course of a study. As stated above, the meaning of 
the term ``human subject'' is consistent with the definition of 
``subject'' in 21 CFR 812.3(p), except that for the purposes of only 
the requirements under this part, the term ``human subject'' does not 
include de-identified human specimens. We interpret the term 
``intervention'' broadly, to include various techniques for using the 
device product such as, among others, device regimens and procedures 
and the use of prophylactic, diagnostic, or therapeutic agents.
    A clinical study is considered, or intended, to ``compare an 
intervention with a device against a control in human subjects'' when 
it compares differences in the biomedical or health-related outcomes 
between human subjects who received an intervention that included a 
device product and human subjects who received other interventions or 
no intervention (e.g., comparison with another device product, 
comparison with usual clinical care that did not involve a device 
product). The intervention under study may be one with a device product 
that has never been cleared or approved or one with a device product 
that has been cleared or approved, regardless of whether the clearance 
or approval is for the use being studied. Such controlled clinical 
studies include not only concurrent control groups, but also non-
concurrent controls such as historical controls (e.g., literature, 
patient records, human subjects as their own control) or outcomes using 
objective performance criteria such as performance criteria based on 
broad sets of data from historical databases (e.g., literature or 
registries) that are generally recognized as acceptable values. As 
discussed further in the definition of ``control or controlled,'' we 
clarify for the purposes of this part that all interventional studies, 
whether single or multi-arm, with a pre-specified outcome are 
considered to be controlled (i.e., comparing an intervention against a 
control).
    As discussed above, expanded access protocols under section 561 of 
the FD&C Act, under which investigational devices are made available 
under certain circumstances, do not fall within the definition of 
``applicable device clinical trial.''
    (3) ``A device subject to section 510(k), 515, or 520(m)'' of the 
FD&C Act. A device product is considered to be subject to section 
510(k), 515, or 520(m) of the FD&C Act if any of the following is 
required before it may be legally marketed in the United States: (1) A 
finding of substantial equivalence under section 510(k) permitting the 
device product to be marketed, (2) an order under section 515 of the 
FD&C Act approving a pre-market approval application for the device 
product, or (3) an HDE under section 520(m) of the FD&C Act. Device 
products that are considered to be subject to section 510(k), 515, or 
520(m) of the FD&C Act include significant risk devices for which 
approval of an IDE is required under section 520(g) of the FD&C Act, 
non-significant risk devices that are considered to have an approved 
IDE in accordance with 21 CFR 812.2(b), or

[[Page 65013]]

device products that are exempt from the submission requirements of 21 
CFR part 812.
    If a clinical study of a device product includes sites both within 
the United States (including any U.S. territory) and outside of the 
United States, and if any of those sites is using (for the purposes of 
the clinical study) a device product that is subject to section 510(k), 
515, or 520(m) of the FD&C Act, we would consider the entire clinical 
study to be an applicable device clinical trial, provided that it meets 
all of the other criteria of the definition under this part. However, a 
clinical study of a device product that is being conducted entirely 
outside of the United States (i.e., does not have any sites in the 
United States or in any U.S. territory) and is not conducted under an 
IDE may not be a clinical study of a device product subject to section 
510(k), 515, or 520(m) of the FD&C Act and, therefore, is not an 
applicable device clinical trial, depending on where the device product 
being used in the clinical study is manufactured. If the device product 
is manufactured in the United States or any U.S. territory, and is 
exported for study in another country (whether it is exported under 
section 801(e) or section 802 of the FD&C Act), the device product is 
considered to be subject to section 510(k), 515, or 520(m) of the FD&C 
Act. If the device product is manufactured outside of the United States 
or its territories, and the clinical study sites are all outside of the 
United States and/or its territories, the device product would not be 
considered to be subject to section 510(k), 515, or 520(m) of the FD&C 
Act. A device product that is packaged and/or labeled in the United 
States would be considered ``manufactured'' in the United States 
subject to section 510(k), 515, or 520(m) of the FD&C Act.
    (4) ``Other than a small clinical trial to determine the 
feasibility of a device, or a clinical trial to test prototype devices 
where the primary outcome measure relates to feasibility and not to 
health outcomes.'' Clinical studies designed primarily to determine the 
feasibility of a device product or to test a prototype device are 
considered by the Agency to be clinical studies conducted to confirm 
the design and operating specifications of a device product before 
beginning a full clinical trial. Feasibility studies are not considered 
applicable device clinical trials under this part.
    The second part of the definition in section 402(j)(1)(A)(ii)(II) 
of the PHS Act specifies that an applicable device clinical trial 
includes ``pediatric postmarket surveillance as required under section 
522 of the Federal Food, Drug, and Cosmetic Act.'' Postmarket 
surveillances can take many forms, from literature reviews to 
controlled clinical trials. Based on the statutory language, any 
pediatric postmarket surveillance of a device product under section 522 
of the FD&C Act, regardless of its design, is an applicable device 
clinical trial.
    In addition, a combination product may include a device subject to 
section 510(k), 515, or 520(m) of the FD&C Act, as well as a drug 
(including a biological product) subject to section 505 of the FD&C Act 
or section 351 of the PHS Act (see 21 CFR 3.2(e)). Drugs (including 
biological products) and devices do not lose their discrete regulatory 
identities when they become constituent parts of a combination product. 
In general, the regulatory requirements specific to each constituent 
part of a combination product also apply to the combination product 
itself. However, because some requirements of section 402(j) of the PHS 
Act are different for applicable device clinical trials than for 
applicable drug clinical trials, there is a need for clarity as to 
which requirements apply to applicable clinical trials of combination 
products that include device and drug constituent parts. In order to 
provide this clarity, the final rule specifies that an applicable 
clinical trial of a combination product with a device primary mode of 
action under 21 CFR part 3 would be considered an applicable device 
clinical trial, provided that it meets all other criteria of the 
definition under Sec.  11.10(a), and likewise, a clinical trial of a 
combination product with a drug primary mode of action under 21 CFR 
part 3 would be considered an applicable drug clinical trial, provided 
that it meets all other criteria of the definition under Sec.  
11.10(a).
Applicable Drug Clinical Trial
    In the NPRM, we defined ``applicable drug clinical trial'' in Sec.  
11.10(a) to mean ``a controlled clinical investigation, other than a 
phase 1 clinical investigation, of a drug subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or to section 351 of the Public 
Health Service Act, where `clinical investigation' has the meaning 
given in 21 CFR 312.3 (or any successor regulation) and `phase 1' has 
the meaning given in 21 CFR 312.21 (or any successor regulation).''
    As we explained in the NPRM, ``applicable drug clinical trial'' is 
the term used in section 402(j)(1)(A) of the PHS Act to designate a 
clinical trial involving a drug (including a biological product) for 
which clinical trial information must be submitted to 
ClinicalTrials.gov under section 402(j) of the PHS Act (79 FR 69601). 
The proposed rule in Sec.  11.10 adopted the definition of applicable 
drug clinical trial in section 402(j)(1)(A)(iii)(I) of the PHS Act and 
further clarified that, as specified in sections 402(j)(1)(A)(iii)(II) 
and (III), the term ``clinical investigation'' has the meaning given in 
21 CFR 312.3 (or any successor regulation) and ``phase I'' has the 
meaning given in 21 CFR 312.21 (or any successor regulation). We did, 
however, propose to replace ``phase I'' with ``phase 1,'' to be 
consistent with the numbering scheme used in FDA regulations (21 CFR 
312.21). We provided additional elaboration of the interpretation of 
the term ``applicable drug clinical trial'' in the NPRM (79 FR 69601).
    In addition, for the purposes of implementing the rule, we proposed 
to treat certain clinical trials of combination products as applicable 
drug clinical trials. Combination products are defined in 21 CFR 
3.2(e). A combination product is comprised of a drug and a device; a 
biological product and a device; a drug and a biological product; or a 
drug, a biological product, and a device that, for example, are 
physically, chemically, or otherwise combined or mixed and produced as 
a single entity or are separate products packaged together in a single 
package or as a unit (see 21 CFR 3.2(e)(1) and (2)). Because the 
definition of a ``drug'' in proposed Sec.  11.10 included a biological 
product, we stated in the proposed rule that a combination product 
would always consist, in part, of a drug. Therefore, we proposed to 
treat clinical trials of combination products that meet the definition 
in 21 CFR 3.2(e) as applicable drug clinical trials, for the purposes 
of the rule, as long as the clinical trial of the combination product 
is a controlled clinical investigation, other than a phase 1 clinical 
investigation, and the combination product is subject to sections 505 
of the FD&C Act and/or section 351 of the PHS Act and/or section 
510(k), 515, or 520(m) of the FD&C Act.
    Several commenters addressed the proposed definition. Many 
commenters requested that the definition of ``applicable drug clinical 
trial'' include ``phase 0'' or phase 1 studies. One commenter requested 
that the definition include all interventional drug clinical trials, 
including phases 1-4, consistent with the EU Clinical Trial 
Registration requirements. Several commenters requested that the 
applicable drug clinical trial definition be expanded to include any 
trials in which a drug is introduced into the human body, but they 
agreed that the definition should

[[Page 65014]]

not include observational studies. One commenter, as noted in the 
discussion of an applicable device clinical trial, opposed considering 
packaging or labeling in the United States as ``manufacture[d] in the 
U.S.'' and requested clarification in the final rule. Another commenter 
requested that the rule clarify whether foreign trials not conducted 
under an IND with a drug product not exported from the United States, 
but which are subsequently included as a pivotal trial in a new drug 
application (NDA) or biologics license application (BLA), should be 
considered applicable clinical trials and therefore listed in Item 10 
of Form FDA 3674.
    Section 402(j)(1)(A)(iii)(I) of the PHS Act explicitly requires 
that the drug must be subject to section 505 of the FD&C Act or section 
351 of the PHS Act and explicitly exempts phase 1 studies from the 
definition of ``applicable drug clinical trial'' and, therefore, from 
the registration and results information submission requirements. With 
respect to the comment regarding packaging or labeling, pursuant to 
section 510 of the FD&C Act, FDA's jurisdiction extends to the 
``manufacture, preparation, propagation, compounding or processing'' of 
drugs, which term is defined to include ``repackaging or otherwise 
changing the container, wrapper, or labeling or any drug package . . . 
in furtherance of the distribution of the drug . . . from the original 
place of manufacture to the person who makes final delivery or sale to 
the ultimate consumer or user.'' The NPRM used the term ``manufacture'' 
as short-hand for all drug activities within FDA's jurisdiction. 
Therefore, a drug product that is packaged and/or labeled in the United 
States would be considered ``manufactured'' in the United States 
subject to section 505 of the FD&C Act or section 351 of the PHS Act. 
With respect to the question about a foreign trial, the issue of which 
trials should be listed on Form FDA 3674 is outside the scope of this 
rulemaking.
    Commenters requested that we change the interpretation of the terms 
``applicable drug clinical trial'' and ``applicable device clinical 
trial'' for combination products. The commenters asked that we rely on 
the ``primary mode of action'' (see 21 CFR 3.2(m)) to determine whether 
a combination product is an applicable drug clinical trial or 
applicable device clinical trial. We agree with these commenters and 
have modified the regulations to incorporate this change. FDA 
regulations in 21 CFR part 3 specify that the primary mode of action of 
a combination product is the single mode of action that provides the 
most important therapeutic action of the intended therapeutic effects 
of the combination product. A combination product with a device primary 
mode of action under 21 CFR part 3 would be considered an applicable 
device clinical trial, provided that it meets all other criteria of the 
definition under this part. A combination product with a drug primary 
mode of action under 21 CFR part 3 would be considered an applicable 
drug clinical trial, provided that it meets all other criteria of the 
definition under this part.
    In Sec.  11.10(a) of the final rule, we define ``applicable drug 
clinical trial'' to mean a controlled clinical investigation, other 
than a phase 1 clinical investigation, of a drug product subject to 
section 505 of the FD&C Act (21 U.S.C. 355) or a biological product 
subject to section 351 of the PHS Act (42 U.S.C. 262), where ``clinical 
investigation'' has the meaning given in 21 CFR 312.3 and ``phase 1'' 
has the meaning given in 21 CFR 312.21. In addition, a clinical trial 
of a combination product, where the combination product meets the 
definition in 21 CFR 3.2(e) and has a drug primary mode of action under 
21 CFR part 3 will be considered an applicable drug clinical trial, as 
long as the clinical trial of the combination product is a controlled 
clinical investigation, other than a phase 1 clinical investigation, 
and the combination product is subject to section 505 of the FD&C Act 
and/or section 351 of the PHS Act.
    We interpret the definition of applicable drug clinical trial under 
section 402(j)(1)(A)(iii) of the PHS Act as having four operative 
elements: (1) ``Controlled''; (2) ``clinical investigation''; (3) 
``other than a phase [1] clinical investigation''; and (4) ``drug 
product subject to section 505 of the Federal Food, Drug, and Cosmetic 
Act or section 351 of th[e] [Public Health Service] Act.'' A clinical 
investigation that meets all four elements is considered an applicable 
drug clinical trial. Conversely, a clinical investigation that does not 
meet one or more of these criteria would not be considered an 
applicable drug clinical trial. We have carefully considered these four 
criteria, and our interpretation follows in an order that facilitates 
the explanation.
    (1) With regard to a ``drug product subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or section 351 of th[e] [Public 
Health Service] Act,'' Sec.  11.10(a) adopts the definition of the term 
``drug'' in section 402(j)(1)(A)(vii) of the PHS Act as follows: ``a 
drug as defined in section 201(g) of the [FD&C Act] or a biological 
product as defined in section 351 of th[e] [PHS Act].'' Section 
11.10(a) also clarifies in the definition of ``applicable drug clinical 
trial'' that the term ``drug'' refers to a particular manufacturer's 
drug product. In keeping with the requirements of the FD&C Act and 
section 351 of the PHS Act, a drug product or a biological product is 
considered to be ``subject to section 505 of the [FD&C Act] or section 
351 of th[e] [PHS Act],'' as applicable, if it is the subject of an 
approved NDA or licensed BLA or if an approved NDA or licensed BLA 
would be required in order for that drug product or biological product 
to be legally marketed. A non-prescription drug product that is or 
could be marketed under an existing over-the-counter drug monograph 
(see 21 CFR 330-358) is not considered ``subject to section 505 of the 
[FD&C Act].''
    As discussed above, a clinical trial of a combination product with 
a drug primary mode of action under 21 CFR part 3 would be considered 
an applicable drug clinical trial, provided that it meets all other 
criteria of the definition under Sec.  11.10(a).
    A drug product or a biological product that is subject to section 
505 of the FD&C Act or section 351 of the PHS Act and, therefore, would 
require an approved NDA or licensed BLA in order to be marketed legally 
can be shipped for the purpose of conducting a clinical investigation 
of that product if an IND is in effect. Drug products (including 
biological products) that are being studied under an IND are considered 
``subject to section 505 of the FD&C Act'' both because (in most 
situations) the drug product being studied would need an approved NDA 
or licensed BLA to be marketed legally, and because INDs are issued by 
FDA pursuant to the authority in section 505(i) of the FD&C Act. We 
note that a substance characterized by a responsible party as a dietary 
supplement could be considered a ``drug'' subject to section 505 of the 
FD&C Act under the applicable drug clinical trial definition if the 
trial is studying a use that meets the drug definition under the FD&C 
Act. Furthermore, whether a drug product or biological product is 
subject to section 505 of the FD&C Act or section 351 of the PHS Act is 
a different question from whether a clinical investigator would need to 
obtain an IND from FDA before beginning to enroll human subjects in a 
clinical investigation. Therefore, a drug product or biological product 
being studied in a clinical investigation can be subject to section 505 
of the FD&C Act or section 351 of the PHS Act, even if a clinical 
investigation of that drug product or biological product is ``IND

[[Page 65015]]

exempt'' (i.e., does not require an IND because that clinical 
investigation falls within 21 CFR 312.2(b)). Therefore, provided it 
meets all other criteria of the definition, a clinical investigation of 
a drug product (including a biological product) can be an applicable 
drug clinical trial under section 402(j) of the PHS Act and this part, 
even if it does not require an IND. Furthermore, if a sponsor chooses 
to obtain an IND (issued under section 505 of the FD&C Act) for a 
clinical investigation of a drug product (including a biological 
product) that is not otherwise subject to section 505 of the FD&C Act 
or section 351 of the PHS Act, the sponsor, in so doing, agrees to 
regulation under section 505 of the FD&C Act, and that clinical 
investigation thus will be considered an applicable drug clinical 
trial, provided that it meets all other criteria of the definition 
under this part.
    If a clinical investigation of a drug product (including a 
biological product) includes sites both within the United States 
(including any U.S. territory) and outside of the United States, and 
any of those sites is using (for the purposes of the clinical 
investigation) a drug product or biological product that is subject to 
section 505 of the FD&C Act or section 351 of the PHS Act, we would 
consider the entire clinical investigation to be an applicable drug 
clinical trial, provided that it meets all other criteria of the 
definition under this part. However, a clinical investigation of a drug 
product (including a biological product) that is being conducted 
entirely outside of the United States (i.e., does not have any sites in 
the United States or in any U.S. territory) may not be a clinical 
investigation of a drug product or biological product subject to 
section 505 of the FD&C Act or section 351 of the PHS Act, and 
therefore not an applicable drug clinical trial, depending on where the 
drug product (including biological product) being used in the clinical 
investigation is manufactured. If the drug product (including a 
biological product) is manufactured in the United States or any U.S. 
territory, and is exported for study in another country under an IND 
(whether pursuant to 21 CFR 312.110 or section 802 of the FD&C Act), 
the drug product or biological product is considered to be subject to 
section 505 of the FD&C Act or section 351 of the PHS Act (as 
applicable), and the clinical investigation may be an applicable drug 
clinical trial, provided that it meets all other criteria of the 
definition under this part. If the drug product (including a biological 
product) is manufactured outside of the United States or its 
territories, the clinical investigation sites are all outside of the 
United States, and the clinical investigation is not being conducted 
under an IND, the drug product or biological product would not be 
considered to be subject to section 505 of the FD&C Act or section 351 
of the PHS Act, and the clinical investigation would not be an 
applicable drug clinical trial. A drug product that is packaged and/or 
labeled in the United States would be considered ``manufactured'' in 
the United States subject to section 505 of the FD&C Act or section 351 
of the PHS Act.
    (2) With regard to ``clinical investigation,'' section 
402(j)(1)(A)(iii)(II) of the PHS Act provides that the term ``clinical 
investigation'' has the meaning given to it in 21 CFR 312.3, which 
defines a ``[c]linical investigation'' as ``any experiment in which a 
drug is administered or dispensed to, or used involving, one or more 
human subjects.'' The regulation further defines an ``experiment'' as 
``any use of a drug except for the use of a marketed drug in the course 
of medical practice.''
    The FDA definition of a ``clinical investigation'' of a drug 
includes studies in which human subjects are assigned to specific 
interventions according to a research protocol. However, a situation in 
which a drug product is administered or provided to a patient as part 
of routine medical care and not under a study or research protocol is 
not considered a clinical investigation for the purposes of this 
rulemaking. A clinical investigation does not include situations in 
which, after a drug product has been administered to patients in the 
course of routine medical practice by a healthcare provider, a 
researcher not associated with the administration of the drug product 
reviews the patients' records to assess certain effects, interviews the 
patients to assess certain impacts, or collects longitudinal data to 
track health outcomes. Similarly, a situation in which a healthcare 
provider only observes and records the effects of the use of a marketed 
drug product in the course of his or her routine medical practice is 
not considered a clinical investigation under this definition. Because 
these activities are not considered clinical investigations under 21 
CFR 312.3, they are not considered applicable drug clinical trials 
under section 402(j) of the PHS Act and this part. Accordingly, in the 
approach described in Sec.  11.22(b)(2), we consider an interventional 
study (or investigation) of a drug product to be one of the criteria 
for determining an applicable drug clinical trial.
    (3) With regard to ``controlled,'' we consider a ``controlled 
clinical investigation'' to be one that is designed to permit a 
comparison of a test intervention with a control to provide a 
quantitative assessment of the effect of the drug product. The purpose 
of the control is to distinguish the effect of a drug product from 
other influences, such as spontaneous change in the course of diseases, 
the placebo effect, or biased observation. The control will provide 
data on what happens to human subjects who have not received the test 
intervention or who have received a different intervention. Generally, 
the types of controls that are used in clinical investigations are as 
follows: (1) Placebo concurrent control, (2) dose-comparison control, 
(3) no intervention concurrent control, (4) active intervention 
concurrent control, and (5) historical control (see 21 CFR 314.126(b)). 
As discussed further in the definition of ``control or controlled,'' we 
are clarifying for the purpose of this part that all interventional 
studies, both single-armed and multi-armed, with a pre-specified 
outcome measure are considered to be controlled (i.e., comparing an 
intervention against a control).
    In our view, a clinical investigation designed to demonstrate that 
an investigational drug product is bioequivalent to a previously 
approved drug product, or to demonstrate comparative bioavailability of 
two products (such as for the purposes of submitting an abbreviated new 
drug application (ANDA) under 21 U.S.C. 355(j) or an NDA as described 
in 21 U.S.C. 355(b)(2)), is considered to be a controlled clinical 
investigation. In this case, the control generally is the previously 
approved drug product. However, as discussed below, a bioequivalence or 
comparative bioavailability study that falls within the scope of 21 CFR 
320.24(b)(1), (2), or (3) shares many of the characteristics of a phase 
1 study and is considered to be a phase 1 trial (and, therefore, not an 
applicable clinical trial) in this rule.
    As discussed above, expanded access protocols under section 561 of 
the FD&C Act do not fall within the definition of ``applicable drug 
clinical trial.''
    (4) With regard to the ``other than a phase [1] clinical 
investigation'' element, an applicable drug clinical trial is defined 
in section 402(j)(1)(A)(iii) of the PHS Act to exclude phase 1 clinical 
investigations, consistent with 21 CFR 312.21. Under 21 CFR 
312.21(a)(1), a phase 1 study ``includes the initial introduction of an 
investigational new drug into humans. Phase 1 studies are typically 
closely monitored and may be

[[Page 65016]]

conducted in patients or normal volunteer subjects. These studies are 
designed to determine the metabolism and pharmacologic actions of the 
drug in humans, the side effects associated with increasing doses, and, 
if possible, to gain early evidence on effectiveness. During phase 1, 
sufficient information about the drug's pharmacokinetics and 
pharmacological effects should be obtained to permit the design of 
well-controlled, scientifically valid, phase 2 studies. The total 
number of subjects and patients included in phase 1 studies varies with 
the drug, but is generally in the range of 20 to 80.'' Under 21 CFR 
312.21(a)(2), ``[p]hase 1 studies also include studies of drug 
metabolism, structure-activity relationships, and mechanism of action 
in humans, as well as studies in which investigational drugs are used 
as research tools to explore biological phenomena or disease 
processes.'' Clinical trials that are phase 1 studies under 21 CFR 
312.21 are not applicable drug clinical trials. Clinical trials that 
are identified as phase 1/phase 2 trials (i.e., trials with 
characteristics of both phase 1 and phase 2 studies) are not considered 
phase 1 studies and may be applicable drug clinical trials if they meet 
the other specified criteria.
    Under certain circumstances, a clinical investigation designed to 
demonstrate that an investigational drug product is bioequivalent to a 
previously approved drug product, or to demonstrate comparative 
bioavailability of two products (such as for the purposes of submitting 
an ANDA under 21 U.S.C. 355(j) or an NDA as described in 21 U.S.C. 
355(b)(2)) will be considered to be a phase 1 clinical investigation 
under 21 CFR 312.21 for the purposes of determining whether a 
particular clinical trial is an applicable drug clinical trial under 
section 402(j)(1)(A)(iii) of the PHS Act. Although phase 1 clinical 
investigations are generally designed to fit sequentially within the 
development plan for a particular drug product, and to develop the data 
that will support beginning phase 2 clinical investigations, 21 CFR 
312.21(a) does not limit phase 1 clinical investigations to that 
situation. A bioequivalence or comparative bioavailability study that 
falls within the scope of 21 CFR 320.24(b)(1), (2), or (3) shares many 
of the characteristics of a phase 1 clinical investigation as described 
in 21 CFR 312.21(a), and, therefore, is considered to be a phase 1 
clinical investigation for the purposes of section 402(j) of the PHS 
Act (including in this rule). However, a bioequivalence or comparative 
bioavailability clinical trial that falls within the scope of 21 CFR 
320.24(b)(4) does not share the characteristics of a phase 1 clinical 
trial as described in 21 CFR 312.21(a), and, therefore, is not 
considered to be a phase 1 clinical trial for the purposes of section 
402(j) of the PHS Act (including in this rule).
Approved Drug
    In the NPRM, we defined ``approved drug'' in proposed Sec.  
11.10(a) to mean ``a drug that is approved for any indication under 
section 505 of the Federal Food, Drug, and Cosmetic Act or a biological 
product licensed for any indication under section 351 of the Public 
Health Service Act'' (see 79 FR 69603). We received several comments on 
this proposed definition asserting that a clinical trial for a new use 
of an approved drug product would subject the clinical trial to the 
rule's requirements. We agree that clinical trials of new uses for an 
approved drug product can be subject to the rule, if the clinical trial 
also meets the definition of an ``applicable drug clinical trial'' and 
meets the requirements of Sec.  11.22.
    In the final rule, we maintain the definition except the final rule 
definition uses the term ``use'' instead of ``indication'' for further 
clarity. As explained elsewhere, for the purposes of this rule only, we 
interpret ``use'' to include ``indication.'' We also clarified in the 
final rule that ``drug'' refers to a particular manufacturer's drug 
product. We also include the applicable U.S.C. statutory citations in 
the definition. Based on our experience with ClinicalTrials.gov and 
routine queries from users, we are also clarifying two issues here. 
First, a drug product that is not approved for any use but is 
``tentatively approved'' by FDA, as described in sections 
505(j)(5)(B)(iv)(II)(dd)(AA) and (BB) of the FD&C Act, is not 
considered to be an approved drug for the purposes of section 402(j) of 
the PHS Act, and therefore is not included in the rule's definition of 
``approved drug.'' Second, a drug product approved by FDA but for which 
approval is later withdrawn under section 505(e) of the FD&C Act, and 
that is no longer approved for any use, is not considered an approved 
drug for purposes of this part.
Approved or Cleared Device
    In the NPRM, we defined ``approved or cleared device'' in Sec.  
11.10(a) to mean ``a device that is cleared for any indication under 
section 510(k) of the Federal Food, Drug, and Cosmetic Act or approved 
for any indication under sections 515 or 520(m) of that Act.'' As we 
explained, section 402(j)(2)(D)(ii)(II) of the PHS Act uses the phrase 
``a device that was previously cleared or approved'' to refer to a 
subset of devices that, if studied in an applicable device clinical 
trial, would trigger certain requirements under this proposed part with 
respect to the public posting of clinical trial information (79 FR 
69603). Accordingly, we proposed defining the term ``approved or 
cleared device'' to refer to any device that has been approved or 
cleared under the applicable section of the FD&C Act for any 
indication, even if the applicable device clinical trial studies the 
device for an unapproved or uncleared use. We received several comments 
on this definition asserting that a clinical trial for a new use of an 
approved or cleared device would subject the clinical trial to the 
rule's requirements. We agree that clinical trials of new uses for an 
approved or cleared device can be subject to the rule, if the clinical 
trial also satisfies the ``applicable device clinical trial'' 
definition elements and other triggering requirements, such as Sec.  
11.22 for registration.
    The final rule maintains the definition, except that the final rule 
definition uses the term ``use'' instead of ``indication'' for further 
clarity. As explained elsewhere, for the purposes of this rule only, we 
interpret ``use'' to include ``indication.'' We also clarified that the 
term ``device'' refers to a particular manufacturer's device product 
and include the applicable U.S.C. statutory citations in the 
definition.
Arm
    In the NPRM, we defined ``arm'' in Sec.  11.10(a) to mean ``a pre-
specified group or subgroup of human subjects in a clinical trial 
assigned to receive specific intervention(s) (or no intervention) 
according to a protocol.'' We received no comments on this definition, 
and we maintain the definition in the final rule, except the final rule 
definition modifies the phrase ``human subjects'' to ``human 
subject(s)'' for further clarity.
Clinical Study
    The NPRM did not propose a definition of ``clinical study'' in 
Sec.  11.10(a) but we are including the term and data element in this 
final rule. The term ``clinical study'' is used in the statutory 
definition of ``applicable device clinical trial'' (see section 
402((j)(1)(A)(ii)(I) of the PHS Act), and the NPRM discussed ``clinical 
study'' in the context of this definition (79 FR 69599). ``Clinical 
study'' is also used in the definition of ``clinical trial'' in Sec.  
11.10(a) of this regulation. To provide

[[Page 65017]]

further clarity, we define the term ``clinical study'' in Sec.  
11.10(a) to mean ``research according to a protocol involving one or 
more human subjects to evaluate biomedical or health-related outcomes, 
including interventional studies and observational studies.'' This 
definition is consistent with our discussion of the term's meaning in 
the NPRM (79 FR 69599).
Clinical Trial
    In the NPRM, we defined ``clinical trial'' in Sec.  11.10(a) to 
mean ``a clinical investigation or a clinical study in which human 
subjects are prospectively assigned, according to a protocol, to one or 
more interventions (or no intervention) to evaluate the effects of the 
interventions on biomedical or health-related outcomes.'' As we 
explained, the definition explicitly included biomedical in addition to 
health-related outcomes because we have defined the term ``clinical 
trial'' to include phase 1 studies, which may measure physiological 
changes that are biomedical in nature but may not be related to health 
effects (79 FR 69603). We defined the term ``clinical trial'' to 
include phase 1 studies, in part, because phase 1 studies may be 
voluntarily submitted under section 402(j)(4)(A) of the PHS Act. The 
restriction of the scope of this definition to clinical investigations 
or studies in which human subjects are prospectively assigned to 
interventions was intended to distinguish clinical trials 
(interventional studies) from observational studies, in which the 
investigator does not assign human subjects to interventions, but, for 
example, observes patients who have been given interventions in the 
course of routine clinical care. Observational studies may also include 
retrospective reviews of patient medical records or relevant 
literature.
    Several commenters addressed the proposed definition. Many 
commenters requested that we define ``clinical trial'' to mean any 
trial in which a drug, biologic, device, radioactive material, or any 
other foreign body is introduced into the human body. We do not use 
this alternative definition because it includes the use of drugs, 
biologics, devices, or radioactive materials provided to a patient as 
part of routine medical care, such as in observational studies. Other 
commenters requested that we resolve any differences between the 
proposed rule's definition and the definitions of ``clinical trial'' 
used by NIH and ICMJE, and the definition of ``qualified clinical 
trial'' used by the Centers for Medicare & Medicaid Services. These 
commenters expressed concern that any differences in definitions could 
lead to inconsistencies in how responsible parties must register and 
report results information across these contexts. We note that the 
definition of ``clinical trial'' we proposed is consistent with the 
NIH, ICMJE, and WHO definitions, although the scope of what needs to be 
registered differs from other contexts because of the requirements of 
section 402(j) of the PHS Act. We note that the ClinicalTrials.gov 
system allows for the reporting of studies that are not subject to (or 
are independent of) requirements under section 402(j) of the PHS Act, 
including under different timelines and with additional information, 
which means that reporting in these other contexts is not impeded. 
Finally, the proposed definition of ``clinical trial'' did not 
distinguish between approved, licensed, or cleared uses and unapproved, 
unlicensed, or uncleared uses, and therefore human testing of an 
approved drug or device for a new use can fall within the scope of a 
clinical trial. These clinical trials, though, must meet the definition 
of an ``applicable clinical trial'' and other conditions of the 
regulation in order for registration and results information reporting 
to be required under section 402(j) of the PHS Act.
    In the final rule, we maintain the proposed definition for 
``clinical trial,'' except the final rule definition modifies the 
phrase ``human subjects'' to ``human subject(s)'' for further clarity. 
In terms of defining the scope of a clinical trial, we recognize that 
it may sometimes be difficult to determine whether two or more closely 
related studies should be considered a single clinical trial for the 
purposes of this part. In general, a clinical trial has a defined group 
of human subjects who are assigned to interventions, and the collected 
data are assessed and analyzed, based on a protocol. However, when two 
different studies use the same protocol but involve different groups of 
human subjects, and the plan is to analyze the data from the two 
studies separately, the two studies should be considered separate 
clinical trials. This is distinct from a situation in which multiple 
sites of the same clinical trial follow the same protocol with 
different groups of human subjects, but the intention is to analyze the 
primary outcome measure(s) with pooled data from all the study sites. 
Additionally, when some (or all) human subjects from a clinical trial 
are offered the opportunity to participate in an additional clinical 
trial that was not part of the original protocol (e.g., a follow-on 
study), and participation requires a separate consent process, the 
additional clinical trial would generally be considered a separate 
clinical trial.
Clinical Trial Information
    In the NPRM, we defined ``clinical trial information'' in Sec.  
11.10(a) to mean ``the data elements, including clinical trial 
registration information and clinical trial results information, the 
responsible party is required to submit to ClinicalTrials.gov under 
this part.'' As we explained, section 402(j)(1)(A)(iv) of the PHS Act 
expressly provides that ``[c]linical trial information'' means ``those 
data elements that the responsible party is required to submit under 
paragraph (2) or under paragraph (3)'' of section 402(j) of the PHS Act 
(79 FR 69603). Paragraph (2) refers to registration requirements, 
including the registration information that is included in proposed 
Sec.  11.28, and paragraph (3) refers to results information submission 
requirements, including results information in proposed Sec.  11.48. 
Section 402(j)(3)(I)(v) of the PHS Act also expressly provides that 
adverse event information included in the data bank pursuant to 
paragraph (3)(I) ``is deemed to be clinical trial information included 
in such data bank pursuant to subparagraph (C).''
    We received no comments on this definition. We are clarifying on 
our own initiative that clinical trial information is submitted to 
ClinicalTrials.gov as specified in section 402(j) of the PHS Act and as 
specified in the final regulations; we also corrected a typographical 
error. Therefore, for the purposes of the final rule, clinical trial 
information means ``the data elements, including clinical trial 
registration information and clinical trial results information, that 
the responsible party is required to submit to ClinicalTrials.gov, as 
specified in section 402(j) of the Public Health Service Act (42 U.S.C. 
282(j)) and this part.''
Clinical Trial Registration Information
    In the NPRM, we defined ``clinical trial registration information'' 
in Sec.  11.10(a) to mean ``the data elements that the responsible 
party is required to submit to ClinicalTrials.gov, as listed under 
Sec.  11.28.'' We received no comments on this definition. We clarify 
that the full set of data elements specified in Sec.  11.28 must be 
submitted in order to register an applicable clinical trial for 
applicable clinical trials with an initiation date on or after the 
effective date of the final rule, as discussed further in section IV.F. 
Effective Date, Compliance Date, and Applicability of Requirements in 
this part. For

[[Page 65018]]

applicable clinical trials with an initiation date before the effective 
date of the final rule, clinical trial registration information must be 
submitted as specified in section 402(j)(2)(A)(ii) of the PHS Act. 
Therefore, for the purposes of the final rule, clinical trial 
registration information means ``the data elements that the responsible 
party is required to submit to ClinicalTrials.gov, as specified in 
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) or Sec.  11.28, as applicable.''
Clinical Trial Results Information
    In the NPRM, we defined ``clinical trial results information'' in 
Sec.  11.10(a) to mean ``the data elements that the responsible party 
is required to submit to ClinicalTrials.gov under Sec.  11.48 or, if 
applicable, Sec.  11.60(a)(2)(i)(B).'' We noted that clinical trial 
results information includes the adverse event information set forth in 
proposed Sec.  11.48(a)(4) pursuant to section 402(j)(3)(I)(v) of the 
PHS Act, which indicates that the adverse event information included in 
the registry and results data bank under section 402(j)(3)(I) of the 
PHS Act ``is deemed to be clinical trial information included in [the] 
data bank pursuant to [section 402(j)(3)(C) of the PHS Act]'' (79 FR 
69603). We received no comments on this definition.
    We clarify in the final rule that the full set of data elements 
under Sec.  11.48 must be submitted when results information is 
submitted for applicable clinical trials with a primary completion date 
on or after the effective date of the final rule, as discussed further 
in section IV.F. Effective Date, Compliance Date, and Applicability of 
Requirements in this part. For applicable clinical trials with a 
primary completion date before the effective date of the final rule, 
results information must be submitted as specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the PHS Act. We also note that, under 
Sec.  11.60, if a responsible party seeks to submit clinical trial 
results information voluntarily for an applicable clinical trial with a 
primary completion date on or after the effective date and for which 
clinical trial registration information is not submitted, clinical 
trial results information is defined to include the data elements in 
Sec.  11.48 and the data elements in Sec.  11.60(b)(2)(i)(B) or 
(c)(2)(i)(B), as applicable. Therefore, for the purposes of the final 
rule, ``clinical trial results information'' means ``the data elements 
that the responsible party is required to submit to ClinicalTrials.gov, 
as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public 
Health Service Act (42 U.S.C. 282(j)(3)(C) and (I)) or Sec.  11.48, as 
applicable. If a responsible party submits clinical trial results 
information voluntarily for a clinical trial, clinical trial results 
information also means Sec.  11.60(b)(2)(i)(B) or Sec.  
11.60(c)(2)(i)(B), as applicable.''
Comparison Group
    In the NPRM, we defined ``comparison group'' in proposed Sec.  
11.10(a) to mean ``a grouping of human subjects in a clinical trial, 
other than an arm, that is used in analyzing the results data collected 
during the clinical trial'' (see 79 FR 69604). We received no comments 
on this definition and maintain the definition in the final rule, 
except the final rule definition clarifies that the grouping ``is or 
may be'' used in analyzing the results data.
    We clarify that, in some trials, results data are not analyzed 
according to the arms to which human subjects were assigned; the data 
may be combined into other groupings for analysis. For example, in a 
cross-over study, human subjects in one arm of a trial may receive 
intervention X for a period of time followed by intervention Y, while 
human subjects in another arm of the trial may receive intervention Y 
for a period of time followed by intervention X. In such studies, 
outcome measures and adverse events are often analyzed and reported by 
intervention (e.g., results for human subjects when receiving 
intervention X versus results for human subjects when receiving 
intervention Y), rather than by arm.[Ref. 84] When submitting results 
information to ClinicalTrials.gov under Sec.  11.48, responsible 
parties must submit data in the way in which they were analyzed, 
whether by arm (as defined above) or by comparison group. We note that, 
in general, the set of comparison groups for a particular trial should 
account for all of the participants in the analysis.
Completion Date
    In the NPRM, we defined ``completion date'' in Sec.  11.10(a) to 
mean ``for a clinical trial, the date that the final subject was 
examined or received an intervention for the purposes of final 
collection of data for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was terminated. In 
the case of clinical trials with more than one primary outcome measure 
with different completion dates, this term refers to the date upon 
which data collection is completed for all of the primary outcomes.''
    As we explained in the NPRM, ``completion date'' is defined in 
section 402(j)(1)(A)(v) of the PHS Act as ``the date that the final 
subject was examined or received an intervention for the purposes of 
final collection of data for the primary outcome, whether the clinical 
trial concluded according to the pre-specified protocol or was 
terminated'' (79 FR 69604). This term has particular significance 
because the responsible party is required to submit ``the expected 
completion date'' to ClinicalTrials.gov upon registration (see section 
402(j)(2)(A)(ii)(I)(jj) of the PHS Act) and submit clinical trial 
results information for certain applicable clinical trials not later 
than 1 year after the earlier of the estimated or the actual completion 
date (see sections 402(j)(3)(E)(i)(I) and (II) of the PHS Act), unless 
the deadline is delayed or extended using one of the mechanisms 
described in Sec.  11.44. For purposes of the proposed rule, we 
interpreted ``expected completion date'' in section 
402(j)(2)(A)(ii)(I)(jj) of the PHS Act to be synonymous with 
``estimated completion date'' in section 402(j)(3)(E)(i)(I) of the PHS 
Act.
    The proposed rule adopted the statutory definition of ``completion 
date'' with respect to applicable clinical trials but proposed one 
modification. For a clinical trial that has multiple primary outcome 
measures each with a different date on which the final human subject is 
examined or receives an intervention for the purposes of final data 
collection, we proposed that ``completion date'' would refer to the 
date on which data collection is completed for all of the primary 
outcomes. The proposed rule also defined ``completion date'' for a 
pediatric postmarket surveillance of a device that is not a clinical 
trial as ``the date on which the final report summarizing the results 
of the pediatric postmarket surveillance is submitted to FDA.'' The 
proposed rule also noted that the current implementation of 
ClinicalTrials.gov uses the term ``primary completion date'' to refer 
to ``completion date,'' as defined in section 402(j)(1)(A)(v) of the 
PHS Act. This was done in the data bank to alert those submitting data 
to ClinicalTrials.gov under section 402(j) of the PHS Act that the 
definition of ``completion date'' differs from that of the term ``study 
completion date,'' which refers to the date on which the last subject 
makes the last visit as part of the clinical trial (commonly referred 
to as Last Patient Last Visit (LPLV)) and is also collected by 
ClinicalTrials.gov as an optional data element [Ref. 85]. We stated 
that

[[Page 65019]]

ClinicalTrials.gov would begin to use the term ``completion date'' once 
the final regulations take effect and that we would include a notice on 
ClinicalTrials.gov to alert responsible parties to this change in data 
element name.
    We received comments on this definition. Commenters expressed 
concern about confusion and possible misinterpretation among 
responsible parties and the public about the definition. Many of these 
commenters suggested replacing ``completion date'' with ``primary 
completion date'' or ``primary outcome measure completion date,'' 
noting that ClinicalTrials.gov has used ``primary completion date'' 
since the enactment of FDAAA. Several other commenters requested that 
``completion date'' be redefined to mean LPLV. In addition, several 
commenters supported the NPRM position that when there are multiple 
primary outcome measures, the completion date is interpreted as ``the 
date upon which data collection is completed for all of the primary 
outcomes.'' Two commenters also requested further clarification in the 
definition about the term's application to trials that are terminated, 
particularly when the decision to terminate occurs more than 1 year 
after the last previously enrolled subject reached the data collection 
point for a primary outcome measure, but before the enrollment goals 
are reached. One commenter requested clarification regarding cases in 
which sample analysis occurs after a patient's last visit. We did not 
receive any comments on the definition of ``completion date'' for a 
pediatric postmarket surveillance of a device that is not a clinical 
trial.
    We generally maintain the definition of ``completion date'' in 
Sec.  11.10(a) in the final rule because the statute explicitly defines 
the term in this way. We have made a minor modification, consistent 
with the statutory definition, to clarify that the term ``clinical 
trial'' includes an applicable clinical trial; we have also clarified 
that ``device'' means ``device product.'' However, we agree with the 
comments, so we are clarifying that ``completion date'' is synonymous 
with ``primary completion date,'' to avoid confusion among researchers 
and the public. We have revised the definition of ``completion date'' 
to state that for purposes of this part, the term ``completion date'' 
is referred to as ``primary completion date.'' We use the term 
``primary completion date'' in this preamble and in the codified 
provisions. We also add to final Sec.  11.10(a) the term ``primary 
completion date,'' which is defined as and refers to the definition of 
``completion date.'' In addition, ClinicalTrials.gov will continue to 
use the term ``primary completion date'' and the related data element 
to refer to ``completion date,'' as defined in Sec.  11.10(a) of the 
final rule. We believe that this approach balances the need to 
implement terms that are specifically defined by section 402(j) of the 
PHS Act while being responsive to commenters' concerns that the 
statutory definition of ``completion date'' differs from the way the 
term is commonly used by the clinical research community. This change 
will also help clarify the meaning of the statutory term for users.
    Also, with regard to comments suggesting that ``completion date'' 
should mean LPLV, we note that adopting such an approach would be 
inconsistent with the statutory definition. However, we do add the 
Study Completion Date data element, which is currently an optional data 
element in ClinicalTrials.gov, as a required component of clinical 
trial registration information in the final rule, and we include a 
definition of ``study completion date'' in Sec.  11.10(a). (See also 
the discussion of ``study completion date'' later in this preamble.) As 
supported by the commenters, we also maintain the definitional element 
for multiple primary outcomes as proposed, i.e., that ``completion 
date'' (and ``primary completion date'') means the date on which data 
collection is completed for all of the primary outcomes. As explained 
in the NPRM, while this approach may delay the submission and public 
availability of clinical trial results information for the earliest 
primary outcomes, we expect any such delays to be minimal (79 FR 
69604). Most clinical trials registered on ClinicalTrials.gov to date 
specify only a single primary outcome, and those with multiple primary 
outcomes have measurement time frames that are relatively close in 
time.
    Moreover, this approach avoids cases in which the submission of 
clinical trial results information would be required before data 
collection has been completed for all of the primary outcomes in a 
clinical trial and before all of the results data for the primary 
outcomes have been ``unblinded,'' a situation that could threaten the 
scientific integrity of the clinical trial. While a responsible party 
could request a good-cause extension of the results information 
submission deadline in such a situation under Sec.  11.44(e), the 
definition in the final rule should reduce the number of good-cause 
extension requests that responsible parties might be expected to file. 
Submission of results information for all primary outcomes at the same 
time will also aid in the interpretation of clinical trial results 
information by providing users of ClinicalTrials.gov with a more 
comprehensive set of results information from the clinical trial, 
rather than results information for only some of the primary outcomes.
    In response to the commenters seeking clarification about the 
completion date for terminated clinical trials, we do not believe that 
any changes to the definition are needed. Under the definition of 
``completion date,'' the completion date of a terminated trial is the 
date that the final subject was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, 
which may be on or before the trial termination. By ``final subject,'' 
the definition means the last subject who was examined or received an 
intervention before the trial was terminated. We do not interpret this 
definition as meaning that all enrolled subjects must be examined or 
receive an intervention before the clinical trial is terminated in 
order for the trial to reach the completion date. As described in the 
discussion of Sec.  11.48 in this preamble, the responsible party would 
provide the clinical trial results information that had been collected 
for those subjects who were examined or received the intervention up to 
the point of termination. In response to one commenter, we clarify that 
if an applicable clinical trial is terminated on a date that is after 
the last subject was examined or received an intervention for a primary 
outcome measure, the completion date would still be the date that the 
final subject was examined or received an intervention for the primary 
outcome before trial termination, regardless of when the decision to 
terminate was made and whether the enrollment goals were reached. In 
this scenario, it is possible that the decision to terminate the trial 
could occur after the standard submission deadline for study results 
information under Sec.  11.44(a) (i.e., 1 year after the primary 
completion date) or may occur during a period that is much less than 1 
year after the primary completion date. We clarify that upon trial 
termination, a responsible party may submit a request demonstrating 
good-cause for extending the results information submission deadline as 
specified in Sec.  11.44(e). Finally, in response to another comment, 
we do not agree that the date of sample analysis after a subject's last 
examination or receipt of the intervention should qualify as the 
``completion date'' under the definition. We view sample analysis as a 
separate

[[Page 65020]]

step from data collection; moreover, including it in the definition of 
``completion date'' would be inconsistent with the statutory 
definition. We also note that an analysis could be conducted months or 
even years after the last subject was examined or received an 
intervention, which could significantly delay the reporting of results 
information under Sec.  11.44. We clarify that if there are extenuating 
circumstances that cause a delay in sample analysis that interferes 
with meeting the results information submission deadline specified in 
Sec.  11.44, the responsible party may submit a request for extending 
the results information submission deadline as specified in Sec.  
11.44(e).
    In Sec.  11.10(a) of the final rule, we define ``completion date'' 
to mean ``for a clinical trial, including an applicable clinical trial, 
the date that the final subject was examined or received an 
intervention for the purposes of final collection of data for the 
primary outcome, whether the clinical trial concluded according to the 
pre-specified protocol or was terminated. In the case of clinical 
trials with more than one primary outcome measure with different 
completion dates, this term refers to the date on which data collection 
is completed for all of the primary outcomes. For a pediatric 
postmarket surveillance of a device product that is not a clinical 
trial, completion date means the date on which the final report of the 
pediatric postmarket surveillance of the device product is submitted to 
FDA. For purposes of this part, completion date is referred to as 
`primary completion date.'''
Control or Controlled
    In the NPRM, we defined ``control or controlled'' in Sec.  11.10(a) 
to mean ``with respect to a clinical trial, that data collected on 
human subjects in the clinical trial will be compared to concurrently 
collected data or to non-concurrently collected data (e.g., historical 
controls, including a human subject's baseline data), as reflected in 
the pre-specified primary or secondary outcome measures.'' ``Control'' 
and ``controlled'' are terms used in sections 402(j)(1)(A)(ii)(I) and 
(iii)(I) of the PHS Act as part of the definitions of ``applicable 
device clinical trial'' and ``applicable drug clinical trial,'' 
respectively. As we explained in the NPRM, the definition is consistent 
with (but broader than) FDA regulations that define the related 
concepts of ``adequate and well-controlled studies'' for drugs (21 CFR 
314.126(b)(1) and (2)) and ``a well-controlled clinical investigation'' 
for devices (21 CFR 860.7(f)) (79 FR 69604). FDA has also adopted as 
guidance the ICH E10: Choice of Control Group and Related Issues in 
Clinical Trials, which describes considerations to be used in choosing 
a control group [Ref. 86]. In FDA regulations, the critical attribute 
of a well-controlled clinical trial, which is the intent of any 
controlled trial, is ``a design that permits a valid comparison with a 
control to provide a quantitative assessment'' of the effect of the 
investigational intervention (see 21 CFR 314.126(b)(2)). The FDA 
regulations recognize several types of concurrent controls (e.g., 
active control) and the non-concurrent, historical control. This can 
refer to a control group for which data were collected at a different 
time or place but can also refer to a clinical trial in which subjects 
serve as their own controls (e.g., the clinical trial measures change 
from baseline).
    We explained in the NPRM that, for purposes of determining whether 
it is an applicable clinical trial subject to this part, the proposed 
definition of ``control or controlled'' would include any clinical 
trial with multiple concurrent arms (79 FR 69574 and 69605). In 
addition, we explained that some single-arm clinical trials would also 
be included in the definition. Such trials would include single-arm 
trials of FDA-regulated products that, as specified in their protocols, 
intend to evaluate an effect by comparing measures taken after an 
intervention to baseline measures taken from the participants prior to 
the intervention. Many of these studies have explicitly defined 
``change from baseline'' measures identified in their protocols, i.e., 
they are designed to compare a measure taken after an intervention to 
the participant's state prior to the intervention. Other single-arm 
trials that would be considered controlled include, for example, 
studies with an identified measure of ``response rate'' or measures in 
which the state prior to or without the intervention can be assumed 
(e.g., studies in conditions that do not resolve over the time period 
studied without the intervention, such as certain types of cancer).
    We proposed in Sec.  11.10(b)(5) that the Study Design data element 
include, for single-armed studies, whether or not the clinical trial is 
controlled, as specified by the protocol or SAP. Accordingly, proposed 
Sec.  11.28(a)(i)(v) would require that a responsible party that 
registers a single-arm trial provide this information. We also proposed 
in Sec.  11.22(b) that a trial or study that was described accurately 
by the data elements listed in Sec.  11.22(b)(1) or (2) would be 
considered to meet the definition of an applicable clinical trial. We 
invited comments on the proposed approach for identifying single-arm 
trials that would be considered controlled and on alternative ways to 
identify such trials (79 FR 69574). In particular, we invited comments 
on whether there are other specific, objective features of clinical 
trials that could serve as the basis for differentiating between 
single-arm studies that are and are not controlled. We also invited 
comments on and information about the types of single-arm trials that 
meet the other criteria for an applicable clinical trial and do or do 
not meet our proposed definition of ``controlled.''
    We received several comments on the definition. One commenter 
supported the proposed definition, particularly including single-arm 
studies. Several commenters sought clarifications of the definition. 
Some commenters stated that all interventional studies in humans should 
be considered controlled for the purposes of the NPRM, including 
single-arm studies. Some commenters indicated that ambiguity around the 
definition of controlled could result in responsible parties making 
erroneous, subjective assessments and failing to register or submit 
information for certain trials. One of these commenters suggested that 
if the definition was not clarified to include all interventional 
studies, the rule should require a responsible party registering a 
single-arm study without a control to explain the trial's purpose, 
ethical approval, justification for the lack of a control, and 
knowledge to be obtained. Another commenter requested that the final 
rule amend the definition of ``controlled'' to include single-arm 
studies assessing changes from historical controls or baseline or, 
alternatively, revise the definition to clarify that all single-arm 
trials are considered controlled. Two commenters indicated that all 
single-arm interventional studies should be considered controlled by 
asserting that all such studies that otherwise meet the definitional 
criteria specified in proposed Sec.  11.22(b) are considered to be 
applicable clinical trials. One of these commenters emphasized that 
single-arm studies should be considered controlled because they compare 
collected data to other information (e.g., participant baseline data); 
the other commenter objected that the NPRM's proposal to distinguish 
controlled clinical trials from other trials is potentially confusing--
especially in light of FDA's regulatory definition of ``[adequate and] 
well-controlled'' trials, and asserted that the ``controlled'' 
definition was

[[Page 65021]]

unnecessary for the applicable clinical trial determination. The 
commenter also noted that removing the ``controlled'' criterion and 
requiring results information reporting for all trials would better 
align the rule to the EU Clinical Trials Regulation. Finally, several 
commenters stated that no control groups should be allowed in clinical 
trials involving life-threatening conditions.
    Other commenters asserted that the current definition of ``control 
or controlled'' is too broad. One stated that only multi-armed studies 
are controlled and that the standard use of the term ``controlled'' in 
the scientific community worldwide includes a comparison group. The 
commenter requested that for any single arm studies to be defined as 
controlled, a separate proposed rule with this approach should be 
issued for comment. Two commenters also expressed concerns that the 
meaning of ``controlled'' in the NPRM's definition differed from the 
FDA's definition of ``adequate and well controlled,'' and one suggested 
harmonizing the final rule with the EU Clinical Trials Regulation 
requirements for results information reporting but limiting the scope 
to ``adequate and well controlled'' studies under 21 CFR 314.126.
    Another commenter suggested that the proposed definition may be too 
broad and that it could conceivably encompass any interventional study 
in which patient data are captured at baseline and post-intervention. 
The commenter suggested that to be included in the definition, a 
single-arm trial would need to be able to plausibly distinguish the 
effect of an intervention from other causes and, furthermore, that the 
definition could be revised to be limited to trials ``designed to 
permit a comparison of a test intervention with a control to provide a 
quantitative assessment of the effect of an intervention.'' The 
commenter also requested that NIH provide additional guidance for 
responsible parties on how to determine whether the study is 
controlled. Another commenter stated that single-arm phase 2 studies 
should be considered controlled only if they involve the comparison of 
primary and secondary endpoints and adverse events with a specific 
historical cohort. The commenter stated that a trial should not be 
considered controlled simply by the use of a pre-specified benchmark 
for the primary endpoint.
    We have reconsidered our proposed approach based on the comments 
and determined that all interventional studies with pre-specified 
outcome measures should be considered controlled under the definition 
in the final rule, whether the trial has a single group of human 
subjects or involves two or more concurrent groups of human subjects. 
We agree with those comments suggesting that any single-arm 
interventional trial with pre-specified outcome measure(s) be 
considered controlled since it implicitly or explicitly compares the 
effect of the intervention to some other information (e.g., patient 
baseline). Under our definition of ``interventional,'' the effect of 
the intervention on biomedical or other health-related outcomes is 
evaluated according to a research protocol. In order to assess the 
effect of the experimental intervention, plans for single-arm trials 
identify how the outcomes will be measured. Either explicitly or 
implicitly, the measured outcomes are compared with either the patients 
themselves prior to the intervention or historical data from other 
patients (or subjects). Therefore, a single-arm interventional study 
with pre-specified outcome measure(s) would always involve the use of 
some type of control to evaluate the intervention's effect.
    This revised approach simplifies the rule's application by making 
it clearer, less subjective, and easier for responsible parties to 
implement. For example, the revised approach eliminates the need for a 
responsible party to rely on a subjective determination of 
``controlled'' for single-group studies. In addition, the approach 
minimizes the chances of an applicable clinical trial not being 
registered (and subsequently not reporting results information). The 
approach also harmonizes the definition of ``control or controlled'' 
for trials of drugs and device products. Importantly, we believe the 
approach supports the purpose of the provisions of section 402(j) of 
the PHS Act to make more information about clinical trials available to 
the public. Accordingly, Sec.  11.10(a) of the final rule defines 
``control or controlled'' to include not only concurrent control 
groups, but also non-concurrent controls, which would include all 
single-arm clinical trials with pre-specified outcome measures. In 
addition, the following clarification is added to the end of the 
definition: ``For purposes of this part, all clinical trials with one 
or more arms and pre-specified outcome measure(s) are controlled.'' We 
wish to note, however, that although in certain circumstances some 
types of expanded access use under section 561 of the FD&C Act arguably 
might fall within this definition, as discussed above, expanded access 
use is not considered to fall within the definition of ``applicable 
drug clinical trial.''
    The definition of ``control or controlled'' in the final rule is 
consistent with the types of controls recognized by FDA and the ICH E10 
guidance (i.e., recognition of both concurrent and non-concurrent 
controls) [Ref. 86]. The definition, however, is necessarily broader 
than the definition of ``adequate and well-controlled'' used in FDA 
regulations and the ICH E10 guidance because the purpose of this term, 
as used in this rule, is different from the more limited circumstances 
in which use of a non-concurrent control constitutes an ``adequate and 
well-controlled'' clinical trial, i.e., one that might serve to support 
marketing authorization. Our definition does not reflect a 
consideration of the adequacy or appropriateness of the control or the 
adequacy of the study design, e.g., whether adequate steps were taken 
to minimize bias. Because the transparency goals underlying this final 
rule also apply to clinical trials that may not be considered 
``adequate and well-controlled'' under FDA regulations, we conclude 
that responsible parties are required to register and submit results 
information for such trials. Therefore, the definitions of ``applicable 
device clinical trial'' and ``applicable drug clinical trial'' include 
clinical trials with pre-specified outcome measures, whether using 
concurrent or non-concurrent controls, regardless of whether they would 
be considered ``adequate and well-controlled.''
Device
    In the NPRM, we defined ``device'' in Sec.  11.10(a) to mean ``a 
device as defined in section 201(h) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321(h))'' as specified in section 
402(j)(1)(A)(vi) of the PHS Act (see 79 FR 69668). We received no 
comments on this definition, and we retain it without modification in 
the final rule.
Director
    In the NPRM, we defined ``Director'' in Sec.  11.10(a) to mean the 
NIH Director or any official of the NIH to whom the NIH Director 
delegates authorities granted in 42 U.S.C. 282(j) (see 79 FR 69668). We 
received no comments on this definition, and we maintain it in the 
final rule, except that we clarify the statutory reference as ``section 
402(j) of the Public Health Service Act (42 U.S.C. 282(j)).''
Drug
    In the NPRM, we defined ``drug'' in Sec.  11.10(a) to mean ``a drug 
as defined in

[[Page 65022]]

section 201(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
321(g)) or a biological product as defined in section 351 of the Public 
Health Service Act (42 U.S.C. 262),'' as specified in section 
402(j)(1)(A)(vii) of the PHS Act (see 79 FR 69668). We received no 
comments on this definition, and we retain it without modification in 
the final rule.
Enroll or Enrolled
    In the NPRM, we defined ``enroll or enrolled'' in Sec.  11.10(a) to 
mean ``a human subject's agreement to participate in a clinical trial, 
as indicated by the signing of the informed consent document(s).'' As 
we explained, ``enroll or enrolled'' is a term used in section 
402(j)(1)(A)(viii)(I) of the PHS Act as part of the definition of 
``[o]ngoing'' and in 402(j)(2)(C)(ii) of the PHS Act as one of the 
criteria used to establish the deadline by which a responsible party is 
required to submit clinical trial registration information (79 FR 
69605).
    We received comments on this definition. Several commenters 
asserted that the proposed definition of ``enrolled'' may be 
inconsistent with the way the term is used for presenting information 
about device studies in the Summary of Safety and Effectiveness or the 
510(k) Summary, which are publicly available on FDA's Web site and to 
which ClinicalTrials.gov is required to link. The commenters stated 
that device trials can include subjects who, according to the trial 
design, provide consent for screening but enroll only those subjects 
who subsequently pass screening. The commenters asserted that the 
definition of ``enrolled'' proposed in the NPRM would require the 
inclusion of those subjects who provide consent for screening but do 
not pass screening, thereby resulting in an inconsistency in enrollment 
numbers reported on the ClinicalTrials.gov Web site and FDA's 510(k) 
Summary or Summary of Safety and Effectiveness, which would lead to 
confusion.
    We acknowledge that there may be differences in the numbers of 
participants who sign an informed consent, are screened for 
participation, and are eligible to participate in the clinical trial. 
Therefore, we clarify that the definition of ``enroll or enrolled'' 
does not include ``potential subjects who are screened for the purpose 
of determining eligibility for the trial but do not participate in the 
trial, unless otherwise specified by the protocol.''
    We note that, in some cases, there may be a separate informed 
consent document for trial screening and trial participation; the 
signing of the latter aligns with the proposed definition. We clarify 
that when there is only one informed consent for both trial screening 
and trial participation, and it is signed prior to participant 
screening, a participant is not considered enrolled until he or she has 
met all the eligibility criteria assessed during screening, unless the 
participant is considered enrolled specifically by the protocol. We 
clarify that for the purposes of the registration submission 
requirement in Sec.  11.24, clinical trial registration information is 
required to be submitted no later than 21 calendar days after the first 
subject signs the informed consent form for trial participation. When 
there is only one informed consent for both trial screening and trial 
participation, we clarify that clinical trial registration information 
is required to be submitted pursuant to Sec.  11.24 no later than 21 
calendar days after the first subject signs the informed consent form 
and begins trial participation, in accordance with the protocol.
    Commenters also stated that the definition of ``enroll or 
enrolled'' should be expanded to include ``unless specifically defined 
differently in the protocol.'' The commenters asserted that not all 
studies consider the signing of informed consent to be the point of 
enrollment, and that the signing of informed consent may not be 
required. Moreover, based on these particular comments, we believe the 
wording of the proposed definition may inadvertently suggest that a 
written signature is the only acceptable confirmation of a subject's 
consent to participate. We have modified the definition to account for 
situations in which consent is provided by a subject's legally 
authorized representative (e.g., a family member) because the subject 
is not able to provide informed consent because of, for example, mental 
incapacity. To address these and the previous comments, we are revising 
the definition of ``enroll or enrolled'' to mean ``a human subject's, 
or their legally authorized representative's, agreement to participate 
in a clinical trial following completion of the informed consent 
process as required in 21 CFR part 50 and/or 45 CFR part 46, as 
applicable. For the purposes of this part, potential subjects who are 
screened for the purpose of determining eligibility for the trial, but 
do not participate in the trial, are not considered enrolled unless 
otherwise specified by the protocol.''
Human Subjects Protection Review Board
    In the NPRM, we defined ``human subjects protection review board'' 
in Sec.  11.10 to mean an ``institutional review board (IRB) as defined 
in 21 CFR 50.3 and 45 CFR 46.102 (or any successor regulation), as 
applicable, or equivalent independent ethics committee that is 
responsible for ensuring the protection of the rights, safety, and 
well-being of human subjects involved in a clinical investigation and 
is adequately constituted to provide assurance of that protection.'' We 
proposed to include this definition to clarify the scope of the review 
boards for which Human Subjects Protection Review Board Status must be 
submitted under Sec.  11.28 (79 FR 69605). We did not receive any 
comments on this definition, but for further clarity we are modifying 
the definition in the final rule to mean ``an institutional review 
board (IRB) as defined in 21 CFR 50.3 or 45 CFR 46.102, as applicable, 
that is responsible for assuring the protection of the rights, safety, 
and well-being of human subjects involved in a clinical trial and is 
adequately constituted to provide assurance of that protection. An IRB 
may also be known as an `independent ethics committee.' '' For clinical 
trials conducted in the United States or under an IND or IDE, the term 
``human subjects protection review board'' means an IRB, as defined in 
the cited regulations issued by FDA and HHS. For clinical trials 
conducted outside the United States or which are otherwise not subject 
to the FDA and/or HHS regulations for IRBs, the term refers to other 
independent ethics committees that are responsible for ensuring the 
protection of the rights, safety, and well-being of human subjects 
involved in a clinical investigation and are adequately constituted to 
provide assurance of that protection. This phrasing is consistent with, 
but not identical to, the definition of the term ``independent ethics 
committee'' in FDA regulations for INDs (see 21 CFR 312.3). It is also 
consistent with longstanding use of the term ``human subjects 
protection review board'' on ClinicalTrials.gov, which instructed 
registrants to provide information about ``[a]ppropriate review 
boards[, including] an Institutional Review Board, an ethics committee 
or an equivalent group that is responsible for review and monitoring of 
this protocol to protect the rights and welfare of human research 
subjects'' [Ref. 85].
Interventional
    In the NPRM, we defined ``interventional'' in Sec.  11.10 to mean 
``with respect to a clinical study or a clinical investigation, that 
participants are assigned prospectively to an intervention or 
interventions according

[[Page 65023]]

to a protocol to evaluate the effect of the intervention(s) on 
biomedical or other health related outcomes.'' The term 
``interventional'' is used in Sec.  11.22 as one of the elements (i.e., 
interventional Study Type) used to determine whether a clinical study 
or a clinical investigation is an applicable clinical trial that is 
required to be registered. We proposed to define this term to 
distinguish interventional studies from observational studies, as those 
terms are used in the clinical research community (79 FR 69605). 
Observational studies consist of medical research in which the 
investigator does not assign human subjects to interventions. 
Observational studies include prospective cohort studies in which 
individuals received interventions as part of their medical care, after 
which the investigator studies prespecified outcomes to examine the 
impact of those interventions. Observational studies also include 
retrospective reviews of patient medical records or relevant 
literature. In contrast, in interventional studies, a researcher 
assigns subjects to specific interventions (e.g., placebo, routine 
medical care, or no intervention) according to a study protocol for the 
purposes of the investigation. We explain in the preamble discussion 
for the definition of ``protocol'' in Sec.  11.10(a) of the final rule 
that a less formal research plan would also be considered a protocol 
for the purposes of this part, including the definition of 
``interventional.''
    We received comments addressing the definition. Several commenters 
requested that the definition of ``interventional'' include a study 
(other than an observational study) of any approved or unapproved drug, 
biologic, device, radionuclide, or any other substance that is 
introduced into the human body during the study's experimental phase 
(i.e., phase 0 through phase 4). As described in the preamble 
discussion for the definition of ``applicable drug clinical trial,'' 
phase 0 and 1 studies are not included in the applicable clinical 
trials that must be registered under Sec.  11.22, but such studies may 
still meet the definition of ``interventional.'' The definition of 
``interventional'' in the NPRM is generally consistent with what the 
commenters recommended, except that we provided more detail to help 
responsible parties apply the definition, including that interventional 
studies are those that: (1) Prospectively assign participants to an 
intervention, (2) do so according to a protocol, and (3) evaluate the 
intervention's effect on biomedical or other health-related outcomes. 
The commenters also described various types of observational studies 
that they believed would be excluded from this definition, including 
studies evaluating patients' responses independent of the actual 
ongoing clinical trial or other activities that have no direct 
interaction with the human body, but little detail was provided about 
these examples. However, we note that certain studies described by 
commenters did seem to fit the definition of ``observational'' (but not 
``interventional'') because assignment to the intervention was based on 
routine care instead of a protocol, such as a study of patients 
receiving an intervention as part of routine medical care to assess any 
correlation between certain biomarkers and the intervention's effect.
    Similarly, a commenter requested that the final rule clarify 
aspects of the ``prospectively assigned to the intervention per 
protocol'' component of the definition. The commenter asked 
specifically whether an intervention would be considered 
``prospectively assigned'' if the administration of the test article 
began before subjects participated in the study (i.e., the study 
assessed the effect of a therapy that was ongoing at the time of 
subject recruitment) and whether a drug provided as part of routine 
medical care would meet the requirement of being ``prospectively 
assigned'' if provision of the drug it occurred after subjects become 
research participants. In general, the timing of the intervention's 
administration in these cases would not be considered as relevant as 
how decisions for the participant to receive the intervention were 
made. If the decision for the participant to receive the intervention 
was based on routine medical care and not on assignment according to a 
protocol or research plan, the study would generally not be considered 
interventional. We note that there may be other aspects of the study 
design that were not described by the commenter that would otherwise 
cause the study to meet the definition of ``interventional'' (e.g., 
other interventions are simultaneously being evaluated for their effect 
on outcomes related to human health, such as an IVD test). We also 
clarified in the NPRM that a study would meet the definition of 
``interventional'' if assignment to the intervention is determined by 
the researcher based on a formal protocol or research plan, even when 
the medical products being studied are being used in a manner 
considered to be the standard of care (79 FR 69605). We also note, as 
discussed in Section V, that we will issue more guidance in the future 
on examples of applicable clinical trials for the checklist described 
in Sec.  11.22.
    Another comment requested clarification of the meaning of 
``biomedical or other health-related outcomes.'' We believe our 
explanation of ``a prospective clinical study of health outcomes'' for 
the definition of ``applicable device clinical trial'' is informative. 
In the NPRM, we explained that a ``prospective clinical study of health 
outcomes'' is a ``clinical study in which the primary objective is to 
evaluate a defined clinical outcome related to human health'' (79 FR 
69599). For example, a clinical study of a diagnostic device (such as 
an IVD) in which the primary purpose is to evaluate the ability of the 
device to make a diagnosis of a disease or condition is related 
directly to human health and, therefore, would be considered a clinical 
study of health outcomes for purposes of this rule.
    After considering these comments, we maintain the definition of 
``interventional'' in the final rule to mean ``with respect to a 
clinical study or a clinical investigation, that participants are 
assigned prospectively to an intervention or interventions according to 
a protocol to evaluate the effect of the intervention(s) on biomedical 
or other health-related outcomes.'' For the purposes of this part, we 
use the term ``clinical trial'' to refer to interventional studies to 
the exclusion of observational studies. (See the definition of 
``clinical trial.'') The term ``interventional'' is one of the 
responses that can be submitted as part of the Study Type data element 
that is included as clinical trial registration information under Sec.  
11.28 and defined in Sec.  11.10. Responsible parties must indicate 
whether a study being registered is ``interventional'' or 
``observational'' or is expanded access (see the discussion below). A 
study that is designated as ``interventional'' can be an applicable 
clinical trial if it meets the other criteria for an applicable 
clinical trial that are specified in this part. (See the definitions of 
``applicable device clinical trial'' and ``applicable drug clinical 
trial.'') A study that is designated ``observational'' can be an 
applicable clinical trial only if it is a pediatric postmarket 
surveillance of a device product as defined in this part. (See the 
definition of ``pediatric postmarket surveillance of a device 
product.'')
Investigational Device Exemption (IDE)
    In the NPRM, we defined ``Investigational Device Exemption (IDE)'' 
in Sec.  11.10(a) to have ``the meaning given in 21 CFR 812, or any

[[Page 65024]]

successor regulation'' (see 79 FR 69668). We did not receive any 
comments on this definition, and we maintain it in the final rule.
Investigational New Drug Application (IND)
    In the NPRM, we defined ``Investigational New Drug Application 
(IND)'' in Sec.  11.10(a) to have ``the meaning given in 21 CFR 312.3, 
or any successor regulation'' (see 79 FR 69668). We did not receive any 
comments on this definition, and we maintain it in the final rule.
NCT Number
    In the NPRM, we defined ``NCT number'' in Sec.  11.10(a) to mean 
``the unique identification code assigned to each record in 
ClinicalTrials.gov, including a record for an applicable clinical 
trial, a clinical trial, or an expanded access program'' (79 FR 69606). 
``NCT number'' refers to the term ``National Clinical Trial number'' 
used in section 402(j)(2)(B)(i)(VIII) of the PHS Act. We did not 
receive any comments on this definition, and we maintain it in the 
final rule.
    Since its launch in 2000, ClinicalTrials.gov has assigned each 
submitted clinical trial record a unique identifier once quality review 
procedures have been completed for the submitted information. While the 
identifier was originally called a ``National Clinical Trial number,'' 
that nomenclature was soon changed to ``NCT number'' in recognition of 
the fact that ClinicalTrials.gov receives clinical trial information 
about trials being conducted in countries other than the United States 
and accommodates the registration of clinical studies other than 
clinical trials (e.g., observational studies). NCT numbers are used in 
many contexts to refer to clinical trial records or other types of 
records (e.g., observational studies, expanded access programs) that 
are accepted by ClinicalTrials.gov. Under the ICMJE registration 
policy, for example, journals publishing original papers on the results 
of clinical trials require the authors to include in their manuscripts 
a unique identification number assigned by a recognized clinical trial 
registry as evidence that the trial has been registered in compliance 
with the ICMJE policy [Ref. 1, 2]. For trials registered on 
ClinicalTrials.gov, this unique identifier is the NCT number. When 
published in journal articles, NCT numbers are also included in the 
Medical Literature Analysis and Retrieval System Online records and are 
searchable through PubMed [Ref. 87]. Furthermore, section 402(j)(5)(B) 
of the PHS Act specifies that ``such certification [to accompany drug, 
biological product, and device applications or submissions to FDA] 
shall include the appropriate National Clinical Trial control 
numbers.''
Ongoing
    In the NPRM, we defined ``ongoing'' in Sec.  11.10(a) to mean 
``with respect to a clinical trial of a drug or a device and to a date, 
that one or more human subjects is enrolled in the clinical trial, and 
the date is before the completion date of the clinical trial.'' As we 
explained in the NPRM, this proposed definition is the same as the 
statutory definition, except the term ``human subjects'' has been 
substituted for the term ``patients'' that is used in section 
402(j)(1)(A)(viii) of the PHS Act (79 FR 69606). The reason for this 
change is that clinical trials may include healthy volunteers as well 
as human subjects who might be considered ``patients.'' With respect to 
a pediatric postmarket surveillance of a device product, we defined the 
term ``ongoing'' to mean ``a date between the date on which FDA 
approves the plan for conducting the surveillance and the date on which 
the final report is submitted to FDA.''
    We received comments addressing this definition. Two commenters 
asked that we clarify the definition and asserted that researchers 
consider trials to be ongoing even after the statutorily defined 
completion date. We note, though, that a trial cannot be considered 
ongoing in accordance with the statutory definition if the date is on 
or after the primary completion date (see the explanation above with 
regard to use of the term ``primary completion date''). Therefore, on 
or after the primary completion date, trials would not be considered 
ongoing for the purposes of this part and the applicable requirements.
    After considering these comments, we maintain the NPRM definition 
of ``ongoing,'' except that (as discussed previously) we replace 
``completion date'' with ``primary completion date,'' consistent with 
the definition of ``completion date'' in this section, and we clarify 
that ``drug'' means ``drug product'' and ``device'' means ``device 
product.'' We define ``ongoing'' in the final rule to mean ``with 
respect to a clinical trial of a drug product or a device product and 
to a date, that one or more human subjects is enrolled in the clinical 
trial, and the date is before the primary completion date of the 
clinical trial. With respect to a pediatric postmarket surveillance of 
a device product, ongoing means a date between the date on which FDA 
approves the plan for conducting the surveillance and the date on which 
the final report is submitted to FDA.''
Outcome Measure
    In the NPRM, we defined ``outcome measure'' in Sec.  11.10(a) to 
mean ``a pre-specified measurement that will be used to determine the 
effect of experimental variables on the human subjects in a clinical 
trial.'' As we explained in the NPRM, the experimental variables may be 
the specific intervention(s) used in the clinical trial or other 
elements of the clinical trial that vary between arms, e.g., diagnostic 
or other procedures provided to participants in different arms (79 FR 
69606). One commenter supported this definition.
    We maintain the definition of ``outcome measure'' in the final rule 
except we make conforming changes to two elements, i.e., we say ``an 
experimental variable'' and ``on the human subject(s)'' to be 
consistent with other definitions in the rule. In this part, ``outcome 
measure'' refers to measurements observed or collected from those human 
subjects who are enrolled in the clinical trial. Although it is not 
uncommon to compare data derived from human subjects enrolled in a 
clinical trial with data derived from other sources (e.g., literature, 
other clinical trials), we believe that only measurements taken from 
participants in the clinical trial of interest should be submitted as 
results information to ClinicalTrials.gov. In our view, comparisons of 
such data with results data derived from other sources are more 
appropriately described in forums other than ClinicalTrials.gov (e.g., 
journal articles) where the other necessary information about the 
comparator group can be provided. Clinical trial information submitted 
to ClinicalTrials.gov would generally not include information or data 
about the human subjects studied in another clinical trial (i.e., the 
clinical trial record would not contain baseline and demographic 
information about them, nor would it describe how they were allocated 
to arms of the clinical trial to receive interventions). (See the 
definitions of ``primary outcome measure'' and ``secondary outcome 
measure.'')
Pediatric Postmarket Surveillance of a Device Product
    Section 402(j)(1)(A)(ii)(II) of the PHS Act defines the term 
``applicable device clinical trial'' to include ``a pediatric 
postmarket surveillance as required under section 522 of the [FD&C] 
Act.'' The term ``[a]pplicable device clinical trial'' includes ``a 
pediatric postmarket surveillance as required under[section

[[Page 65025]]

522 of the FD&C Act].'' In the NPRM, we defined the term ``pediatric 
postmarket surveillance of a device'' in Sec.  11.10(a) to mean ``the 
active, systematic, scientifically valid collection, analysis, and 
interpretation of data or other information conducted under section 522 
of the [FD&C] Act about a marketed device that is expected to have 
significant use in patients who are 21 years of age or younger at the 
time of diagnosis or treatment (see 79 FR 69606). A pediatric 
postmarket surveillance of a device may be, but is not always, a 
clinical trial.'' Pursuant to section 522 of the FD&C Act, FDA defines 
the term ``postmarket surveillance'' as ``the active, systematic, 
scientifically valid collection, analysis, and interpretation of data 
or other information about a marketed device'' (see 21 CFR 822.3(h)). 
In Title III of FDAAA, Congress directed that the term ``pediatric,'' 
when used with respect to devices, refers to patients 21 and younger 
(see Title III of FDAAA (``Pediatric Medical Device Safety and 
Improvement Act of 2007''), amending section 520(m) of the FD&C Act).
    FDA may order a pediatric postmarket surveillance of a device under 
section 522 of the FD&C Act for any class II or class III device, as 
defined by 21 U.S.C. 360c(a) and 21 CFR 860.3, meeting any of the 
following criteria: (1) Its failure would be reasonably likely to have 
serious adverse health consequences, (2) it is expected to have 
significant use in pediatric populations, (3) it is intended to be 
implanted in the body for more than 1 year, or (4) it is intended to be 
a life-sustaining or life-supporting device outside a device user 
facility (see 21 U.S.C. 360l(a)). Pediatric postmarket surveillances 
under section 522 of the FD&C Act can take various forms, including a 
detailed review of the complaint history and the scientific literature, 
non-clinical testing, observational studies, and controlled clinical 
trials.
    Because section 402(j)(1)(A)(ii)(II) of the PHS Act defines the 
term ``applicable device clinical trial'' to include pediatric 
postmarket surveillances of a device, such surveillances must be 
registered, and clinical trial results information must be submitted 
for them. The final rule's approach for applying the registration 
requirements to a pediatric postmarket surveillance of a device that is 
not a clinical trial is described in Sec.  11.28(b), and the final 
rule's approach for applying the results information submission 
requirements to a pediatric postmarket surveillance of a device that is 
not a clinical trial is described in Sec.  11.48(b). A pediatric 
postmarket surveillance of a device that is a clinical trial is subject 
to the general requirements of this final rule, including the clinical 
trial registration and results information submission requirements in 
Sec. Sec.  11.28(a) and 11.48(a), respectively.
    We received no comments on this proposed definition, and we 
maintain it in the final rule. However, for clarity and consistency, 
``device'' is changed to ``device product.'' For completeness, we also 
include the applicable U.S.C. statutory citation in the definition.
Primary Completion Date
    As discussed above, based on comments we received, we have decided 
to maintain the proposed rule's definition of ``completion date'' in 
Sec.  11.10(a) of the final rule but, in order to prevent confusion 
among researchers and the public, we use the term ``primary completion 
date'' in this preamble and the codified provisions. Therefore, we add 
the term ``primary completion date'' to Sec.  11.10(a), define it as 
``completion date,'' and refer to the definition of that term.
Primary Outcome Measure(s)
    In the NPRM, we defined ``primary outcome measure(s)'' in Sec.  
11.10(a) to mean ``the outcome measure(s) of greatest importance 
specified in the protocol, usually the one(s) used in the power 
calculation. Most clinical trials have one primary outcome measure, but 
a clinical trial may have more than one.'' The NPRM also noted that, 
for the purpose of this part, ``primary outcome'' has the same meaning 
as ``primary outcome measure'' (79 FR 69606). The term ``primary 
outcome measure(s)'' is used, but not defined, in section 402(j) of the 
PHS Act. Section 402(j)(2)(A)(ii)(I)(ll) of the PHS Act expressly 
requires primary outcome measures to be submitted as a clinical trial 
registration information data element. In addition, section 
402(j)(1)(A)(v) of the PHS Act defines the completion date in relation 
to the ``final collection of data for the primary outcome.'' Primary 
outcome measure(s) is also expressly required as a clinical trial 
results information data element by section 402(j)(3)(C)(ii) of the PHS 
Act. As we explained in the NPRM, we believe this approach enables 
users of ClinicalTrials.gov to identify the pre-specified primary 
outcome measure(s) for the clinical trial submitted as part of the 
clinical trial registration information and to examine the results data 
collected for those outcome measures and submitted to the data bank as 
part of clinical trial results information. (See also the discussion in 
Sections IV.B.4 and IV.C.4 of this preamble regarding primary outcome 
measure as a clinical trial registration information data element in 
Sec.  11.28(a)(2)(i)(W) and as a clinical trial results information 
data element in Sec.  11.48(a)(3).) We received one comment in support 
of the proposed definition. We maintain the definition in the final 
rule, except, for greater clarity about the definition's scope, we add 
the phrase ``for purposes of this part.''
Principal Investigator
    In the NPRM, we defined ``principal investigator'' in Sec.  11.10 
to mean ``the individual who is responsible for the scientific and 
technical direction of the study.'' As we explained, ``principal 
investigator'' is a term used in the definition of ``responsible 
party'' in section 402(j)(1)(A)(ix) of the PHS Act and in the 
description of the Certain Agreements results data element in section 
402(j)(3)(C)(iv) of the PHS Act, but the term itself is not defined in 
section 402(j) of the PHS Act (79 FR 69607). The definition uses 
terminology derived from 42 CFR 52.2, which defines ``principal 
investigator'' in the context of an NIH grant as ``the individual(s) 
judged by the applicant organization to have the appropriate level of 
authority and responsibility to direct the project or program supported 
by the grant and who is or are responsible for the scientific and 
technical direction of the project.'' We did not include the phrases 
``applicant organization'' and ``project or program supported by the 
grant,'' which are specific to NIH-funded grants, because these 
references would not necessarily apply to applicable clinical trials 
that are funded by industry or other non-governmental organizations. We 
used the term ``study'' in place of ``project'' because the projects of 
relevance to this rule would be clinical studies, whether clinical 
trials or pediatric postmarket surveillances of a device. We also made 
it clear that the definition applies to only a single individual. This 
is consistent with our interpretation that there cannot be more than 
one responsible party for a clinical trial that is subject to section 
402(j) of the PHS Act. We would expect a principal investigator to have 
full responsibility for the treatment and evaluation of human subjects 
in the study and for the integrity of the research data for the full 
study. In keeping with this approach, an investigator for an individual 
site in a multi-site clinical trial would not be considered the 
principal investigator unless he or she also has overall responsibility 
for the clinical trial at all sites at which it is being conducted.

[[Page 65026]]

This interpretation is consistent with the requirement in section 
402(j)(1)(A)(ix) of the PHS Act that a principal investigator may be 
designated by the sponsor as a responsible party only if he or she is 
responsible for conducting the trial, has access to and control over 
the data from the clinical trial, has the right to publish the clinical 
trial results, and has the ability to meet all the requirements for the 
submission of clinical trial information under section 402(j) of the 
PHS Act and this part.
    We received comments on this proposed definition. Commenters 
requested that we make the proposed definition of ``principal 
investigator'' consistent with relevant FDA definitions. ``Principal 
investigator'' is not defined in FDA regulations or HHS ``Common Rule'' 
regulations (45 CFR part 46). However, FDA regulations in 21 CFR part 
312 define ``investigator'' as ``an individual who actually conducts a 
clinical investigation (i.e., under whose immediate direction the drug 
is administered or dispensed to a subject). In the event an 
investigation is conducted by a team of individuals, the investigator 
is the responsible leader of the team'' (see 21 CFR 312.3(b)). Other 
FDA regulations in 21 CFR parts 50, 56, and 812 define ``investigator'' 
similarly. The commenters noted that for large academic consortium 
studies, there may be an investigator who is responsible for the 
study's scientific and technical direction and who is commonly referred 
to as the ``overall principal investigator'' or ``study director.'' As 
the commenters noted, FDA regulations do not define ``principal 
investigator,'' and our proposed definition is for the purposes of this 
rule.
    We do not believe that the proposed definition is inconsistent with 
FDA's definition of an ``investigator.'' As we explained above, the 
definition is based on the NIH regulation applying to grants (42 CFR 
52.2), with which academic medical centers should be familiar. We 
clarify that in the commenters' examples, the ``overall principal 
investigator'' or ``study director'' responsible for the study's 
overall scientific and technical direction would be considered the 
``principal investigator'' for the purpose of this part. If there are 
clinical trials for which there is more than one individual whom the 
sponsor considers to be a principal investigator for the overall study, 
the sponsor may designate only one of these principal investigators as 
the responsible party. Another commenter also stated that the 
definition should include a qualifier to designate the principal 
investigator for the overall study (with multiple sites) or an 
individual site.
    After considering these comments, we modify the definition of 
``principal investigator'' to clarify that the principal investigator 
is responsible for the overall study (as distinguished from the 
individual study sites). The definition of ``principal investigator'' 
in the final rule means ``the individual who is responsible for the 
overall scientific and technical direction of the study.'' We note that 
the principal investigator of a grant awarded by a Federal Government 
agency that funds a clinical trial may not necessarily be the principal 
investigator for that clinical trial for the purposes of this part. For 
example, for the purposes of grant funding, NIH defines ``program 
director/principal investigator'' in part as ``[t]he individual(s) 
designated by the applicant organization to have the appropriate level 
of authority and responsibility to direct the project or program to be 
supported by the award.'' [Ref. 87a]. Such an individual may or may not 
be ``the individual who is responsible for the overall scientific and 
technical direction of the study'' as defined in Sec.  11.10(a) of this 
regulation.
    In addition, the principal investigator on a Federal grant who has 
responsibility for only one site of a multi-site clinical trial (see, 
for example, 42 CFR 52.2) would neither have the requisite 
responsibility for conducting the entire trial nor the requisite access 
to data from all sites involved in the clinical trial, both of which 
are required by section 402(j) of the PHS Act and this part in order to 
meet the definition of ``responsible party.'' Accordingly, the 
principal investigator on such a grant could not be designated by the 
sponsor to be the responsible party for the purposes of registering a 
clinical trial and submitting clinical trial results information under 
section 402(j) of the PHS Act and this part.
Protocol
    In the NPRM, we defined ``protocol'' in Sec.  11.10(a) to mean 
``the written description of the clinical trial, including 
objective(s), design, and methods. It may also include relevant 
scientific background and statistical considerations.'' As we explained 
in the NPRM, the protocol is the document that describes the design of 
a clinical trial. It may be, and frequently is, amended after a 
clinical trial has begun (79 FR 69607). This definition is derived from 
ICH E6(R1): Good Clinical Practice: Consolidated Guideline [Ref. 81] 
which defines the term as ``[a] document that describes the 
objective(s), design, methodology, statistical considerations, and 
organization of a trial. The protocol usually also gives the background 
and rationale for the trial, but these could be provided in other 
protocol referenced documents.'' The protocol generally addresses major 
statistical considerations, such as the number of human subjects 
required to provide adequate statistical power, but it may or may not 
include detailed information about the specific statistical analyses to 
be performed as part of the clinical trial. Such information may be 
contained in a separate SAP. We received no comments on this 
definition, and we maintain it in the final rule. We note, for the 
purposes of this part, that the written description may vary in the 
degree of detail, structure, or format. This clarification is relevant 
for other definitions in this part that include the ``protocol'' 
component, including the definitions for ``clinical trial'' and 
``interventional.''
Responsible Party
    In the NPRM, we defined ``responsible party'' in Sec.  11.10(a) to 
mean ``with respect to a clinical trial, (i) the sponsor of the 
clinical trial, as defined in 21 CFR 50.3 (or any successor 
regulation); or (ii) the principal investigator of such clinical trial 
if so designated by a sponsor, grantee, contractor, or awardee, so long 
as the principal investigator is responsible for conducting the trial, 
has access to and control over the data from the clinical trial, has 
the right to publish the results of the trial, and has the ability to 
meet all of the requirements under this part for the submission of 
clinical trial information. For a pediatric postmarket surveillance of 
a device that is not a clinical trial, the responsible party is the 
entity whom FDA orders to conduct the pediatric postmarket surveillance 
of a device.'' As we explained, ``responsible party'' is the term 
defined in section 402(j)(1)(A)(ix) of the PHS Act and used in section 
402(j) of the PHS Act to refer to the entity or individual who is 
responsible for registering a clinical trial or a pediatric postmarket 
surveillance of a device that is not a clinical trial, for submitting 
clinical trial results information to ClinicalTrials.gov, and for 
updating all submitted clinical trial information (79 FR 69607). We 
received no comments on this definition, and we maintain it in the 
final rule. We have, however, made a minor formatting change and 
grammatical correction (changing ``whom'' to ``who''). As we have 
elsewhere, we also now use the term ``device product.'' The procedures 
for determining which individual or entity meets the definition of

[[Page 65027]]

``responsible party'' are specified in Sec.  11.4(c) and described in 
Section IV.A.2 of this preamble. We address the comments on these 
procedures in that section.
Secondary Outcome Measure(s)
    In the NPRM, we defined ``secondary outcome measure'' in Sec.  
11.10(a) to mean ``an outcome measure that is of lesser importance than 
a primary outcome measure, but is part of a pre-specified plan for 
evaluating the effects of the intervention or interventions under 
investigation in a clinical trial.'' As we explained in the NPRM, a 
``clinical trial may have more than one secondary outcome measure'' (79 
FR 69607). We also noted that for the purpose of this part, ``secondary 
outcome'' has the same meaning as ``secondary outcome measure.'' 
``Secondary outcome measure'' is a term used, but not defined, in 
section 402(j) of the PHS Act. Section 402(j)(2)(A)(ii)(I)(ll) of the 
PHS Act expressly requires secondary outcome measures to be submitted 
as a clinical trial registration information data element, as a 
component of the outcome measures data element. In addition, secondary 
outcome measure(s) is also expressly required as a clinical trial 
results information data element by section 402(j)(3)(C)(ii) of the PHS 
Act. As we said, we believe this structure enables users of 
ClinicalTrials.gov to identify the pre-specified secondary outcome 
measures for the clinical trial submitted as part of the clinical trial 
registration information and to examine the results data collected for 
those outcome measures and submitted to the data bank as part of 
clinical trial results information. We also pointed out that the 
definition is consistent with the WHO Trial Registration standard and 
ICMJE registration policies [Ref. 2, 73].
    We received comments on this definition. One commenter supported 
this definition. We also heard from others that we should clarify 
whether any outcomes that are not part of the SAP, or are indicated to 
be tertiary or exploratory, are secondary outcome measures. We consider 
secondary outcome measures to be those outcome measures (other than the 
primary outcome measures) that are not considered exploratory or 
tertiary and for which there is a specific analysis plan. In general, 
the analysis plan would be specified in the protocol or SAP, but 
protocols do not always contain detailed information about statistical 
analyses, and SAPs may not be complete at the time a trial is 
registered. Therefore, the plan to analyze the secondary outcome 
measures may only be expressed in other formal trial documentation 
(e.g., a grant application, contract, or published journal article). 
Therefore, in response to these comments, we confirm that outcome 
measures that are not part of an analysis plan, or are indicated to be 
exploratory or tertiary, are lower-level outcome measures and not 
secondary outcome measures. These lower-level outcome measures are not 
required to be submitted to ClinicalTrials.gov, but the information may 
be submitted voluntarily. (See the discussions in Sections IV.B.4 and 
IV.C.3 of this preamble, respectively, regarding secondary outcome 
measure(s) as a clinical trial information data element to be submitted 
at the time of registration, pursuant to Sec.  11.28(a)(2)(i)(X), and 
at the time of results information submission, pursuant to Sec.  
11.48(a)(3).) After consideration of these comments, we clarify that a 
pre-specified exploratory or tertiary measure is not considered a 
secondary outcome. The definition of ``secondary outcome measure(s)'' 
in Sec.  11.10(a) of this final rule is ``an outcome measure that is of 
lesser importance than a primary outcome measure, but is part of a pre-
specified analysis plan for evaluating the effects of the intervention 
or interventions under investigation in a clinical trial and is not 
specified as an exploratory or other measure. A clinical trial may have 
more than one secondary outcome measure.'' For the purpose of this 
part, ``secondary outcome'' has the same meaning as ``secondary outcome 
measure.'' We include the phrase ``and is not specified as an 
exploratory or other measure'' to be clear that a pre-specified 
exploratory or other measure is not considered a secondary outcome 
measure.
Secretary
    In the NPRM, we defined ``Secretary'' in Sec.  11.10(a) to mean 
``the Secretary of Health and Human Services or any other official(s) 
to whom the Secretary delegates authority contained in 42 U.S.C. 
282(j)'' (see 79 FR 69669). We received no comments on this definition. 
We maintain it, except that we make clear that that the Secretary's 
authority is contained in ``section 402(j) of the Public Health Service 
Act (42 U.S.C. 282(j).''
Serious Adverse Event
    In the NPRM, we defined ``serious adverse event'' in Sec.  11.10(a) 
to mean ``an adverse event that results in any of the following 
outcomes: Death, a life-threatening adverse event as defined in 21 CFR 
312.32 (or any successor regulation), inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal 
life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the human subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of a substance use disorder.'' As 
we explained in the NPRM, ``serious adverse event'' is a term used, but 
not defined, in section 402(j)(3)(I) of the PHS Act (79 FR 69608). 
Section 402(j)(3)(I)(iii)(I) of the PHS Act requires the submission to 
ClinicalTrials.gov of specific information about ``anticipated and 
unanticipated serious adverse events'' for applicable clinical trials 
of drugs as well as devices.
    We received comments on this definition. Commenters suggested that 
the adverse event reporting requirements for devices should be 
consistent with the definition of ``serious adverse event'' used by the 
international standard for clinical investigations of medical devices 
in human subjects (ISO 14155) [Ref. 88]. As we noted in our discussion 
of the term in the NPRM, the definition is consistent with established 
FDA standards, and we drew on the FDA definition of ``serious adverse 
event'' in 21 CFR 312.32(a) for IND applications in developing the 
definition because that FDA definition more fully characterizes the 
criteria for ``other serious problems'' as well as ``any life-
threatening problem'' or ``[d]eath.'' In defining the term ``serious 
adverse event'' in its IND Safety Reporting regulations in 21 CFR 
312.32(a), FDA considers an adverse event to be ``serious'' when, in 
the view of either the sponsor or the investigator, it ``results in any 
of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, 
a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon appropriate

[[Page 65028]]

medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.'' The other points we made in the NPRM are also relevant, 
and we reiterate them here to explain why we are not adopting the 
commenters' suggestion. A ``serious adverse event,'' as defined in 21 
CFR 312.32(a), applies only in the context of drugs (including 
biological products). No fully equivalent term is defined in FDA 
regulations for medical devices. In 21 CFR 812.3(s), FDA defines an 
``unanticipated adverse device effect'' as, in part, ``any serious 
adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device'' that ``was not 
previously identified . . . in the investigational plan or application 
. . . or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.'' 
However, we did not consider this definition to be sufficient to meet 
the statutory requirement in section 402(j)(3)(I)(iii) of the PHS Act 
for submission of serious adverse event information that encompasses 
both anticipated and unanticipated events because it is restricted to 
unanticipated effects.
    After considering the comments, we maintain the NPRM definition of 
``serious adverse event'' in Sec.  11.10(a) to mean ``an adverse event 
that results in any of the following outcomes: Death, a life-
threatening adverse event as defined in 21 CFR 312.32, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the human 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of a 
substance use disorder.'' Although we adopted terms from an FDA drug 
regulation, we emphasize that ``serious adverse event,'' as defined for 
the purposes of this part, applies to both drugs and devices. Further, 
and as explained more fully in section IV.C.4. of this preamble, the 
rule does not require investigators or responsible parties to collect 
information that is not specified in the clinical trial protocol.
    We use the phrase ``a substance use disorder'' instead of the 
phrase ``drug dependency or drug abuse,'' which is used in the FDA 
definition, for consistency with the latest version (fifth edition) of 
the Diagnostic and Statistical Manual of Mental Disorders [Ref. 89]. By 
referring to adverse events (and thus the definition of that term in 
this part), our definition of ``serious adverse event'' is broader than 
the FDA definition of ``serious adverse event'' in 21 CFR 312.32(a) 
because it encompasses any untoward or unfavorable medical occurrences 
associated with any intervention included in a clinical trial (not just 
the use of the FDA-regulated product), including any intervention(s) in 
any arm of the clinical trial that does not involve FDA-regulated 
products. In addition, as with our definition of ``adverse event,'' our 
definition of ``serious adverse event'' encompasses both anticipated 
and unanticipated effects regardless of attribution or association with 
the intervention.
Sponsor
    In the NPRM, we defined ``sponsor'' in Sec.  11.10(a) to mean 
``either a `sponsor' or `sponsor-investigator,' as each is defined 21 
CFR 50.3 or any successor regulation.'' As we explained, ``[s]ponsor'' 
is a term used in section 402(j) of the PHS Act to define responsible 
party (79 FR 69608). Section 402(j)(1)(A)(ix)(I) of the PHS Act 
explicitly defines ``sponsor'' as such term is defined at 21 CFR 50.3 
or any successor regulation. Two types of sponsors are defined in 21 
CFR 50.3, both of which, we noted, meet the definition of ``sponsor'' 
for the purposes of this part. The first type is a ``sponsor,'' defined 
in 21 CFR 50.3 as ``a person who initiates a clinical investigation but 
who does not actually conduct the investigation, i.e., the test article 
is administered or dispensed to or used involving, a subject under the 
immediate direction of another individual. A person other than an 
individual (e.g., corporation or agency) that uses one or more of its 
own employees to conduct a clinical investigation it has initiated is 
considered to be a sponsor (not a sponsor-investigator), and the 
employees are considered to be investigators.'' The second type is a 
``sponsor-investigator,'' defined in 21 CFR 50.3 as ``an individual who 
both initiates and actually conducts, alone or with others, a clinical 
investigation, i.e., under whose immediate direction the test article 
is administered or dispensed to, or used involving, a subject. The term 
does not include any person other than an individual, e.g., corporation 
or agency.'' As we noted, we believe that the definition of ``sponsor'' 
used in this part must encompass both a sponsor and a sponsor-
investigator because both terms are relevant in determining who 
initiates the clinical trial.
    We did not receive any comments on this definition, and we maintain 
it in the final rule to mean ``either a `sponsor' or `sponsor-
investigator', as each is defined 21 CFR 50.3.'' Procedures for 
determining which individual or entity would be considered the sponsor 
of an applicable clinical trial or other clinical trial subject to this 
part are specified in Sec.  11.4(c) and described in Section IV.A.2 of 
this preamble. As those sections explain, the individual or entity that 
is the sponsor is considered to be the responsible party of an 
applicable clinical trial or other clinical trial, unless and until 
that responsibility is delegated to the principal investigator, 
consistent with the requirements of section 402(j)(1)(A)(ix) of the PHS 
Act and this part.

Study Completion Date

    The NPRM did not use the term ``study completion date'' or propose 
either a definition of it in Sec.  11.10(a) or a data element for it in 
Sec.  11.28, but we are including the term and data element in this 
final rule. We define the term ``study completion date'' in Sec.  
11.10(a) to mean ``for a clinical trial, the date the final subject was 
examined or received an intervention for purposes of final collection 
of data for the primary and secondary outcome measures and adverse 
events (e.g., last subject's last visit), whether the clinical trial 
concluded according to the pre-specified protocol or was terminated.'' 
Section 402(j)(2)(A)(ii) of the PHS Act specifies the clinical trial 
registration information that must be submitted, although study 
completion date is not included. However, section 402(j)(2)(A)(iii) of 
the PHS Act permits the Secretary to ``modify the requirements for 
clinical trial [registration] information'' by regulation, provided 
that ``such a modification improves and does not reduce such clinical 
trial information.''

[[Page 65029]]

As discussed in Section IV.B.4, we believe that the study completion 
date is helpful in indicating when all primary and secondary outcome 
measures and the collection of all adverse event information, as 
specified in the protocol, will be completed and when final data 
collection has occurred. Therefore, we believe that requiring the 
submission of the study completion date improves and does not reduce 
clinical trial information.
    Section 11.64(a)(3) describes when a responsible party's obligation 
to submit updates ends. Our definition of ``study completion date'' 
identifies the final date of data collection for the study, including 
for any primary and secondary outcomes and for adverse events. For 
adverse events, the last date of data collection is the end of the 
adverse event collection period specified by the protocol. The study 
completion date will be the end of this adverse event collection period 
if this period ends later than the last subject's last visit for the 
primary and secondary outcomes. As discussed in other sections of this 
preamble, the study completion date is relevant in determining the 
obligations for responsible parties to submit registration and results 
information. As described in Section IV.C.3 for partial results 
information deadlines under Sec.  11.44(d), clinical trial results 
information specified in Sec.  11.48 must be submitted no later than 
one year after the study completion date. In addition, the Study 
Completion Date,'' which is a registration data element, will be 
displayed on the posted record.
    Although we did not receive any specific comments about adding a 
Study Completion Date data element, commenters did request that a 
mechanism be included in the PRS to make clear to responsible parties 
when they have fulfilled all obligations to update the study record, 
and when no further updates are required. A responsible party can use 
the ``study completion date'' definition and related data element in 
determining various obligations under this part, such as the deadlines 
for submitting partial results information under Sec.  11.44(d). The 
``study completion date'' is distinct from ``completion date,'' which, 
as discussed above, we refer to as the ``primary completion date.''
U.S. FDA-Regulated Device Product
    In the NPRM, we defined ``FDA-regulated device'' in Sec.  11.10(a) 
to mean ``for purposes of this part, a device subject to section 
510(k), 515, 520(m), or 522 of the Federal Food, Drug, and Cosmetic 
Act.'' As we explained, this term and its definition are based on 
section 402(j)(1)(A)(ii) of the PHS Act, which defines ``applicable 
device clinical trial'' as including studies of a ``device subject to 
section 510(k), 515, or 520(m) of the Federal Food, Drug, and Cosmetic 
Act.'' We did not receive any comments on this definition and maintain 
it in Sec.  11.10(a) of the final rule. However, because ``FDA'' is a 
term used by similar regulatory agencies in other countries, we have 
changed the term ``FDA-regulated device'' to ``U.S. FDA-regulated 
device product'' for clarity. As we have elsewhere, we now also use the 
term ``device product.'' A responsible party must submit information, 
in accordance with Sec.  11.28, about whether the trial ``studies a 
U.S. FDA-regulated device product.'' We explain further whether a trial 
studies a U.S. FDA-regulated device product in Section IV.B.2 of this 
preamble in our elaboration on the meaning of an ``applicable device 
clinical trial.'' We also include the applicable U.S.C. statutory 
citations in the definition.
U.S. FDA-Regulated Drug Product
    In the NPRM, we defined ``FDA-regulated drug'' in Sec.  11.10(a) to 
mean ``for purposes of this part, a drug subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or a biological product subject to 
section 351 of the Public Health Service Act.'' As we explained, this 
term and its definition are based on section 402(j)(1)(A)(iii) of the 
PHS Act, which defines ``applicable drug clinical trial'' as including 
studies of a ``drug subject to section 505 of the Federal Food, Drug, 
and Cosmetic Act or to section 351 of the [Public Health Service 
Act].'' We did not receive any comments on this definition and maintain 
it in Sec.  11.10(a) of the final rule. However, because ``FDA'' is a 
term used by similar regulatory agencies in other countries, we have 
changed the term ``FDA-regulated drug'' to ``U.S. FDA-regulated drug 
product'' for further clarity. Additionally, for clarity, we now use 
the term ``drug product'' rather than ``drug.'' A responsible party 
must submit information in accordance with Sec.  11.28 about whether 
the trial ``studies a U.S. FDA-regulated drug product.'' We explain 
further whether a trial studies a U.S. FDA-regulated drug product in 
Section IV.B.2 of this preamble in our elaboration on the meaning of an 
``applicable drug clinical trial''. We also include the applicable 
U.S.C. statutory citations in the definition.
    Section 11.10(b) defines certain data elements that are part of the 
clinical trial registration information that must be submitted to 
ClinicalTrials.gov under this part. The data elements defined in Sec.  
11.10(b) are enumerated in Sec.  11.28(a).

B. Subpart B--Registration

1. 11.20--Who must submit clinical trial registration information?
Overview of Proposal
    Proposed Sec.  11.20 required that ``[t]he responsible party for an 
applicable clinical trial specified in Sec.  11.22 must register the 
applicable clinical trial by submitting clinical trial registration 
information specified in Sec.  11.28 for that clinical trial.'' As we 
explained in the NPRM, this approach is consistent with section 
402(j)(2)(C) of the PHS Act, which states that the ``responsible party 
for an applicable clinical trial . . . shall submit to the Director of 
NIH for inclusion in the registry data bank the [clinical trial 
registration information]'' (79 FR 69609).
Comments and Response
    There were no comments received on this section.
Final Rule
    The final rule maintains Sec.  11.20 as proposed, except clarifies 
the wording for consistency with Sec.  11.40. Section 11.20 requires 
that ``[t]he responsible party for an applicable clinical trial 
specified in Sec.  11.22 must submit clinical trial registration 
information for that clinical trial.''
2. 11.22--Which applicable clinical trials must be registered?
Overview of Proposal
    In proposed Sec.  11.22(a), the Agency interpreted section 
402(j)(2)(C) of the PHS Act to specify which applicable clinical trials 
must be registered with ClinicalTrials.gov. As we explained in the 
NPRM, proposed Sec.  11.22(b) set forth an approach for determining 
whether or not a clinical trial meets the statutory definitions of an 
applicable device clinical trial and an applicable drug clinical trial, 
as established in section 402(j)(1) of the PHS Act (79 FR 69610). The 
proposed approach used a series of specific registration data elements 
and corresponding criteria to determine whether a clinical trial or 
study meets the definition of an applicable clinical trial (i.e., Study 
Type of the trial is ``interventional,'' Study Phase is other than 
``Phase 1,'' etc.). We also pointed out that ``algorithms'' following 
the approach outlined in the regulations would also be made available 
outside the registration process (e.g., online at http://prsinfo.clinicaltrials.gov/fdaaa.html), and study sponsors could use 
such algorithms to evaluate whether a particular trial meets the 
definition of

[[Page 65030]]

applicable clinical trial (79 FR 69610). The NPRM invited public 
comment on the approach proposed in Sec.  11.22(b) for determining 
whether a clinical trial or study is an applicable clinical trial. It 
also requested comments on whether there are any types of applicable 
clinical trials that would be misidentified by this approach.
Comments and Response
    Commenters addressed the NPRM's approach for facilitating the 
determination of which clinical trials or studies are applicable 
clinical trials that must be registered with ClinicalTrials.gov. 
Several commenters supported the proposed approach for determining 
whether a study is an applicable clinical trial, with a few commenters 
suggesting that the rationale and approach would likely reduce 
administrative burden for stakeholders. One suggested that the data 
elements required for the determination process be made available to 
sponsors outside of the registration process and that 
ClinicalTrials.gov issue dated receipts to provide an audit trail 
detailing whether or not a clinical trial was determined to be an 
applicable clinical trial. In order to assist users in evaluating, 
prior to beginning the registration process, whether their clinical 
trial or study is an applicable clinical trial and potentially subject 
to the requirements of the statute and the final rule, a checklist-
based tool will be made available at https://prsinfo.clinicaltrials.gov 
(or successor site) for sponsors and others before the effective date 
of the rule. Although proposed Sec.  11.22(b) included the criteria for 
determining whether a trial is an applicable clinical trial, the 
checklist tool is external to the ClinicalTrials.gov PRS and separate 
from the registration process. The outcome generated by the checklist 
tool will not be retained by the Agency and will not be binding on 
either the user or any government Agency in any future actions. While 
the tool is intended to be useful, it is not intended to be 
determinative of the applicability of the statute or this rule. Thus, 
we do not agree that a dated receipt for the outcome is necessary.
    A few commenters opposed the overall proposed approach. One stated 
that it would be neither helpful nor appropriate and requested that 
study sponsors be allowed to make the determination rather than respond 
to each specific element. As noted, the Agency is not making the 
checklist tool available within the internal PRS system. The proposed 
approach provides responsible parties or other users with a method to 
help evaluate whether a particular clinical trial is an applicable 
clinical trial prior to data submission. Since 2009, a draft 
Elaboration of Definitions, which expounds on the definition of 
applicable clinical trial [Ref. 90], and ClinicalTrials.gov 
registration data elements have been available to allow sponsors to 
indicate whether a clinical trial or study is an applicable clinical 
trial (i.e., ``Section 801 Clinical Trial'') [Ref. 85]. However, based 
on requests for clarification we have received to date, some users have 
found application of these definitions and data elements difficult to 
implement in practice. Building on our experience in responding to such 
requests and the comments received, breaking the definition of 
applicable clinical trial into components that can be explained in 
terms of objective data elements has often facilitated understanding of 
the applicable clinical trial definition and the user's evaluation 
process for their particular clinical trial or study. Other than 
comments on the interpretation of the definition of applicable clinical 
trial and its components (e.g., definition of ``controlled,'' 
application to studies of ``combination products''), which are 
discussed elsewhere in the preamble (see Section IV.A.5), we did not 
receive any specific examples, as invited, of situations in which the 
proposed approach would misidentify an applicable clinical trial. 
However, as addressed below, other commenters offered suggestions or 
raised questions about our proposal.
    Some commenters observed that the data elements used for the 
Applicable Clinical Trial assessment checklist were either too broadly 
or too poorly defined. One commenter suggested that additional data 
elements be added to determine whether a study is interventional. We 
clarify or provide elaboration on the definitions (see Sec.  11.10) for 
a number of data elements, such as ``interventional,'' used to 
determine whether a study is an applicable clinical trial. In addition, 
we are committed to providing additional guidance as needed when new 
issues with interpretation are raised. The Agency believes that this 
data element-based approach provides an objective, transparent set of 
criteria for responsible parties and other users to evaluate, prior to 
registering a trial, whether a clinical trial or study is an applicable 
clinical trial and for such users of ClinicalTrials.gov to understand 
the data elements used in evaluating whether a clinical trial or study 
is an applicable clinical trial. Prior to registration a sponsor or 
other user will be able to use the external checklist tool, which will 
be based on the set of data elements identified in Sec.  11.22(b), to 
assess whether a clinical trial or study is considered an applicable 
clinical trial. Once clinical trial registration information has been 
submitted, the Agency will be able to identify applicable clinical 
trials based on the set of data elements identified in Sec.  11.22(b). 
Public users of ClinicalTrials.gov, other than responsible parties, 
should be able to understand whether a registered trial is an 
applicable clinical trial. Although we have not conducted a formal 
pilot study, as suggested by a commenter, the approach is responsive to 
the challenges users have experienced in the past while trying to 
determine whether their clinical trial or study meets the definition of 
applicable clinical trial.
    Commenters requested that the Agency provide examples of clinical 
trials that do not fulfill the proposed criteria for applicable 
clinical trials, and a couple of commenters observed that case studies 
would be helpful for clarification purposes. The Agency intends to 
continue making explanatory documents and other materials available, 
including examples, case studies, and a publicly-accessible checklist-
based tool (described above) consisting of the relevant data elements 
and detailed explanation of each criterion at https://prsinfo.clinicaltrials.gov (or successor stite). Finally, the Agency 
believes that it has identified the minimum set of criteria 
(corresponding to the registration data elements) needed to identify 
applicable clinical trials, which should minimize burden on the 
responsible parties.
    Several commenters recommended that the Agency provide responsible 
parties with a mechanism to explain why a clinical trial is not an 
applicable clinical trial and/or to appeal the outcome of the proposed 
approach. However, although we specifically asked in the NPRM for 
examples of cases in which the approach outlined in the NPRM and 
discussed above would lead to a misclassification of a clinical trial 
(i.e., either by inappropriately including a trial that is not an 
applicable clinical trial or excluding a trial that is), no examples 
were submitted. Further, as mentioned previously, the checklist will be 
available as a tool separate from the ClinicalTrials.gov registration 
process in the PRS. By having each criterion correspond to one or more 
standard data elements, the evaluation and assessment process follows a 
checklist approach based on factual information (e.g.,

[[Page 65031]]

whether or not the Study Type is ``interventional'' as defined; whether 
a drug is regulated by the U.S. FDA under section 505 of the FD&C Act 
or section 351 of the PHS Act). Responsible parties or other users who 
use the checklist tool are responsible for using accurate data about a 
clinical trial or study and for conducting the evaluation. Since the 
outcome is dependent on the factual data relied on by a responsible 
party or other user, and the outcome of the assessment will not be 
binding on either the user or any government Agency in any future 
actions, we do not see a need for a mechanism for responsible parties 
or other users to comment on a particular outcome of the external 
checklist tool or an appeal process to dispute the outcome. The Agency 
will provide contact information for obtaining assistance with 
questions that arise about the interpretation of a criterion or a 
relevant data element definition for which answers cannot be found in 
Agency documents or other existing materials.
    Another commenter requested that the ClinicalTrials.gov Web site 
remove the ``late'' status and ``problems'' designation for trials that 
do not meet the definition of ``applicable clinical trial'' under the 
regulation. It is our understanding that this comment refers to an 
online tool that is currently available to help responsible parties 
manage their study records when using the PRS. Since all of the data 
elements needed to evaluate whether a clinical trial or study is an 
applicable clinical trial are not yet available, the current online 
tool only approximates which submissions may be ``late'' and which 
trials are ``probable applicable clinical trials.'' The Agency used the 
term ``probable applicable clinical trials'' (pACTs) to refer to the 
estimated number of clinical trials subject to section 402(j) of the 
PHS Act prior to the effective date of the rule. This approach relied 
on the set of clinical trial registration data elements available prior 
to enactment of the final rule, but did not include all of the data 
elements necessary to determine which studies are applicable clinical 
trials as specified in Sec.  11.22(b) of the final rule. The pACTs were 
defined as records listing an ``interventional'' Study Type; with at 
least one Intervention Type as ``Biological,'' ``Drug,'' ``Device,'' 
``Genetic,'' or ``Radiation;'' a Study Phase other than ``Phase 0'' or 
``Phase 1;'' a Primary Completion Date on or after January 2008 or, if 
the Primary Completion Date was missing, a Study Completion Date on or 
after January 2008, or any record for which both the Primary Completion 
Date and the Study Completion Date are missing; an Overall Recruitment 
Status other than ``Withdrawn,'' and at least one Facility Location 
Country in the ``United States'' or if none, indication that the study 
is conducted under an FDA IND or IDE.
    Promulgation of the final rule and implementation of several new 
data elements (e.g., Studies an FDA-regulated Drug [or Device]), 
enables the Agency to be better able to identify applicable clinical 
trials more accurately in the PRS and on the public Web site. In 
addition, it enables the Agency to create other tools within the PRS to 
assist responsible parties with managing their responsibilities. 
Misidentified trials, as referred to in the comments, should be able to 
be addressed.
Final Rule
    Taking into consideration the submitted comments, as well as the 
statutory definitions of the terms, ``applicable device clinical 
trial'' and ``applicable drug clinical trial,'' the rule retains the 
proposed scope for required registration of applicable clinical trials, 
but modifies the approach for evaluating whether a study is an 
applicable clinical trial as specified in Sec.  11.22(b) based on the 
Agency's revised interpretation of ``control or controlled,'' as 
described elsewhere in the preamble (Section IV.A.5). Additionally, the 
final rule clarifies that ``device'' means ``device product'' and 
``drug'' means ``drug product.'' The final rule also clarifies that the 
approach in Sec.  11.22(b) for evaluating whether a study is an 
applicable clinical trial applies to trials initiated on or after the 
effective date of the final rule.
    Section 11.22(a)(1) and (2) state that registration is required 
for: (1) ``[a]ny applicable clinical trial that is initiated after 
September 27, 2007;'' and (2) ``[a]ny applicable clinical trial that is 
initiated on or before September 27, 2007 and is ongoing on December 
26, 2007 [ . . . ].'' Section 11.22(a)(3) provides clarification for 
determining the date on which an applicable clinical trial is 
initiated, stating that ``[a]n applicable clinical trial, other than a 
pediatric postmarket surveillance of a device product that is not a 
clinical trial, is considered to be initiated on the date on which the 
first human subject is enrolled.''
    Based on the Agency's interpretation of the term ``applicable 
device clinical trial'' as defined in section 402(j)(1) of the PHS Act, 
Sec.  11.22(b)(1) states that a clinical trial is considered an 
applicable device clinical trial if (1) it is a pediatric postmarket 
surveillance of a device product required by FDA under section 522 of 
the FD&C Act (regardless of whether the pediatric postmarket 
surveillance is a clinical trial), or (2) it is a clinical trial with 
one or more arms that meets all of the following criteria: (a) The 
Study Type is interventional; (b) the Primary Purpose selected is any 
other than feasibility; (c) the clinical trial Studies a U.S. FDA-
regulated Device; and, (d) one or more of the following applies: At 
least one Facility Location is within the U.S. or one of its 
territories, the device under investigation is a Product Manufactured 
in and Exported from the U.S. or one of its territories for study in 
another country, or the clinical trial has a U.S. Food and Drug 
Administration IDE Number. We also note that the final rule does not 
include the proposed criterion regarding the Number of Arms and Single 
Arm Controlled data elements in Sec.  11.22(b)(1)(ii)(C) and 
(b)(2)(iii) of the NPRM because the Agency considers all clinical 
trials with one or more arms and pre-specified primary or secondary 
outcome measures controlled for purposes of the final rule (see 
discussion of ``control or controlled'' in Section IV.A.5 of this 
preamble).
    Based on the Agency's interpretation of the term ``applicable drug 
clinical trial'' as defined in section 402(j)(1) of the PHS Act, Sec.  
11.22(b)(2) states that a clinical trial with one or more arms is 
considered an applicable drug clinical trial if it meets all of the 
following: (1) The Study Type is interventional; (2) the Study Phase is 
other than phase 1; (3) the clinical trial Studies a U.S. FDA-regulated 
Drug Product; and, (4) one or more of the following applies: At least 
one Facility Location is within the U.S. or one of its territories, the 
drug product under investigation is a Product Manufactured in and 
Exported from the U.S. for study in another country, or the clinical 
trial has a U.S. Food and Drug Administration IND Number.
    With respect to Study Phase and the determination process, we do 
not consider a phase 1/phase 2 trial (i.e., a trial with 
characteristics of both phase 1 and phase 2 studies trials) to be a 
phase 1 trial. If a clinical trial is initially registered as phase 1/
phase 2 trial, it is considered to be a phase 2 trial. If the trial 
subsequently proceeds through only the phase 1 stage and/or is 
terminated before reaching phase 2, the Study Phase data element may be 
updated to indicate that the trial is a phase 1 trial, in which case it 
would not be considered an applicable drug clinical trial and would not 
be subject to the requirements for results information submission 
specified in subpart C. However, submitted registration information 
would continue

[[Page 65032]]

to be posted in the ClinicalTrials.gov data bank.
    While most applicable clinical trials will meet the definition of 
either an applicable device clinical trial or an applicable drug 
clinical trial, some applicable clinical trials that study multiple 
intervention types (e.g., in different arms of the clinical trial) 
could meet both definitions. For example, a clinical trial with 
facility locations in the U.S. that studies a U.S. FDA-regulated drug 
product in one arm, studies a U.S FDA-regulated device product in 
another arm, and compares outcomes of the two arms would meet both 
definitions. If the U.S. FDA-regulated device product studied in such 
an applicable clinical trial is not approved or cleared by FDA for any 
use, we will not post clinical trial registration information for that 
applicable clinical trial prior to the date of approval or clearance of 
the device product, consistent with Sec.  11.35(b)(2)(i), unless the 
responsible party indicates, pursuant to Sec.  11.35(b)(2)(ii), that it 
authorizes such posting.
3. 11.24--When must clinical trial registration information be 
submitted?
Overview of Proposal
    Proposed Sec.  11.24 specified the deadlines by which a responsible 
party must submit clinical trial registration information for an 
applicable clinical trial to ClinicalTrials.gov, implementing section 
402(j)(2)(c) of the PHS Act. As explained in the NPRM, proposed Sec.  
11.24(a) specified the general registration deadline requiring 
submission by the later of December 26, 2007, or 21 calendar days after 
enrollment of the first human subject in a clinical trial, as specified 
in section 402(j)(2)(C)(i) and (ii) (79 FR 69611). Proposed Sec.  
11.24(b) implemented two exceptions: (1) For applicable clinical trials 
that are not for a serious or life-threatening disease or condition and 
that were initiated on or before enactment of FDAAA, the registration 
deadline is not later than September 27, 2008, or 21 calendar days 
after the first human subject is enrolled, whichever date is later, 
consistent with section 402(j)(2)(C)(iii) of the PHS Act, and (2) for a 
pediatric postmarket surveillance of a device product that is not a 
clinical trial, which is defined as an applicable device clinical trial 
in section 402(j)(1)(A)(ii)(II) of the PHS Act, the registration 
deadline is not later than December 26, 2007, or 21 calendar days after 
FDA approves the postmarket surveillance plan, whichever date is later 
(79 FR 69611).
Comments and Response
    Commenters addressed the registration submission deadlines in 
proposed Sec.  11.24. The commenters suggested that the final rule 
require general registration prior to enrollment of the first human 
subject, rather than allow up to an additional 21 calendar days as 
proposed. One commenter noted that such a deadline would be consistent 
with requirements specified in the EU Clinical Trials Regulation as 
well as the Declaration of Helsinki. Another commenter also requested 
that the final rule omit the exception to the general deadline for 
registering applicable clinical trials not for a serious or life-
threatening disease or condition specified in proposed Sec.  
11.24(b)(1). The Agency is not revising proposed Sec.  11.24 as 
suggestedby the comments. Section 11.24 accurately reflects the 
statutory requirements for submission of registration information.
Final Rule
    Taking into consideration the commenters' suggestions and the 
statutory requirements for registration information submission 
deadlines, the final rule maintains the approach proposed in Sec.  
11.24(a) and (b) except that it clarifies that ``device'' means 
``device product.'' In addition, we have clarify that the clinical 
trial registration information that must be submitted will either be 
the information specified in section 402(j)(2)(A)(ii) of the PHS Act or 
in Sec.  11.28(a). Consistent with the discussion in section IV.F., the 
requirements for applicable clinical trials will differ based on the 
initiation date of the applicable clinical trial. Final Sec.  11.24(a) 
generally requires a responsible party to submit clinical trial 
registration information 21 calendar days after the first human subject 
is enrolled in the clinical trial. Final Sec.  11.24 also provides 
exceptions to this general registration submission deadline for 
applicable clinical trials that are clinical trials and were (1) 
initiated on or before September 27, 2007, and (2) ongoing as of 
December 26, 2007. For applicable clinical trials for a serious or 
life-threatening disease or condition, responsible parties were 
required to submit registration information by December 26, 2007, under 
Sec.  11.24(a). Examples of serious or life-threatening diseases or 
conditions include acquired immunodeficiency syndrome, all other stages 
of human immunodeficiency virus (HIV), Alzheimer's disease, cancer, or 
heart failure [Ref. 78, 79]. For applicable clinical trials not for a 
serious or life-threatening disease or condition, responsible parties 
were required to submit registration information by September 27, 2008, 
under Sec.  11.24(b)(1).
4. Sec.  11.28--What constitutes clinical trial registration 
information?
Sec.  11.28--Overall
Overview of Proposal
    Proposed Sec.  11.28 identified the structured information, or data 
elements, that constitute clinical trial information that a responsible 
party must submit in order to register an applicable clinical trial. 
Section 402(j)(2)(A)(ii) of the PHS Act specifies a number of data 
elements that must be submitted to ClinicalTrials.gov for registration. 
In general, the proposed data elements in Sec.  11.28 conformed to the 
items enumerated in section 402(j)(2)(A)(ii) of the PHS Act. In many 
instances, the Agency, through the proposed rulemaking, had restated or 
clarified the registration data elements required by section 
402(j)(2)(A)(ii) of the PHS Act. In addition, section 402(j)(2)(A)(iii) 
of the PHS Act expressly authorizes the Secretary to modify the 
registration data elements, by regulation, if a rationale is provided 
as to why such a modification ``improves and does not reduce'' such 
information. In developing the proposed set of data elements for 
registration, we carefully considered the items enumerated in section 
402(j)(2)(A)(ii) of the PHS Act, the mandate in section 402(j)(2)(A)(i) 
to ``expand'' the existing registration data bank, and the intent to 
expand the data bank ``to enhance patient enrollment and provide a 
mechanism to track subsequent progress of clinical trials'' (see 
section 402(j)(2)(A)(i) of the PHS Act). We also took into 
consideration the WHO Trial Registration Data Set and have sought to 
maintain consistency with the clinical trial registration requirements 
of ICMJE [Ref. 73, 2].
    As we noted in the NPRM, careful consideration was given to the 
data elements that were part of the data bank prior to passage in 2007 
of section 402(j) of the PHS Act, some of which are not expressly 
required under section 402(j)(2)(A)(ii) of the PHS Act, but which we 
considered necessary to fulfill both the purpose of the expansion of 
registration information contained in ClinicalTrials.gov and certain 
other requirements of section 402(j) of the PHS Act. We later consulted 
with a wide range of groups, including the NLM Board of Directors 
Working Group on Clinical Trials, internal NIH and joint NIH-FDA 
working groups and committees, the FDA Risk Communication Advisory 
Committee, the HHS Secretary's Advisory

[[Page 65033]]

Committee on Human Research Protections, the Drug Information 
Association Clinical Trial Disclosure Special Interest Area Community, 
and a Clinical and Translational Science Awards ClinicalTrials.gov Task 
Force [Ref. 72, 91, 91]. We believe, in general, that maintaining 
consistency with the pre-existing ClinicalTrials.gov data elements is 
consistent with the intent of section 402(j) of the PHS Act. Not only 
do we presume that Congress was familiar with those existing 
definitions when it developed and passed section 402(j) of the PHS Act, 
we also believe that maintaining consistency achieves several important 
goals. It is intended to minimize confusion for those who submitted 
registration information to ClinicalTrials.gov prior to enactment of 
section 402(j) of the PHS Act as well as minimize the level of effort 
required by those who previously established automated computer-based 
processes for submitting and updating registration data in 
ClinicalTrials.gov, rather than entering the data manually into the 
data bank. We believe that maintaining consistency serves the public by 
facilitating cross-comparison of entries made before and after 
enactment of section 402(j) of the PHS Act and that it also ensures 
that the proposed clinical trial registration information requirements 
would not have the effect of reducing the amount of information 
available for newly registered clinical trials as compared to those 
registered prior to the passage in 2007 of section 402(j) of the PHS 
Act, a result that we believe would be contrary to the intent of 
section 402(j) of the PHS Act. For these reasons, we believe that 
requiring the submission of data elements that were expected to be 
submitted to ClinicalTrials.gov prior to the passage in 2007 of section 
402(j) of the PHS Act in order to register a clinical trial improves 
and does not reduce the clinical trial information submitted to 
ClinicalTrials.gov.
    While developing our proposed set of data elements for clinical 
trial registration information for the NPRM, we decided to exercise our 
authority under section 402(j)(2)(A)(iii) of the PHS Act to modify the 
section 402(j)(2)(A)(ii) requirements for registration information in 
order to achieve the following objectives:
    (1) Specify a particular structure for submitting certain clinical 
trial registration information in order to (a) help the public use the 
data bank more easily and be able to compare entries, consistent with 
section 402(j)(2)(B)(iv) of the PHS Act; (b) enable searching of the 
data bank using criteria listed in sections 402(j)(2)(B)(i) and (ii) of 
the PHS Act; and (c) facilitate the submission of complete and accurate 
information by responsible parties.
    (2) Enable effective implementation of, or compliance with, other 
provisions of section 402(j) of the PHS Act and this part, e.g., 
proposed adding data elements to indicate whether a product under study 
in a clinical trial is manufactured in the United States and whether a 
study is a pediatric postmarket surveillance of a device product, both 
of which are important to help determine whether a study meets the 
definition of an applicable clinical trial.
    (3) Improve the quality and consistency of clinical trial 
registration information, e.g., proposed adding the Other Intervention 
Name(s) and Intervention Description data elements to help users 
identify and differentiate among similar interventions studied in 
registered clinical trials.
    (4) Demonstrate whether clinical trials registered in the data bank 
have complied with ethical and scientific review procedures in 
accordance with applicable statutes and regulations, e.g., proposed 
adding the Human Subjects Protection Review Board Status data element 
to indicate to potential human subjects and other users whether an 
applicable clinical trial has received needed approvals or is not 
subject to such requirements (79 FR 69611).
    Several commenters supported the additional registration data 
elements proposed in the NPRM. An additional commenter requested that 
the final rule minimize the number of required registration data 
elements to provide more flexibility for the reporting of different 
types of trials. In developing the proposed registration data elements, 
the Agency carefully considered the statutory provisions and additional 
requirements in order to carry out those mandates. We believe that the 
data elements proposed in the NPRM represent a ``minimum'' data set of 
the information required to describe and understand key information 
about a clinical trial. Nevertheless, we have modified some of the 
proposed definitions and requirements for particular data elements in 
the final rule in response to public comments as well as on our own 
initiative (e.g., for clarity or consistency).
Sec.  11.28(a)--Clinical Trial
Overview of Proposal
    Proposed Sec.  11.28(a) specified the data elements that a 
responsible party would be required to submit to ClinicalTrials.gov to 
register an applicable clinical trial other than a pediatric postmarket 
surveillance of a device that is not a clinical trial. As we described 
in the NPRM, the clinical trial registration information data elements 
are grouped into the four categories used in section 402(j)(2)(A)(ii) 
of the PHS Act: (1) Descriptive information, (2) recruitment 
information, (3) location and contact information, and, (4) 
administrative data. Additional data elements that the Agency proposed 
were listed in the categories in which they best fit. The proposed 
clinical trial registration information data elements, grouped by 
category, were described in detail in the NPRM. See Section IV.B.4(a) 
of the NPRM for details about the data elements under proposed Sec.  
11.28(a) (79 FR 69612).
    For each data element defined in proposed Sec.  11.28(a), we 
describe the following: (1) The proposed definition, (2) any specific 
public comment(s) we received about the data element and our 
response(s), and (3) the definition used in Sec.  11.28(a) of the final 
rule. The information about each data element is ordered by section 
number as assigned in the codified section of the final rule, which 
also parallels section 402(j)(2)(A)(ii) of the PHS Act. We note that in 
the final rule some of the names of the data elements, as well as their 
numbers, differ from those assigned in the NPRM because of 
modifications to the data elements, all of which are described in the 
context of each specific data element. After discussing the last 
registration data element listed under Sec.  11.28(a) of the final rule 
(i.e., Responsible Party Contact Information in Sec.  
11.28(a)(2)(iv)(F)), we address data elements that were suggested in 
the public comments but were not added in the final rule.
    We have made one overall change to the structure of Sec.  11.28(a) 
and (b). In light of our determination that the registration 
requirements that apply to an applicable clinical trial are determined 
by the date on which the trial is initiated, i.e., the actual Study 
Start Date, as defined in Sec.  11.10(b)(16) (see discussion below in 
section IV.F.), we have indicated in both Sec.  11.28(a) and (b) that 
for applicable clinical trials that must be registered with 
ClinicalTrials.gov as specified in section 402(j)(2)(C) of the PHS Act 
or Sec.  11.22, the responsible party must submit the information 
specified in section 402(j)(2)(A)(ii) of the PHS Act or the data 
elements listed in Sec.  11.28, as applicable.
    Based on this modification, Sec.  11.28(a)(1) requires that ``[f]or 
such applicable clinical trials that were initiated before January 18, 
2017, the responsible party must submit the

[[Page 65034]]

information specified in section 402(j)(2)(A)(ii) of the Public Health 
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).'' Section 11.28(a)(2) 
requires the data elements described below for such applicable clinical 
trials that are initiated on or after January 18, 2017.
(i) Descriptive Information
    (A) Brief Title. In Sec.  11.10(b)(1) of the NPRM, Brief Title was 
defined as ``a short title of the clinical trial written in language 
intended for the lay public, including any acronym or abbreviation used 
publicly to identify the clinical trial.'' Section 
402(j)(2)(A)(ii)(I)(aa) of the PHS Act specifically requires the 
submission of a brief title as part of the clinical trial information 
submitted at registration, but it does not define the term, other than 
to indicate that the title is ``intended for the lay public.'' As 
explained in the NPRM, we interpreted this requirement to mean that 
potential human subjects should be able to understand, from the brief 
title, the general purpose of the clinical trial and distinguish it 
from others listed in the data bank. Additionally, based on our 
experience to date with ClinicalTrials.gov, we recognized that acronyms 
are frequently used to refer to clinical trials (e.g., ``ACCORD'' for 
the Action to Control Cardiovascular Risk in Diabetes trial or 
``STAR*D'' for the Sequenced Treatment Alternatives to Relieve 
Depression trial), and we believe that it is important for such 
acronyms to be included in the registry to enable users of the data 
bank to identify clinical trials that they may see referenced in other 
media (e.g., news reports, journal articles). As such, we considered an 
acronym used to identify a clinical trial to be part of the brief title 
(79 FR 69612). We received no comments on this description and 
therefore maintain the proposed description in the final rule. We note 
that a Brief Title intended for the lay public should include, where 
possible, information on the participants, condition being evaluated, 
and intervention(s) studied.
    (B) Official Title. In Sec.  11.10(b)(2) of the NPRM, we defined 
Official Title as ``[t]he title of the clinical trial, corresponding to 
the title of the protocol.'' As described in the NPRM, while not 
explicitly required in section 402(j)(2)(A)(ii)(I) of the PHS Act, we 
used the authority in section 402(j)(2)(A)(iii) of the PHS Act to 
propose to require a responsible party to submit an official title as 
part of clinical trial information when registering an applicable 
clinical trial on ClinicalTrials.gov. We expressed our belief that the 
Official Title will complement the Brief Title that is intended for the 
lay public by providing a technical title that will help researchers 
understand the general purpose of the study. The official title would 
also be helpful in associating the clinical trial on ClinicalTrials.gov 
with information about the clinical trial contained in other sources, 
such as scientific publications, regulatory submissions, and media 
reports, which often use the official title of the study protocol (79 
FR 69612). We received no comments on this description and therefore 
maintain the proposed description in the final rule. We note that 
Official Title is also consistent with the WHO Trial Registration Data 
Set (version 1.2.1) (WHO data item #10) and ICMJE registration 
policies, which require the submission of a ``scientific title'' [Ref. 
73, 2].
    (C) Brief Summary. In Sec.  11.10(b)(3) of the NPRM, Brief Summary 
was described as ``a short description of the clinical trial, including 
a brief statement of the clinical trial's hypothesis, written in 
language intended for the lay public.'' As noted in the NPRM, section 
402(j)(2)(A)(ii)(I)(bb) of the PHS Act expressly requires a ``brief 
summary'' to be submitted as clinical trial registration information, 
but it does not define the term other than to indicate that the brief 
summary is ``intended for the lay public'' (79 FR 69612). We received 
no comments on this description and therefore maintain the proposed 
description in the final rule.
    (D) Primary Purpose. Under Sec.  11.10(b)(4) of the NPRM, Primary 
Purpose referred to ``the main objective of the intervention(s) being 
evaluated by the clinical trial.'' We noted in the NPRM that section 
402(j)(2)(A)(ii)(I)(cc) of the PHS Act expressly requires the ``primary 
purpose'' of the intervention(s) to be submitted as clinical trial 
registration information, but it does not define the term (79 FR 
69612). We received no comments on this description and maintain the 
proposed definition in the final rule.
    In the NPRM, we stated that we would require a responsible party to 
provide a response selected from the following set of options: 
``Treatment,'' ``prevention,'' ``diagnostic,'' ``supportive care,'' 
``screening,'' ``health services research,'' ``basic science,'' 
``feasibility,'' or ``other'' (79 FR 69612) We are modifying the name 
of one of these options, from ``feasibility'' to ``device 
feasibility.'' This change helps responsible parties more easily 
recognize that the option is intended to be limited to the type of 
feasibility study of a device that is described as being excluded from 
the definition of an applicable device clinical trial as specified in 
section 402(j)(1)(A)(ii) of the PHS Act and defined in Sec.  11.10(a) 
of this part. ``Device feasibility'' is distinguished from the general 
term ``feasibility,'' which is sometimes used in research to describe a 
study that is performed to determine the practicality of conducting a 
full clinical trial. We also note that a responsible party may 
nevertheless voluntarily register a clinical trial that is a 
feasibility study of a device. Such registration would be a voluntary 
submission of clinical trial information under section 402(j)(4)(A) of 
the PHS Act and Sec.  11.60 of the final rule.
    In addition, we would like to provide additional clarification for 
responsible parties regarding the options available under Primary 
Purpose. These clarifications are as follows: ``Treatment'' should be 
selected when one or more interventions are being evaluated for 
treating a disease, syndrome, or condition; ``prevention'' should be 
selected when one or more interventions are being assessed for 
preventing the development of a specific disease or health condition; 
``diagnostic'' should be selected when one or more interventions are 
being evaluated for identifying a disease or health condition; 
``supportive care'' should be selected when one or more interventions 
are being evaluated for maximizing comfort, minimizing side effects, or 
mitigating against a decline in the subject's health or function; 
``screening'' should be selected when one or more interventions are 
being assessed or examined for identifying a condition, or risk factors 
for a condition, in people who are not yet known to have the condition 
or risk factor; ``health services research'' should be selected when 
one or more interventions are being evaluated for the delivery, 
processes, management, organization or financing of health care; 
``basic science'' should be selected when one or more interventions are 
being used for examining the basic mechanism of action (e.g., 
physiology, biomechanics), of an intervention or disease process; 
``device feasibility'' should be selected when a device product is 
being evaluated for the feasibility of the product or of a test 
prototype device and not health outcomes; and ``other'' should be 
selected when none of the other options apply.
    (E) Study Design. Proposed Sec.  11.10(b)(5) defined Study Design 
as ``a description of the manner in which the clinical trial will be 
conducted'' and required information about the following important 
aspects of a clinical

[[Page 65035]]

trial: Interventional study model, number of arms, arm information, 
allocation, masking, and whether a single-armed clinical trial is 
controlled. As we noted in the NPRM, this proposed definition of Study 
Design, including the key attributes, conforms to ICH Guidelines [Ref. 
56] and is consistent with ``study type'' of the WHO Trial Registration 
Data Set (version 1.2.1) (WHO data item #15) and ICMJE registration 
policies [Ref. 2, 73]. Section 402(j)(2)(A)(ii)(I)(dd) of the PHS Act 
expressly requires ``study design'' to be submitted as part of clinical 
trial registration information, but it does not define the term. 
Because there are many important aspects of a study design, and 
information about each is relevant to ensuring that the descriptions of 
study designs are complete and comparable across clinical trials, we 
proposed to require that several components of study design be 
submitted, as described below. Although none of these terms is used in 
section 402(j) of the PHS Act, we pointed out that we believe that each 
is a key component of study design (79 FR 69613). We received no 
comments on the overall definition and therefore generally maintain the 
proposed definition of Study Design in the final rule, with one 
exception.
    The final rule does not include the proposed Single Arm Controlled? 
data item of the Study Design data element, which was defined in Sec.  
11.10(b)(5)(vi) of the NPRM as ``[f]or a single-armed clinical trial 
only, whether or not the clinical trial is controlled, as specified by 
the protocol or statistical analysis plan.'' This data item of the 
Study Design data element was proposed in the NPRM to assist the 
Agency, responsible parties, and users of the data bank in determining 
whether a clinical trial with only one arm meets the definition of an 
applicable clinical trial because it includes a control or is 
controlled. However, as described in Section IV.A.5, the Agency has 
clarified its interpretation of ``control or controlled'' to make clear 
that all single-arm interventional studies or clinical trials with pre-
specified primary or secondary outcome measures are considered to be 
``controlled'' for purposes of this part. As such, the proposed Single 
Arm Controlled? component of the Study Design data element is not 
necessary and has been removed from Sec. Sec.  11.10(b) and 11.22(b) of 
the final rule.
    Interventional Study Model. In Sec.  11.10(b)(5)(i) of the NPRM, 
this data item was defined as ``[t]he strategy for assigning 
interventions to human subjects.'' As stated in the NPRM, responsible 
parties would be required to select an entry from the following limited 
set of proposed options: ``single group'' (i.e., clinical trials with a 
single arm), ``parallel'' (i.e., participants are assigned to one of 
two or more groups in parallel for the duration of the study), ``cross-
over'' (i.e., participants receive one of two alternative interventions 
during the initial phase of the study and receive the other 
intervention during the second phase of the study), and ``factorial'' 
(i.e., two or more interventions, each alone and in combination, are 
evaluated in parallel against a control group). No ``other'' option was 
proposed. To address situations in which a clinical trial might use a 
modified version of one of these models, or the responsible party might 
wish to provide more information about the specific implementation of 
the model, we proposed that responsible parties also be able to provide 
an optional additional free-text description containing more specific 
details about the interventional study model. We invited public comment 
on this proposed definition and approach (79 FR 69613). A few 
commenters recommended that the final rule add an ``other'' option for 
Interventional Study Model, with one commenter suggesting ``enrichment 
designs'' and ``adaptive borrowing of historical data'' as examples. We 
note that these examples do not appear to represent interventional 
study models that differ conceptually from those proposed in the NPRM. 
For example, even though ``enrichment designs'' involve prespecified 
study periods that allow researchers to select subsets of enrolled 
participants who are likely to be particularly sensitive to the studied 
intervention (e.g., to demonstrate the effect of a drug), we believe 
that the underlying interventional study model involves at least one of 
the suggested options (i.e., ``single-group,'' ``parallel,'' ``cross-
over,'' or ``factorial''). The fact that a study involves an enrichment 
design could be noted in the proposed optional additional free-text 
description field. The final rule retains the name and definition of 
Interventional Study Model as proposed in the NPRM. In reviewing this 
proposed data item, however, we identified two modifications to the set 
of proposed options. First, based on our experience in operating 
ClinicalTrials.gov, we add the option of ``sequential'' as we believe 
that it represents an Interventional Study Model that is fundamentally 
different from the other options available for selection under 
Interventional Study Model and is fairly common among drug studies 
(e.g., dose escalation). Thus, we have added ``sequential'' as an 
option under the Interventional Study Model data item; responsible 
parties would select this option to indicate that groups of 
participants are assigned to receive interventions based on prior 
milestones being reached in the study, such as in some dose escalation 
and adaptive design studies. Second, we have also modified the 
description of the ``cross-over'' option to clarify that this term 
refers to study designs in which participants are assigned to receive 
one of two (or more) alternative interventions during the initial phase 
of the study followed by the other intervention(s) during subsequent 
phase(s) of the study. This modification clarifies that cross-over 
studies are not restricted to just two interventions, but may involve 
two (or more) interventions [Ref. 84].
    Number of Arms. In Sec.  11.10(b)(5)(ii) of the NPRM, this data 
item was defined as ``[t]he number of arms in the clinical trial. For a 
trial with multiple periods or phases that have different numbers of 
arms, the maximum number of arms during any period or phase.'' We noted 
that the term ``arm'' was defined in proposed Sec.  11.10(a) and that 
some clinical trials contain multiple periods or phases, each of which 
might use different numbers of arms. We also clarified in the NPRM that 
we do not consider historical controls to be an ``arm'' of a clinical 
trial for the purposes of this part, therefore, they would not be 
counted in the number of arms (79 FR 69613). One commenter suggested 
that, for reporting trials with ``mutually reporting arms,'' the 
maximum number of arms listed should be inclusive of all arms from all 
periods. This commenter also suggested that historical controls not be 
counted in the Number of Arms data item of the Study Design data 
element, which is specified in proposed Sec.  11.28(a)(1)(v) and 
defined in proposed Sec.  11.10(b)(5)(ii). We interpreted this comment 
to refer to ``mutually exclusive reporting arms,'' agree with the 
commenter, and note that the definition in Sec.  11.10(b)(5)(ii) 
specifies that ``[f]or a trial with multiple periods or phases that 
have different numbers of arms, it means the maximum number of arms 
during all periods or phases.'' We also reiterate, as stated in the 
preamble of the NPRM, that ``historical controls are not considered to 
be an `arm' of a clinical trial and thus are not counted in the number 
of arms'' (79 FR 69613). After considering this comment, we maintain 
the proposed definition in the final rule, except the definition 
clarifies that for a trial with multiple periods or phases

[[Page 65036]]

that have different numbers of arms, the ``number of arms'' means the 
maximum number of arms during ``all periods or phases''.
    Arm Information. In Sec.  11.10(b)(5)(iii) of the NPRM, this data 
item was defined as ``[a] description of each arm of the clinical trial 
that indicates its role in the clinical trial, provides an informative 
title, and, if necessary, additional descriptive information to 
differentiate each arm from other arms in the clinical trial.'' As 
stated in the NPRM, responsible parties would be required to select 
from the following list of options for describing the role of each arm 
in the clinical trial: ``Experimental,'' ``active comparator,'' 
``placebo comparator,'' ``sham comparator,'' ``no intervention,'' or 
``other.'' The informative title would consist of a label or short name 
to identify the arm in the clinical trial record (e.g., the name of the 
experimental intervention used in the arm or placebo). Additional 
descriptive information would be required if the informative title does 
not sufficiently differentiate among arms in the clinical trial (e.g., 
in a clinical trial that compares two different dosages of the same 
investigational drug, the descriptive information would have to 
indicate which is the higher dose arm versus the lower dose arm). Even 
if the informative title and/or additional descriptive information vary 
sufficiently among the arms of the clinical trial, responsible parties 
may voluntarily include additional details about the interventions or 
the arms in this field (79 FR 69613). We received a few comments about 
Arm Information. One commenter requested that the final rule clarify 
that a historical-control arm be considered ``other'' from the list of 
options available for Arm Information. Another commenter asked for a 
way to distinguish between study designs that incorporate 
``concurrent'' and ``nonconcurrent'' controls, which are described in 
the preamble discussion of the term ``controlled'' in the NPRM. As 
noted in the preamble of the NPRM, we do not consider historical 
controls or other types of non-concurrent controls to be arms for the 
purposes of the Number of Arms data item defined in proposed Sec.  
11.10(b)(5)(ii) (79 FR 69613). Because Arm Information is used to 
describe each arm identified by Number of Arms, the need to identify an 
arm as ``historical'' or ``nonconcurrent'' should not arise when 
submitting Arm Information in ClinicalTrials.gov. However, if a 
responsible party wishes to identify and/or describe a historical or 
non-concurrent control used in the study, we note that such information 
could be submitted using an optional data item such as Detailed 
Description. After consideration of these comments, we generally are 
maintaining the proposed definition in the final rule. However, we are 
revising it slightly to specify that if more than one arm is specified 
for the clinical trial, the responsible party must designate the listed 
intervention(s) to the arm in which they are administered. Therefore, 
``arm information'' is defined as ``[a] description of each arm of the 
clinical trial that indicates its role in the clinical trial, provides 
an informative title, and, if necessary, additional descriptive 
information (including which interventions are administered in each 
arm) to differentiate each arm from other arms in the clinical trial.'' 
This designation approach (currently implemented using the ``[Arm or 
Group]/Intervention Cross-Reference'' data element) will allow for 
continuing to display on ClinicalTrials.gov arm and intervention 
information as a table, helping users understand the relationship 
between arm information and intervention information.
    Allocation. In Sec.  11.10(b)(5)(iv) of the NPRM, this data item 
was defined as ``[t]he method by which human subjects are assigned to 
arms in a clinical trial.'' As stated in the NPRM, responsible parties 
would be required to select from the following limited set of options: 
``randomized'' (participants are assigned to intervention groups by 
chance), or ``nonrandomized'' (participants are expressly assigned to 
intervention groups through a non-random method, such as physician 
choice), or ``not applicable'' (for a single-arm study). No ``other'' 
option was proposed (79 FR 69613). We invited public comment, but did 
not receive any, therefore, we maintain the proposed definition and 
approach in the final rule.
    Masking. In Sec.  11.10(b)(5)(v) of the NPRM, this data item was 
defined as ``[t]he party or parties, if any, involved in the clinical 
trial who are prevented from having knowledge of the interventions 
assigned to individual human subjects.'' As stated in the NPRM, 
responsible parties would be required to select from the following 
limited set of choices for describing which party(ies) is/are masked: 
``human subject,'' ``care provider,'' ``investigator,'' and/or an 
``outcomes assessor'' (i.e., the individual who evaluates the 
outcome(s) of interest). No ``other'' option was proposed, but 
responsible parties would have the ability to provide additional, 
optional free-text information about other parties who may be blinded 
in the clinical trial (79 FR 69614). We received no comments, however, 
for clarity, we are adding to the limited menu of choices ``no 
masking'' for the responsible party to indicate that the study design 
does not include masking (e.g., open-label). We otherwise maintain the 
proposed definition in the final rule.
    Single Arm Controlled. In Sec.  11.10(b)(5)(vi) of the NPRM, this 
data item was defined as ``for a single arm clinical trial only, 
whether or not the clinical trial is controlled, as specified by the 
protocol or statistical analysis plan.'' We have deleted this data item 
in the final rule because the information is no longer necessary to 
determine whether a clinical trial is ``controlled'' under the 
definition in Sec.  11.10(a) and therefore an ``applicable drug 
clinical trial'' or ``applicable device clinical trial'' under the 
regulations, as discussed in the preamble for Sec.  11.22.
    (F) Study Phase. In Sec.  11.10(b)(6) of the NPRM, this data 
element was defined as ``for a clinical trial of a drug, the numerical 
phase of such clinical trial, consistent with terminology in 21 CFR 
312.21, or any successor regulation, such as phase 2 or phase 3, and in 
21 CFR 312.85, or any successor regulation, for phase 4 studies.'' 
Section 402(j)(2)(A)(ii)(I)(ee) of the PHS Act expressly requires, for 
an applicable drug clinical trial, the ``study phase'' to be submitted 
as a clinical trial registration information data element, but it does 
not define the term. As stated in the NPRM, responsible parties would 
be required to select one response from a limited list of options that 
includes phases 1, 2, 3, and 4, consistent with the terminology in 21 
CFR 312.21 and 21 CFR 312.85. In addition, responsible parties would be 
able to select from other options that are commonly used in practice: 
Phase 1/phase 2 (for trials that are a combination of phases 1 and 2; 
as discussed previously, phase 1/phase 2 studies are not considered 
phase 1 studies and may be applicable drug clinical trials) and phase 
2/phase 3 (for trials that are a combination of phases 2 and 3). No 
``other'' option was proposed. Although we are aware that the term 
``phase 0'' is used in practice (e.g., to refer to clinical trials that 
are exploratory in nature and are not designed to evaluate therapeutic 
or diagnostic intent), any trial that would be referred to as ``phase 
0'' meets the definition of a phase 1 trial under FDA regulations (21 
CFR 312.21). Therefore, we did not propose to include ``phase 0'' as an 
option for the Study Phase data element, and responsible parties 
registering a clinical trial that might be referred to as ``phase 0'' 
would select ``phase 1'' for the Study Phase (79 FR 69614). We received 
no comments on

[[Page 65037]]

this description and therefore maintain the proposed description in the 
final rule except that we clarify that ``drug'' means ``drug product.'' 
We note that study phases are not intended for use in describing 
clinical trials of devices; therefore, consistent with section 
402(j)(2)(A)(ii)(I)(ee) of the PHS Act, responsible parties for 
applicable device clinical trials would not be required to submit this 
data element.
    (G) Study Type. In Sec.  11.10(b)(7) of the NPRM, we defined this 
data element as ``the type of study for which clinical trial 
information is being submitted.'' Section 402(j)(2)(A)(ii)(I)(ff) of 
the PHS Act expressly requires ``study type'' to be submitted as 
clinical trial information at the time of registration, but it does not 
define the term. Consistent with practice prior to FDAAA, we stated in 
the NPRM that responsible parties would be required to select one of 
the following limited set of options: ``Interventional,'' 
``observational,'' or ``expanded access program.'' No ``other'' option 
was proposed. We expressed our belief that all applicable clinical 
trials and all other clinical studies that might be registered 
voluntarily on ClinicalTrials.gov could be accurately characterized as 
either ``interventional'' or ``observational,'' depending on whether 
human subjects studied are assigned to interventions based on a 
research protocol (interventional) or whether patients receive 
interventions as part of routine medical care, and a researcher studies 
the effect of the intervention (observational). We indicated that we 
would consider observational studies to include a wide range of non-
interventional studies, including retrospective reviews of patient 
records or relevant literature (79 FR 69614). (See the elaboration of 
the terms ``applicable device clinical trial'' and ``applicable drug 
clinical trial'' in Section IV.A.5 of this preamble). We received one 
comment requesting that we provide clarification by either providing 
examples or modifying the definition so that it does not use the term 
being defined. We believe ``type of study'' in the proposed definition 
is sufficiently clear, particularly with the three options described 
for the Study Type data element. In addition, the elaboration of the 
terms ``applicable device clinical trial'' and ``applicable drug 
clinical trial'' in Section IV.A.5 of this preamble provide further 
details about interventional and observational studies. We also plan to 
provide additional guidance, including examples, as needed.
    After considering the comments, we maintain the NPRM definition in 
the final rule, except we clarify that Study Type means ``the nature of 
the investigation or investigational use for which clinical trial 
information is being submitted, e.g., interventional, observational.'' 
We note that a study that is designated ``interventional,'' as that 
term is defined in this part, may or may not be an applicable clinical 
trial, depending on whether it meets the other criteria for an 
applicable clinical trial that are specified in this part. A study that 
is designated ``observational'' would be an applicable clinical trial 
only if it is a pediatric postmarket surveillance of a device product 
as defined in this part. (See the definition of ``pediatric postmarket 
surveillance of a device product'' in Sec.  11.10, the discussion of 
Sec.  11.28(b), and the discussion of observational studies in Section 
IV.A.5 of this preamble). Conversely, any applicable clinical trial 
other than a pediatric postmarket surveillance of a device product must 
have a Study Type of ``interventional.'' An applicable clinical trial 
that is a pediatric postmarket surveillance of a device product could 
have a Study Type of ``interventional'' or ``observational.'' The term 
``expanded access'' is provided as an option for Study Type because 
responsible parties who are both manufacturers of an investigational 
drug product (including a biological product) that is available for 
expanded access use and sponsors of an applicable clinical trial of the 
investigational product are required to create an expanded access 
record for the investigational drug product (including a biological 
product) if such a record does not already exist at the time the 
applicable clinical trial is registered. As discussed in section IV.A.5 
of this preamble, expanded access use is not considered to be an 
applicable clinical trial. Therefore, the Study Type for all expanded 
access use is ``expanded access'' (see the discussion of Sec.  
11.28(c)).
    (H) Pediatric Postmarket Surveillance of a Device Product. In Sec.  
11.10(b)(8) of the NPRM, we defined the Whether the Study is a 
Pediatric Postmarket Surveillance of a Device data element to mean 
``for a study that includes a device as an intervention and is a 
pediatric postmarket surveillance of a device, an affirmation that the 
study is a pediatric postmarket surveillance of a device.'' Although 
this data element is not explicitly listed in section 402(j) of the PHS 
Act as part of clinical trial information, we proposed it to identify a 
subset of applicable device clinical trials. As we noted in the NPRM, 
the term ``applicable device clinical trial'' is defined, in part, as 
``a pediatric postmarket surveillance as required under section 522 of 
the Federal Food, Drug, and Cosmetic Act'' (see section 
402(j)(1)(A)(ii)(II) of the PHS Act). A responsible party would be 
required to provide this data element only if the study is a pediatric 
postmarket surveillance of a device product; a responsible party would 
not be required to submit this data element if the device study is not 
a pediatric postmarket surveillance of a device product (79 FR 69615). 
We received no comments addressing this data element. In the final 
rule, we modify the name of the data element to ``Pediatric Postmarket 
Surveillance of a Device Product'' to clarify that ``device'' means 
``device product'' and modify the definition to clarify that the term 
refers only to ``a clinical trial or study that includes a U.S. FDA-
regulated device product as an intervention'' and is a pediatric 
postmarket surveillance of a device product ``ordered under section 522 
of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 369l).'' In the 
final rule, we also removed from the definition the requirement for an 
affirmation that the study is a pediatric postmarket surveillance of a 
device. By indicating that a study is a pediatric postmarket 
surveillance of a device product, users of the data bank and the Agency 
will be able to confirm that the study is an applicable device clinical 
trial. In addition, by combining this information with other submitted 
clinical trial registration information (e.g., the Study Type data 
element), the Agency could confirm whether the pediatric postmarket 
surveillance of a device product is a clinical trial and indicate which 
other data elements must be submitted at the time of registration. If a 
pediatric postmarket surveillance of a device product is a clinical 
trial, the clinical trial registration information data elements set 
forth in Sec.  11.28(a) will be required to be submitted. If a 
pediatric postmarket surveillance of a device product is not a clinical 
trial (i.e., it is a form of observational study, including a 
retrospective review of patient records or relevant literature), then 
the clinical trial registration information data elements specified in 
Sec.  11.28(b) will be required to be submitted.
    (I) Primary Disease or Condition Being Studied in the Trial, or the 
Focus of the Study. In Sec.  11.10(b)(9) of the NPRM, we defined this 
data element as ``the name(s) of the disease(s) or condition(s) studied 
in the clinical trial, or the focus of the clinical trial, using, if 
available, appropriate descriptors from the NLM's

[[Page 65038]]

MeSH controlled vocabulary thesaurus http://www.nlm.nih.gov/mesh/, or 
terms from another vocabulary, such as the SNOMED CT, that has been 
mapped to MeSH within the UMLS Metathesaurus, https://uts.nlm.nih.gov.'' As we noted in the NPRM, section 
402(j)(2)(A)(ii)(I)(gg) of the PHS Act expressly requires ``the primary 
disease or condition being studied, or the focus of the study'' to be 
submitted as part of clinical trial registration information, but it 
does not define the term. Section 402(j)(2)(B)(i)(I) of the PHS Act 
further requires the data bank to be searchable by one or more of eight 
listed criteria, including ``the disease or condition being studied in 
the clinical trial, using Medical Subject Headers (MeSH) descriptors.'' 
To support searching using MeSH descriptors, the primary disease or 
condition being studied in the clinical trial, or the focus of the 
study, must be described using either MeSH terminology (http://www.nlm.nih.gov/mesh/) or another terminology that has been mapped to 
MeSH, when available (if the other terminology is mapped to MeSH, the 
data bank can be searched using MeSH terms and retrieve the correct 
record(s)) (79 FR 69615). We received no comments on this proposed data 
element, but we slightly modify the proposed description in the final 
rule for clarity as follows: ``the name(s) of the disease(s) or 
condition(s) studied in the clinical trial, or the focus of the 
clinical trial. Use, if available, appropriate descriptors from NLM's 
Medical Subject Headings (MeSH) controlled vocabulary thesaurus, or 
terms from another vocabulary, such as the Systematized Nomenclature of 
Medicine--Clinical Terms (SNOMED CT), that has been mapped to MeSH 
within the Unified Medical Language System (UMLS) Metathesaurus.'' We 
note that this definition is consistent with ``health condition(s) or 
problem(s) studied'' of the WHO Trial Registration Data Set (version 
1.2.1) (WHO data item #12) and ICMJE registration policies [Ref. 2, 
73].
    (J) Intervention Name(s). Under Sec.  11.10(b)(10) of the NPRM, 
Intervention Name was specified as ``a brief descriptive name used to 
refer to the intervention(s) studied in each arm of the clinical trial. 
A non-proprietary name of the intervention must be used, if available. 
If a non-proprietary name is not available, a brief descriptive name or 
identifier must be used.'' Section 402(j)(2)(A)(ii)(I)(hh) of the PHS 
Act expressly requires ``intervention name'' to be submitted as part of 
clinical trial information at the time of registration, but it does not 
define the term. As we explained in the NPRM, we believe the purpose of 
this data element is to enable interested parties to readily identify 
the intervention(s) being studied in each arm of a clinical trial and 
compare clinical trials by intervention. While some clinical trials 
compare a single intervention against a placebo, many compare multiple 
interventions (e.g., a newly developed drug product versus standard 
treatment, or different dosages of the same drug product). We believe 
it is important for the names of all interventions studied in a 
clinical trial to be submitted to the data bank (79 FR 69616). We 
received no comments on this proposed data element and therefore are 
maintaining it in the final rule, although we slightly modify its name 
to ``Intervention Name(s)'' and specify in the definition that ``it'' 
refers to ``the intervention'' for clarity. Based on our experience in 
operating ClinicalTrials.gov, we recognize that there are inherent 
difficulties in determining the level of detail that should be required 
for naming interventions, especially those without non-proprietary 
(i.e., generic) names [Ref. 23]. We believe that non-proprietary names 
must be provided for interventions (e.g., drug products (including 
biological products) and device products) when available. For 
interventions for which a non-proprietary name is not available, our 
prior experience suggests that a brief descriptive name can suffice. In 
either case, additional descriptive information is often needed to 
distinguish the intervention(s) under study from other, similar 
interventions used in practice or studied in the same or other clinical 
trials. Examples of a brief descriptive name or identifier include a 
chemical name, company code, or serial number. We note that this 
description of Intervention Name(s) is consistent with the 
``intervention(s)'' of the WHO Trial Registration Data Set (version 
1.2.1) (WHO data item #13) and ICMJE registration policies [[Ref. 2, 
73].
    (K) Other Intervention Name(s). In Sec.  11.10(b)(11) of the NPRM, 
this term was defined as ``other current and former name(s) or 
alias(es), if any, different from the Intervention Name(s), that the 
sponsor has used publicly to identify the intervention, including, but 
not limited to, past or present names such as brand name(s), serial 
numbers, or chemical descriptions.'' As noted in the NPRM, ``other 
intervention name(s)'' is a term that is not used in section 402(j) of 
the PHS Act, but it is proposed as a data element that responsible 
parties must submit if the sponsor has used more than one name publicly 
to identify the intervention under study in a clinical trial. Based on 
our experience operating ClinicalTrials.gov, we are aware that 
interventions often have multiple names, including, for example, a 
sponsor code name, brand name(s), or a name or identifier from a 
standard vocabulary, such as RxNorm for drugs (http://www.nlm.nih.gov/research/umls/rxnorm/index.html). Accordingly, providing only a single 
name for each intervention (as is required under the Intervention 
Name(s) data element) does not necessarily provide enough information 
to allow users to find and compare all clinical trials in 
ClinicalTrials.gov that involve a specific intervention, as a different 
clinical trial with the same intervention may have been registered by 
another responsible party under a different intervention name. 
Therefore, we noted that we believe that adding a requirement to submit 
Other Intervention Name(s) improves and does not reduce the clinical 
trial information available in the data bank. We also noted that this 
requirement could mean that, in some circumstances (e.g., when the 
responsible party is a designated principal investigator), the 
responsible party would need to communicate with the sponsor or the 
manufacturer of the intervention(s) to determine whether another name 
has been used publicly. We indicated that we do not believe such 
additional communication would be frequent or onerous. The proposal 
would not have required a responsible party to submit names that have 
not been used publicly because users of ClinicalTrials.gov would be 
unlikely to search for a clinical trial using such names. We asked for 
comment on this approach (79 FR 69616) and some commenters addressed 
the Other Intervention Name(s) data element. A few commenters suggested 
requiring the use of a universally recognized standard, such as the WHO 
International Nonproprietary Names (INN) or the FDA unique device 
identifier (UDI). While we agree that the Other Intervention Name(s) 
data element includes all standardized names, we note that the data 
element is not limited to only those intervention names that are 
compliant with a particular naming standard or convention. As stated in 
the proposed definition, this data element is intended to broadly 
capture all ``other current and former name(s) or alias(es) . . . that 
the sponsor has used publicly to identify the intervention.'' 
Therefore, we clarify that all names, including internationally 
recognized standard names, must be

[[Page 65039]]

submitted for the Other Intervention Name(s) data element.
    One commenter indicated that displaying other intervention names 
would be confusing to the public and suggested that the final rule 
remove Other Intervention Name(s) as a required data element. Another 
commenter requested that only the U.S. generic and proprietary names be 
required for submission. We disagree with both commenters. Because 
users of ClinicalTrials.gov may encounter a number of names for an 
intervention depending on the source or context (e.g., drug code name), 
we believe that providing access to all the different public names of 
an intervention would help users find potentially relevant information. 
Additionally, requiring responsible parties to provide all public names 
for an intervention allows the ClinicalTrials.gov system to identify 
and retrieve clinical studies records listing any of the relevant 
intervention names. After consideration of these comments, we generally 
maintain this data element as proposed in the final rule. We modify the 
definition by deleting the phrase ``chemical descriptions'' to avoid 
any suggestion that chemical descriptions are required to be submitted. 
Chemical descriptions are, however, an example of another type of name 
that would be appropriate to include for Other Intervention Name(s).
    (L) Intervention Description. In Sec.  11.10(b)(12) of the NPRM, we 
defined this term to mean ``details that can be made public about the 
intervention, other than the Intervention Name and Other Intervention 
Name(s), sufficient to distinguish it from other, similar interventions 
studied in the same or another clinical trial.'' As we described in the 
NPRM, while this term is not used in section 402(j) of the PHS Act, we 
proposed it as an additional data element to be submitted as clinical 
trial information at the time of registration. Based on prior 
experience, we recognize that the Intervention Name(s) and Other 
Intervention Name(s) data elements, whether providing information on 
brand or non-proprietary names, do not always provide enough 
information to allow potential human subjects or other 
ClinicalTrials.gov users to differentiate among similar interventions 
used in different arms of a clinical trial, distinguish the 
intervention used in one clinical trial from a similar intervention 
used in another clinical trial, or understand the differences between 
interventions studied in a clinical trial and those used in routine 
medical practice. For example, a clinical trial might compare two or 
more dosages of the same drug or two different clinical trials might 
examine drug-eluting stents that are similar to those used in standard 
medical practice. To reduce this ambiguity, additional descriptive 
information about the intervention is needed, such as information about 
the dosage, dosage form, frequency of administration, route of 
administration, and/or duration of administration of a drug, or a 
general description of the device, including how the device functions; 
the scientific concepts that form the basis for the device; and the 
significant physical and performance characteristics of the device, 
such as its key components and the general types of materials used. The 
submission of such information would enable users (whether subjects, 
patients, physicians, researchers, or others) to understand key 
elements of a clinical trial, and compare information among clinical 
trials. For these reasons, requiring the submission of an intervention 
description would improve but not reduce the clinical trial information 
available in the data bank (79 FR 69616). A few commenters suggested 
that the Agency consider making optional some of the details required 
to be submitted for the Intervention Description data element; other 
commenters recommended that the entire data element be considered 
optional in the final rule. The reasons provided were that such 
detailed information may contain confidential commercial information 
and providing such details would be burdensome. The Agency disagrees 
with these commenters and continues to believe that users of the public 
site must be able to understand the interventions that are being 
compared in a trial and how the comparators differ from each other and/
or other similar interventions. For example, the Consolidated Standards 
Of Reporting Trials (CONSORT) guidelines recommend that each 
intervention, including control interventions, be described thoroughly 
so that published studies may be understood more clearly [Ref. 93]. The 
submission of these details at study registration could also give 
earlier insight to the problem of study sponsors choosing 
inapprorpriate comparison groups, which can bias study results [Ref. 
94]. As specified in the NPRM, the Agency also believes that 
sufficiently detailed information could be made public without 
including information that the sponsor may consider sensitive or 
proprietary (79 FR 69616). While the final rule retains the name of the 
proposed data element, we have modified the proposed definition by 
adding an example for clarity as a second sentence. Thus, the final 
rule defines the term to mean ``details that can be made public about 
the intervention, other than the Intervention Name(s) and Other 
Intervention Name(s), sufficient to distinguish it from other, similar 
interventions studied in the same or another clinical trial. For 
example, interventions involving drugs may include dosage form, dosage, 
frequency and duration.'' We clarify that Intervention Description 
should be sufficiently detailed to differentiate the specified 
intervention from other similar interventions, but should not include 
information that the responsible party cannot make public. For example, 
if the specific dosage of a drug being studied cannot be divulged, a 
responsible party could instead indicate whether the dosage is higher 
or lower than that used in an approved or licensed drug or in another 
arm of the study. If an experimental device uses different material 
than previous versions of the device, or than other marketed devices, 
the responsible party could provide a general description of the new 
material without including its specific formulation.
    (M) Intervention Type. In Sec.  11.10(b)(13) of the NPRM, 
Intervention Type was defined as ``for each intervention studied in the 
clinical trial, the general type of intervention.'' As we pointed out 
in the NPRM, section 402(j)(2)(A)(ii)(I)(hh) of the PHS Act expressly 
requires ``intervention type'' to be submitted as part of clinical 
trial information at the time of registration, but it does not define 
the term. We further proposed that responsible parties would be 
required to select one of the following options for each intervention 
studied: ``drug'' (including placebo), ``device'' (including sham), 
``biological/vaccine,'' ``procedure/surgery,'' ``radiation,'' 
``behavioral'' (e.g., psychotherapy, lifestyle counseling), ``genetic'' 
(including gene transfer, stem cell and recombinant DNA), ``dietary 
supplement'' (e.g., vitamins, minerals), ``combination product'' 
(combining a drug and device, a biological product and device; a drug 
and biological product; or a drug, biological product, and device), 
``diagnostic test'' (e.g., imaging, in-vitro), and ``other.'' We noted 
that when the intervention used is a combination product (e.g., drug-
eluting stent), the responsible party must select ``combination 
product'' as the Intervention Type (79 FR 69617). We received one 
comment requesting clarification by either providing examples or 
modifying the definition so that it does not use the term being 
defined. We believe ``type of intervention'' in the proposed definition

[[Page 65040]]

is sufficiently clear, particularly with the options described for the 
Intervention Type data element. We also plan to provide additional 
guidance as needed.
    After considering the comments, we maintain the NPRM definition in 
the final rule, except that we add ``e.g., drug, biological/vaccine, or 
device'' as examples for clarification. Note that, as specified in 
Sec.  11.28(a)(2)(i)(M) of the final rule, selection of an Intervention 
Type is required for each intervention studied in each arm of the 
clinical trial. Some clinical trials will therefore include multiple 
intervention types. As discussed in Section IV.B.2 of this preamble, a 
clinical trial that studies a drug and a device as separate, 
independent interventions would list both ``drug'' and ``device'' as 
Intervention Types and may meet the definitions of both an applicable 
device clinical trial and an applicable drug clinical trial. If the 
U.S. FDA-regulated device product studied in such an applicable 
clinical trial is not approved or cleared by FDA for any use, we would 
not post clinical trial registration information for that applicable 
clinical trial prior to the date of approval or clearance of the device 
product, consistent with Sec.  11.35(b)(2)(i), unless the responsible 
party indicates, pursuant to Sec.  11.35(b)(2)(ii), that it authorizes 
such posting. In addition, if the Intervention Type is specified as a 
``drug,'' ``biological/vaccine,'' or ``device,'' but both the Studies a 
U.S. FDA-regulated Device Product and Studies a U.S. FDA-regulated Drug 
Product data elements are specified as ``no,'' the clinical trial would 
not be an applicable clinical trial under the definition in Sec.  
11.10(a). For this reason, we note that the Intervention Type data 
element is not used in determining whether a clinical trial is an 
applicable clinical trial as specified in Sec.  11.22(b).
    (N) Studies a U.S. FDA-regulated Device Product. In Sec.  
11.10(b)(39) of the NPRM, we defined this data element to mean ``a 
clinical trial that studies a device subject to section 510(k), 515, or 
520(m) of the Federal Food, Drug, and Cosmetic Act.'' As we described 
in the NPRM, although section 402(j) of the PHS Act does not explicitly 
require submission of such a clinical trial registration information 
data element, we proposed to require such a data element using our 
authority under section 402(j)(2)(A)(iii) of the PHS Act, to assist 
responsible parties, users of ClinicalTrials.gov, and the Agency in 
determining whether a clinical trial is an applicable device clinical 
trial, using the approach specified in proposed Sec.  11.22(b)(1). As 
specified in the elaboration of the definition of an ``applicable 
device clinical trial'' in Section IV.A.5 of this preamble, one 
criterion for an applicable device clinical trial is that the clinical 
trial studies a device product ``subject to section 510(k), 515, or 
520(m) of the [FD&C Act].'' It is possible that a clinical trial with 
an Intervention Type of ``device'' would not be an applicable device 
clinical trial because the device is not subject to section 510(k), 
515, or 520(m) of the FD&C Act. Conversely, it is possible that a 
clinical trial could be an applicable device clinical trial even if 
none of the specified Intervention Types is a ``device.'' For example, 
a clinical trial for which a responsible party indicates the 
Intervention Type is ``radiation,'' ``genetic,'' or ``procedure'' could 
in fact be an applicable device clinical trial studying a device 
product subject to section 510(k), 515, or 520(m) of the FD&C Act 
(e.g., an x-ray device, a genetic test, or a surgical instrument). If 
the responsible party has obtained an IDE and submitted an IDE number 
to ClinicalTrials.gov, the clinical trial is considered an applicable 
device clinical trial as defined in this part. If the responsible party 
does not submit an IDE number, however, ambiguity would arise because 
the lack of an IDE number (or an IDE) does not necessarily indicate 
that a clinical trial is not an applicable device clinical trial. We 
proposed requiring the Studies an FDA-regulated Device data element in 
the NPRM to avoid this ambiguity and help ensure that applicable 
clinical trials can be properly identified. Consistent with the 
elaboration of the term applicable device clinical trial in Section 
IV.A.4 of this preamble, we interpreted this definition to mean that 
the clinical trial studies a device that would require any of the 
following before it may be legally marketed in the United States: (1) A 
finding of substantial equivalence under section 510(k) of the FD&C 
Act, (2) an order under section 515 of the FD&C Act approving a 
premarket approval application (PMA) for the device, or (3) an HDE 
under section 520(m) of the FD&C Act. We believe that submission of 
this information would improve and not reduce the clinical trial 
information submitted at the time of registration by making it clear to 
the responsible party, the Agency, and users of ClinicalTrials.gov 
whether a clinical trial without an IDE studies an FDA-regulated 
device. This information would, in turn, be used in determining whether 
a clinical trial meets the definition of an applicable device clinical 
trial, following the approach specified in proposed Sec.  11.22(b)(1). 
We also noted that, to reduce the data entry burden on responsible 
parties, ClinicalTrials.gov could automatically pre-populate this data 
field to indicate ``yes'' if a responsible party submits an IDE number 
as part of the FDA IND or IDE Number data element specified in proposed 
Sec.  11.10(b)(35) (79 FR 69617).
    We received no comments addressing the proposed data element and 
therefore retain the proposed definition in the final rule, except that 
the definition clarifies that ``device'' is ``device product'' and 
includes the applicable U.S.C. statutory citations in the final rule. 
The name has also been changed from the proposed ``Studies an FDA-
regulated Device'' to ``Studies a U.S. FDA-regulated Device Product'' 
in the final rule for clarity. We also note that we are aware that 
device products may be used in clinical trials even though they are not 
the intervention studied in the clinical trial or the experimental 
variable of interest in the study. For example, clinical trials of 
procedures involving surgical device products may not be designed to 
study the effect of those device products. Therefore, when considering 
whether a clinical trial Studies a U.S. FDA-regulated Device Product a 
responsible party should consider whether (a) the study is designed to 
examine the effect or performance of an FDA-regulated device product or 
differences in the intended use, for example, variations in frequency 
of use, method of administration, design specifications, and other 
characteristics (e.g., used in one or more, but not all, arms in a 
multi-arm study); and/or (b) at least one pre-specified primary or 
secondary outcome measure reflects a characteristic, effect, or 
performance of an FDA-regulated device product (e.g., need for 
replacement or maintenance of the device). As described in the preamble 
discussion of an applicable device clinical trial in Sec.  11.10(a), a 
clinical trial of a combination product with a device primary mode of 
action that otherwise meets the definition of an ``applicable clinical 
trial'' will be considered an applicable device clinical trial. We note 
that for such trials, the responsible party must indicate that the 
trial Studies a U.S. FDA-regulated Device Product.
    (O) Studies a U.S. FDA-regulated Drug Product. In Sec.  
11.10(b)(40) of the NPRM, we defined this data element to mean ``a 
clinical trial that studies a drug subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or to section 351 of the Public 
Health Services Act.'' As we described in the NPRM, section 402(j) of 
the PHS Act does not explicitly require submission of such a clinical 
trial registration

[[Page 65041]]

information data element. We proposed to require this data element, 
however, using our authority under section 402(j)(2)(A)(iii) of the PHS 
Act to assist responsible parties, users of ClinicalTrials.gov, and the 
Agency in determining whether or not a clinical trial is an applicable 
drug clinical trial using the approach specified in proposed Sec.  
11.22(b)(2). As specified in the elaboration of the definition of an 
``applicable drug clinical trial'' in Section IV.A.5 of this preamble, 
one criterion for an applicable drug clinical trial is that the 
clinical trial studies a drug ``subject to section 505 of the [FD&C] 
Act or [a biological product subject] to section 351 of [the PHS] 
Act.'' We noted that it is possible that a clinical trial with an 
Intervention Type of ``drug'' or ``biological/vaccine'' would not be an 
applicable drug clinical trial because the drug product is not subject 
to section 505 of the FD&C Act (e.g., a non-prescription drug product 
that is marketed under an over-the-counter drug monograph) and/or the 
biological product is not subject to section 351 of the PHS Act. 
Conversely, we indicated that it is possible that a clinical trial 
could be an applicable drug clinical trial even if the responsible 
party does not select ``drug'' or ``biological/vaccine'' as the 
Intervention Type. A clinical trial for which the responsible party 
indicates the Intervention Type to be ``dietary supplement'' or 
``genetic'' or ``procedure'' could in fact be an applicable drug 
clinical trial studying a drug product subject to section 505 of the 
FD&C Act or a biological product subject to section 351 of the PHS Act. 
For example, a product otherwise marketed as a dietary supplement could 
be studied for the treatment of cancer, or a genetic trial could study 
a gene therapy. If the responsible party has obtained an IND and 
submitted an IND number to ClinicalTrials.gov, the clinical trial would 
generally be an applicable drug clinical trial as defined in the NPRM. 
If the responsible party does not submit an IND number, however, 
ambiguity would arise because the lack of an IND number (or an IND) 
does not necessarily indicate that a trial is not an applicable drug 
clinical trial. To avoid this ambiguity and help ensure that applicable 
clinical trials can be properly identified, we proposed to require a 
responsible party to specifically indicate whether a clinical trial 
studies an FDA-regulated drug by submitting the Studies an FDA-
regulated Drug data element. Consistent with the elaboration of the 
term ``applicable drug clinical trial'' in the NPRM, we interpreted 
this definition to mean that the clinical trial studies a drug that is 
the subject of an approved NDA or BLA or that would require an approved 
NDA or BLA to be legally marketed in the United States. We noted in the 
NPRM our belief that submission of this information would improve, and 
not reduce, the clinical trial information submitted at the time of 
registration by making it clear to the responsible party, the Agency, 
and users of ClinicalTrials.gov whether a clinical trial without an IND 
studies an FDA-regulated drug product (including a biological product). 
This information would, in turn, be used in determining whether a 
clinical trial meets the definition of an ``applicable drug clinical 
trial,'' following the approach specified in proposed Sec.  
11.22(b)(2). To reduce the data entry burden on responsible parties, we 
noted that ClinicalTrials.gov could automatically pre-populate this 
data field to indicate ``yes'' if a responsible party submits an IND 
number as part of the FDA IND or IDE Number data element specified in 
proposed Sec.  11.10(b)(35) (79 FR 69618).
    We received no comments addressing the proposed data element and 
therefore retain the proposed definition in the final rule, except that 
the definition clarifies that ``drug'' is ``drug product'' and includes 
the applicable U.S.C. statutory citations in the final rule. However, 
the name has been changed from ``Studies an FDA-regulated Drug'' in the 
NPRM to ``Studies a U.S. FDA-regulated Drug Product'' in the final rule 
for clarity. We also note that we are aware that a clinical trial may 
include an FDA-regulated drug product even though the drug product is 
not a variable of interest. For example, a clinical trial of a device 
product may involve the surgical insertion of the device product under 
anesthesia, but the anesthesia drug product is not studied in the 
clinical trial. In determining whether a clinical trial studies a U.S. 
FDA-regulated drug product, a responsible party should consider whether 
(a) the clinical trial is designed to examine the effect of the FDA-
regulated drug product(s) or of differences in the intended use, 
including differences in dosing, frequency of use, or route of 
administration; and/or (b) at least one of the pre-specified primary or 
secondary outcome measures reflects a characteristic or effect of the 
FDA-regulated drug product(s). As described in the preamble discussion 
of applicable drug clinical trial in Sec.  11.10(a), a clinical trial 
of a combination product with a drug primary mode of action will be 
considered an applicable drug clinical trial. We note that for such 
trials, the responsible party must indicate that the trial Studies a 
U.S. FDA-regulated Drug Product.
    (P) Device Product Not Approved or Cleared by U.S. FDA. In proposed 
Sec.  11.10(b)(14), we defined U.S. FDA Approval, Licensure, or 
Clearance Status to mean ``for each drug or device studied in the 
clinical trial, whether that drug or device is approved, licensed, or 
cleared by the U.S. Food and Drug Administration for any use.'' 
Although section 402(j) of the PHS Act does not explicitly require that 
such a data element be submitted as part of clinical trial information, 
we proposed it to help ensure that the data bank operates in compliance 
with statutory requirements, e.g., knowledge of the approval or 
clearance status of a device is necessary to determine when clinical 
trial registration information submitted for an applicable device 
clinical trial may be posted publicly in the data bank (see section 
402(j)(2)(D)(ii) of the PHS Act.) We indicated that this information 
would also be helpful for users of ClinicalTrials.gov, including 
potential participants, who may wish to know whether or not the 
product(s) under study have been approved, licensed, or cleared for the 
use studied in the clinical trial. Requiring submission of the 
approval, licensure, or clearance status for each drug or device 
studied in an applicable clinical trial would therefore improve and not 
reduce the clinical trial information available in the data bank, 
consistent with section 402(j)(2)(A)(iii) of the PHS Act for proposed 
modifications to clinical trial registration information. We also 
stated in the NPRM that we would require responsible parties to select 
a response from the following limited list of choices: ``for studied 
use(s)'' (the drug, biological product, or device is approved, 
licensed, or cleared for the use studied in the clinical trial), ``for 
other use(s)'' (the drug, biological product, or device is approved, 
licensed, or cleared for use(s) other than those studied in the 
clinical trial, e.g., the clinical trial studies a new use of the 
product), or ``No'' (the product has not been approved, licensed, or 
cleared for any use). No ``other'' option was proposed, but a 
responsible party would also be able to provide additional, optional 
free-text information to further describe the approval, licensure, or 
clearance status (e.g., to indicate that the product has been approved 
in another dose or dosage form, or to list the indications for which it 
has been approved). We invited public comment

[[Page 65042]]

on whether the set of proposed options is sufficient (79 FR 69618).
    Some commenters addressed the proposed U.S. FDA Approval, 
Licensure, or Clearance Status data element. One commenter requested 
clarification on whether more information than the FDA approval, 
licensure, or clearance status would be required for this data element, 
while another commenter recommended that the Agency itself submit 
information for this data element. In reviewing these comments and 
assessing ways to reduce reporting burden where possible, we 
reconsidered the proposed approach of requiring the FDA approval, 
licensure, or clearance status information for each product studied in 
the clinical trial. A separate data element about the approval, 
licensure, or clearance status for each drug product, biological 
product, or device product studied in an applicable clinical trial is, 
for the most part, not necessary to implement these regulations, 
because that information is provided via other data elements, when 
necessary. For example, responsible parties will notify the Agency that 
they are seeking ``initial'' approval, licensure or clearance of a 
product or approval, licensure, or clearance of a ``new use'' for a 
product studied in the trial by submitting a certification for delayed 
submission of results information in accordance with Sec.  11.44(b) and 
11.44(c), respectively. A key exception, however, is the need for 
ClinicalTrials.gov to identify applicable device clinical trials that 
study a device product that has not been previously approved or cleared 
in order to delay public posting of the submitted clinical trial 
registration information, as specified in Sec.  11.35(b)(2)(i). 
Therefore, the final rule replaces the proposed U.S. FDA Approval, 
Licensure, or Clearance Status data element with the Device Product Not 
Approved or Cleared by U.S. FDA data element in Sec.  
11.28(a)(2)(i)(P), which is defined in Sec.  11.10(b)(14) of the final 
rule to mean ``that at least one device product studied in the clinical 
trial has not been previously approved or cleared by FDA for one or 
more uses.'' As discussed below, this data element must be updated not 
later than 15 calendar days after a change in approval or clearance 
status of one or more of the device products studied in the applicable 
clinical trial.
    A responsible party would only be required to complete this data 
element for a record in which ``Yes'' is selected as the response to 
the Studies a U.S. FDA-regulated Device Product data element in Sec.  
11.28(a)(2)(i)(N). We would require responsible parties to select a 
response from the following limited list of choices: ``Yes'' (at least 
one studied FDA-regulated device product has not been previously 
approved or cleared by FDA for one or more uses and therefore the 
applicable device clinical trial may be subject to the delayed posting 
requirements specified in Sec.  11.35(b)(2)(i)) or ``No'' (all studied 
FDA-regulated device products have been previously approved or cleared 
by FDA for at least one use and therefore the applicable device 
clinical trial is not subject to the delayed posting requirement 
specified in Sec.  11.35(b)(2)(i)).
    We included the word ``product'' in the name of the Device Product 
Not Approved or Cleared by U.S. FDA data element in Sec.  
11.28(a)(2)(i)(P) to clarify that, as explained in Section IV.C.3, the 
Agency in the final rule is focusing on the device ``product'' rather 
than the device ``type'' when determining which PMA approvals or 510(k) 
clearances are considered ``initial'' approvals or clearances versus 
approvals or clearances of a ``new use.'' For example, with respect to 
510(k) clearances, the Agency is interpreting ``initial clearance'' in 
the final rule to pertain to the clearance of a manufacturer's original 
510(k) submission for a particular device product whereas ``clearance 
of a new use'' of a device pertains to the clearance of the same 
manufacturer's subsequent 510(k) submission for an additional use for 
the same device product. The term ``manufacturer'' means a manufacturer 
who is the sponsor of the applicable clinical trial.
    This interpretation subjects clinical trial registration 
information for more devices to delayed posting under section 
402(j)(2)(D)(ii)(I) of the PHS Act as compared with the NPRM approach, 
because each individual device manufacturer seeking initial clearance 
of its device product would be subject to delayed posting of its 
clinical trial registration information, as specified in Sec.  
11.35(b)(2)(i) of the final rule, rather than only the first 
manufacturer to obtain clearance for the device type. Consistent with 
this interpretation, under the definition of ``Device Product Not 
Approved or Cleared by U.S. FDA,'' if a manufacturer's original 510(k) 
submission for its particular device product has not been previously 
cleared, then that manufacturer's device product would be considered a 
``device product not cleared by FDA,'' even if another manufacturer has 
already obtained 510(k) clearance of its device product within the same 
product type.
    A few commenters suggested that the final rule include an option 
for providing information about the use for which the product has been 
approved, and additional commenters requested the addition of the 
option ``Approved but not for use being studied.'' We agree that 
choices other than the three proposed in the NPRM (i.e., ``for studied 
uses(s),'' ``for other uses,'' and ``no'') could provide other useful 
information about a product's approval status. However, because of 
changes to the data element in the final rule (to indicate ``whether at 
least one device product studied in the clinical trial has not been 
previously approved or cleared by FDA for one or more uses,'' as 
described below) the options proposed by the commenters for specifying 
the approval, licensure, or clearance status of each studied drug 
product or device product will no longer be necessary. Another 
commenter requested that the final rule require the submission of 
information about the particular approved, licensed, or cleared uses of 
each product using a standardized terminology to ensure the usefulness 
and consistency of this information within and across study records. We 
note that section 402(j)(3)(A)(ii) of the PHS Act requires 
ClinicalTrials.gov to link to information about approved, licensed, or 
cleared products available on the FDA Web site (e.g., FDA advisory 
committee meeting summaries, public health advisories, and action 
package for approval documents) as well as citations from the published 
literature and structured product labels in NLM's PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and DailyMed (https://dailymed.nlm.nih.gov/dailymed/) databases, respectively.
    (Q) Post Prior to U.S. FDA Approval or Clearance. This data element 
was neither specified as clinical trial registration information in 
section 402(j)(2)(A)(ii) of the PHS Act nor proposed in the NPRM. We 
define the term in Sec.  11.10(b)(40) of the final rule to mean ``for 
an applicable device clinical trial of a device product that has not 
been previously approved or cleared, the responsible party indicates to 
the Director that it is authorizing the Director, in accordance with 
Sec.  11.35(b)(2)(ii), to publicly post its clinical trial registration 
information, which would otherwise be subject to delayed posting, as 
specified in Sec.  11.35(b)(2)(i), prior to the date of FDA approval or 
clearance of its device product.'' We also list the data element as a 
component of clinical trial registration information in Sec.  
11.28(a)(2)(i)(Q) in accordance with the statutory authority in section 
402(j)(2)(A)(iii) of the PHS Act, which

[[Page 65043]]

permits the Secretary to ``modify the requirements for clinical trial 
[registration] information'' by regulation, provided that ``such a 
modification improves and does not reduce such clinical trial 
information.'' The Post Prior to U.S. FDA Approval or Clearance data 
element is needed to allow a responsible party for an applicable 
clinical trial of a device product that is unapproved or uncleared to 
indicate to the Director that it is authorizing the Director to 
publicly post on ClinicalTrials.gov its clinical trial registration 
information, which would otherwise be subject to delayed posting as 
specified in Sec.  11.35(b)(2)(i), prior to the date of approval or 
clearance of the product, pursuant to Sec.  11.35(b)(2)(ii). Otherwise, 
all such trials are subject to the posting deadline specified in Sec.  
11.35(b)(2)(i), which states that the Director will post publicly the 
clinical trial registration information, except for certain 
administrative data, not earlier than the date of FDA approval or 
clearance of the device product (see the preamble discussion of Sec.  
11.35 for further details). To reduce data submission burden, a 
responsible party would have this option if the Studies a U.S. FDA-
regulated Device Product and the Device Product Not Approved or Cleared 
by U.S. FDA data elements indicate that at least one studied device 
product has not been approved or cleared by FDA.
    (R) Product Manufactured in and Exported from the U.S. In Sec.  
11.10(b)(15) of the NPRM, we proposed the following definition for the 
Product Manufactured in the U.S. data element: ``For a drug or device 
studied in a clinical trial, whether or not the drug or device is 
manufactured in the U.S. or one of its territories.'' Although section 
402(j) of the PHS Act does not explicitly require that such a data 
element be submitted as part of clinical trial information, we proposed 
to include it, using our authority under section 402(j)(2)(A)(iii) of 
the PHS Act to allow users to determine whether a registered clinical 
trial is an applicable clinical trial. As explained in the definitions 
of ``applicable device clinical trial'' and ``applicable drug clinical 
trial,'' the NPRM noted that even if a clinical trial is being 
conducted entirely outside of the United States or one of its 
territories, it is still an applicable clinical trial when the drug 
product or device product is manufactured in the United States or one 
of its territories. We noted that a drug product or device product 
manufactured in the United States or one of its territories is subject 
to regulation under the FD&C Act, even if it is exported for study in 
another country (see, for example, 21 CFR 312.110 and section 802 of 
the FD&C Act). Therefore, we proposed that information indicating 
whether each intervention studied in a clinical trial is manufactured 
in the United States or one of its territories would be essential in 
some situations for determining whether such trial is subject to FDA 
jurisdiction and meets the definition of an ``applicable clinical 
trial.'' We indicated that including this information in the data bank 
would improve and not reduce clinical trial information by publicly 
providing data necessary to determine whether such trial is an 
applicable clinical trial (79 FR 69618). We did not receive any public 
comments on this proposed data element, but we have modified the 
definition in the final rule. In assessing ways to reduce reporting 
burden where possible, we reconsidered the proposed requirement for 
United States product manufacturing information for each drug product 
(including a biological product) or device product studied in a 
clinical trial. To determine whether a clinical trial that is not 
conducted under an IND or IDE and that does not have any study 
facilities in the United States or its territories meets the definition 
of an ``applicable clinical trial,'' the Agency, responsible parties, 
and the public only need information about whether at least one drug 
product (including biological product) or device product was 
manufactured in the United States and exported for research. Therefore, 
we renamed the data element ``Product Manufactured in and Exported from 
the U.S.'' in Sec.  11.28(a)(2)(i)(R) to clarify that the intent is to 
identify a U.S.-manufactured product that is exported for research 
purposes. Additionally, we clarify that ``drug'' means ``drug product'' 
and ``device'' means ``device product.'' In Sec.  11.10(b)(15) of the 
final rule, we define this data element to mean ``that any drug product 
(including a biological product) or device product studied in the 
clinical trial is manufactured in the United States or one of its 
territories and exported for study in a clinical trial in another 
country.'' To reduce data submission burden, a responsible party would 
be required to complete this data element only if the entry submitted 
for the U.S. Food and Drug Administration IND or IDE Number data 
element indicates that there is no IND or IDE for the clinical trial, 
and the entry(ies) for the Facility Information data element include no 
facility locations in the United States or its territories.
    (S) Study Start Date. In Sec.  11.10(b)(16) of the NPRM, we defined 
Study Start Date to mean: ``the estimated date on which the clinical 
trial will be open to enrollment of human subjects. If the clinical 
trial has enrolled the first human subject, the actual date on which 
the first human subject was enrolled.'' Section 402(j)(2)(A)(ii)(I)(ii) 
of the PHS Act expressly requires ``study start date'' to be submitted 
as clinical trial information at the time of registration, but it does 
not define the term. Section 402(j)(2)(C)(ii) of the PHS Act and 
proposed Sec.  11.24(a) generally required that clinical trial 
registration information be submitted to ClinicalTrials.gov not later 
than 21 calendar days after the first human subject is enrolled in the 
clinical trial. In practice, however, many responsible parties submit 
clinical trial registration information to ClinicalTrials.gov before 
the first subject is enrolled. In some cases, at the time the clinical 
trial is registered, the responsible party may not have information 
about when the first subject will be enrolled or was enrolled (e.g., in 
a large multi-site trial) but may only know when the clinical trial was 
or will be opened for enrollment. To account for these potential 
scenarios, we proposed that responsible parties be required to provide 
an estimated study start date (i.e., the estimated date on which the 
clinical trial will be open to enrollment of human subjects), unless 
and until the responsible party knows the actual study start date 
(i.e., the actual date on which the first human subject is enrolled). 
The responsible party would be required to update the Study Start Date 
data element to reflect the actual study start date not later than 30 
calendar days after the first human subject is enrolled, consistent 
with proposed Sec.  11.64. We suggested in the NPRM that providing the 
estimated study start date to the public, even before the first subject 
is enrolled, has important benefits to potential human subjects because 
it will allow them to know when a clinical trial will likely be open to 
enrollment. We clarified that the Study Start Date must include the 
day, month, and year (79 FR 69619).
    We received comments on this definition. Several commenters 
requested that we change the term ``Study Start Date'' to ``Date of 
First Enrolled Participant'' to avoid confusion with other contexts, 
such as those related to human subjects protection and IRB oversight, 
in which the study start date is considered to be when the study is 
first approved by the IRB and is recruiting. Another comment stated

[[Page 65044]]

that the WHO Trial Registration Data Set, defines study start date as 
the date of first enrollment. One commenter requested that we change 
the definition of ``Study Start Date'' to ``date of first enrollment'' 
for consistency with these other policies. Another comment asserted 
that ICMJE, WHO, FDA, and EMA consider the study start date to be the 
``First-Patient-First-Visit,'' which is the first participant's 
anticipated or actual enrollment date, rather than when the trial is 
first opened to enrollment. Another commenter acknowledged that our 
definition requires the Study Start Date to be updated with the 
``First-Patient-First-Visit'' (i.e., actual enrollment date) but stated 
that the other, estimated date on which the clinical trial will be open 
to enrollment is inconsistent with these other study start date 
definitions. The commenter requested that we change the definition to 
``First-Patient-First-Visit.'' After considering these comments, we 
maintain the proposed definition for Study Start Date in Sec.  
11.10(b)(16) of the final rule, with slight modifications for 
consistency of phrasing with similar data elements concerning when the 
responsible party would update the data element with the actual 
enrollment date. As such, we define Study Start Date as ``the estimated 
date on which the clinical trial will be open for recruitment of human 
subjects, or the actual date on which the first human subject was 
enrolled.'' If the estimated date is used, the responsible party must 
update the Study Start Date data element to the actual date on which 
the first human subject was enrolled. We also decline to define Study 
Start Date as only the ``First-Patient-First-Visit'' or actual 
enrollment date. The definition already incorporates the actual 
enrollment date, which the responsible party will use when the first 
subject has been enrolled. By including the date when recruitment opens 
and the date of first enrollment, we believe the definition maintains 
consistency with prior practice at ClinicalTrials.gov and addresses 
commenters' request to document the date of first human subject 
enrollment as in the WHO Trial Registration Data Set. As stated in the 
NPRM, we believe that providing the estimated study start date to the 
public, even before the first subject is enrolled, has important 
benefits to potential human subjects because it will provide them with 
the date on which a clinical trial will likely be open to enrollment. 
To minimize the burden associated with this requirement and to reflect 
that it is an estimated date, the date may be provided as ``month, 
year'' when estimated and updated to ``day, month, year'' when actual. 
We also note that, as discussed above, the final rule modifies the 
proposed definition of ``enroll or enrolled,'' a component of the 
definition of Study Start Date (see Section IV.A.5 of this preamble). 
We note that if a clinical trial is registered with an estimated study 
start date but the clinical trial is then halted before enrolling the 
first subject (e.g., because of difficulties in recruitment or loss of 
funding), the responsible party would not be expected to update the 
study start date. Instead, the responsible party would be expected to 
update the Overall Recruitment Status data element defined in Sec.  
11.10(b)(25) and specified in Sec.  11.28(a)(2)(ii)(E) to indicate that 
the clinical trial has been ``withdrawn,'' as such term is used for the 
purpose of this regulation, and update the Why Study Stopped data 
element defined in Sec.  11.10(b)(26) and specified in Sec.  
11.28(a)(2)(ii)(F).
    We note that, as stated in Sec.  11.22(a)(3), an applicable 
clinical trial, other than a pediatric postmarket surveillance of a 
device product that is not a clinical trial, is considered to be 
initiated on the date on which the first human subject is enrolled. 
Therefore, we consider the actual Study Start Date to be the date of 
initiation for an applicable clinical trial other than a pediatric 
postmarket surveillance of a device product that is not a clinical 
trial.
    (T) Primary Completion Date. In Sec.  11.28(a)(1)(xiv) of the NPRM, 
we proposed that when registering a clinical trial, a responsible party 
must submit the Completion Date for the clinical trial, which was 
defined in proposed Sec.  11.10(b)(17) of the NPRM as ``the estimated 
completion date. Once the clinical trial has reached the completion 
date, the responsible party must update the Completion Date data 
element to reflect the actual completion date.'' Section 
402(j)(2)(A)(ii)(I)(jj) of the PHS Act requires the responsible party 
to submit information on the ``expected completion date'' of an 
applicable clinical trial when registering a clinical trial. We noted 
in the NPRM that the public availability of information about the 
expected primary completion date (i.e., the expected completion date) 
is important for an ongoing clinical trial because it provides an 
indication of the relative progress of the clinical trial and the 
expected date on which results information may be submitted to the data 
bank because section 402(j)(3)(c)(i) of the PHS Act requires that, in 
general, clinical trial results information be submitted not later than 
1 year after the earlier of the estimated completion date of the 
applicable clinical trial or the actual completion date of the 
applicable clinical trial. We note that certain exceptions apply to 
this general deadline for the submission of clinical trial results 
information (see discussion of Sec.  11.44). In addition, we 
interpreted the phrase ``estimated completion date,'' as such term is 
used in section 402(j)(3)(c)(i)(I) of the PHS Act, to have the same 
meaning as ``expected completion date,'' as such term is used in 
section 402(j)(2)(A)(ii)(I)(jj) of the PHS Act, because both indicate 
the date on which the responsible party anticipates that the clinical 
trial will be completed in relation to the primary outcome measures. In 
addition, we expressed our belief that it is important for users to 
have information about the actual completion date of a clinical trial, 
so they know when clinical trial results information would ordinarily 
be due under section 402(j)(3)(c)(i) of the PHS Act and proposed Sec.  
11.44(a), absent certain specified circumstances in which the 
submission of clinical trial results information may be delayed. 
Because clinical trial results information generally is required under 
section 402(j)(3)(c)(i) of the PHS Act and under proposed Sec.  11.44 
to be submitted not later than 1 year after the estimated or actual 
completion date, whichever is earlier, we expressed our belief that it 
is important for the Completion Date data element to be updated 
promptly after the completion date is reached. We proposed to require 
the responsible party to take the following steps with regard to the 
Completion Date data element: (1) Provide a reasonable estimated 
completion date at the time of registration; (2) update the estimated 
completion date at least once every 12 months during the course of the 
clinical trial, in accordance with proposed Sec.  11.64(a)(2), if the 
estimate changes; and (3) update the Completion Date information to 
indicate the actual completion date not later than 30 calendar days 
after the clinical trial reaches its completion date, in accordance 
with proposed Sec.  11.64(b)(1)(viii) (79 FR 69619).
    Commenters expressed concern about possible confusion and 
misinterpretation among responsible parties and the public resulting 
from the proposed data element name and uniformly suggested replacing 
``completion date'' with ``primary completion date'' or ``primary 
outcome measure completion date,'' with several noting that 
ClinicalTrials.gov has used the term ``primary completion date'' since 
the enactment of FDAAA. We

[[Page 65045]]

agree with these comments and note that the Primary Completion Date 
data element was created in response to section 402(j) of the PHS Act 
to avoid confusion with the Study Completion Date data element, which 
existed prior to the law and is currently an optional data element. 
Furthermore, the final rule in Sec.  11.28(a)(2)(i)(U) adds the Study 
Completion Date data element as a component of clinical trial 
registration information. In response to these comments and taking into 
consideration statutory requirements, we rename the Completion Date 
data element ``Primary Completion Date'' in Sec.  11.28(a)(2)(i)(T) of 
the final rule and use the term ``Primary Completion Date'' throughout 
the final rule for clarity. Primary Completion Date is defined in Sec.  
11.10(b)(17) of the final rule to mean ``the estimated or actual 
primary completion date. If an estimated primary completion date is 
used, the responsible party must update the Primary Completion Date 
data element once the clinical trial has reached the primary completion 
date to reflect the actual primary completion date.'' We also note that 
the term ``completion date'' in Sec.  11.10(a) of the final rule 
states, in part, that ``[f]or purposes of this part, completion date is 
referred to as `primary completion date.'''
    (U) Study Completion Date. This data element was neither specified 
as clinical trial registration information in section 402(j)(2)(A)(ii) 
of the PHS Act nor proposed in the NPRM. We define the term ``study 
completion date'' in Sec.  11.10(a) of the final rule to mean ``for a 
clinical trial, the date the final subject was examined or received an 
intervention for purposes of final collection of data for the primary 
and secondary outcome measures and adverse events (e.g., last subject's 
last visit), whether the clinical trial concluded according to the pre-
specified protocol or was terminated.'' The final rule also lists Study 
Completion Date as a required registration data element under Sec.  
11.28(a)(2)(i)(U) and specifies the data element definition in Sec.  
11.10(b)(41) as ``the estimated or actual study completion date. Once 
the clinical trial has reached the study completion date, the 
responsible party must update the Study Completion Date data element to 
reflect the actual study completion date in accordance with Sec.  
11.64(a)(1)(ii)(J).'' We have included the study completion date as a 
component of clinical trial registration information in accordance with 
the statutory authority in section 402(j)(2)(A)(iii) of the PHS Act, 
which permits the Secretary to ``modify the requirements for clinical 
trial [registration] information'' by regulation, provided that ``such 
a modification improves and does not reduce such clinical trial 
information.'' We believe that Study Completion Date is helpful to 
indicate to the Agency, responsible parties, and the public when all 
primary and secondary outcome measures and collection of all adverse 
event information, as specified in the protocol, will be completed and 
when final data collection for all primary and secondary outcomes and 
all adverse events has occurred. Some commenters requested that a 
mechanism be included in the PRS to make clear to responsible parties 
when they have fulfilled all obligations to update the study record as 
specified in proposed Sec.  11.64(a)(3) and that no further updates are 
required. Several other commenters suggested that ``completion date,'' 
defined in proposed Sec.  11.10(a), be redefined to mean ``final visit/
final patient'' or ``final visit/final patient for all outcome 
measures.'' Following an internal review of the proposed rule, we also 
note that while proposed Sec.  11.44(d) described the procedure for 
submitting partial results information, it did not specify how to 
determine when the responsible party's obligation under subpart C is 
fulfilled. While the Study Completion Date does not specify when these 
obligations are fulfilled per se, it does provide the minimum amount of 
information needed to make such a determination based on when all of 
the data for a trial is to be collected. Note that Sec.  
11.64(a)(1)(ii)(J) of the final rule requires the responsible party to 
update the Study Completion Date within 30 calendar days after the 
clinical trial reaches its actual study completion date.
    (V) Enrollment. We defined this data element in Sec.  11.10(b)(18) 
of the NPRM as ``the estimated total number of human subjects to be 
enrolled or target number of human subjects in the clinical trial.'' 
Section 402(j)(2)(A)(ii)(I)(kk) of the PHS Act expressly requires 
submission of ``the target number of subjects'' to be enrolled in an 
applicable clinical trial, but this phrase is not defined. We expressed 
our belief that this data element is intended to describe the intended 
or estimated size of the clinical trial, in terms of the estimated 
total number of human subjects (including healthy volunteers) or target 
number of human subjects to be enrolled in the clinical trial. We 
therefore proposed in Sec.  11.28(a)(1)(xx) of the NPRM to require the 
submission of enrollment information at the time of registration (79 FR 
69620). We received a few comments addressing the Enrollment data 
element. One commenter suggested that the final rule require submission 
of information about target enrollment goals by gender, age, and race/
ethnicity during registration but did not provide any specific 
justification or evidence that such information is necessary for 
registration. We note that the clinical trials results information 
submission requirements under Demographic and baseline characteristics 
in proposed Sec.  11.48(a)(2)(iii) included the reporting of ``age, 
gender, and any other measure(s) that were assessed at baseline . . .'' 
and the final rule further requires the submission of baseline measure 
information by race and ethnicity, if collected during the clinical 
trial. ClinicalTrials.gov also provides pre-formatted categories that 
enable responsible parties to submit common demographic 
characteristics, including age, sex/gender, race, ethnicity, and region 
of enrollment (if assessed at baseline), to facilitate comparison 
across study records. Another commenter suggested requiring the listing 
of the targeted and actual numbers of subjects enrolled in each trial. 
Two specific required registration data elements proposed in the NPRM, 
and combined in the final rule, address this comment. The Enrollment 
data element specified in proposed Sec.  11.28(a)(1)(xx) is defined in 
proposed Sec.  11.10(b)(18) as ``the estimated total number of human 
subjects to be enrolled or target number of human subjects in the 
clinical trial,'' and the Actual Enrollment data element specified in 
proposed Sec.  11.28(a)(2)(vii) is defined as ``for a clinical trial 
for which recruitment of human subjects has terminated or completed, 
the actual number of human subjects enrolled in the clinical trial'' in 
proposed Sec.  11.10(b)(27). After consideration of these comments, we 
maintain the proposed name of the Enrollment data element in the final 
rule, but we combine it with the proposed Actual Enrollment data 
element for convenience and consistency with the format on 
ClinicalTrials.gov prior to this rule. We clarify that with the 
approach in the final rule, the estimated number of human subjects to 
be enrolled will be retained, to allow for later display of both the 
estimated and actual total number of human subjects enrolled in the 
clinical trial. We have therefore changed the definition of Enrollment 
to ``the estimated total number of human subjects to be enrolled 
(target number) or the actual total number of human subjects that are 
enrolled in the clinical

[[Page 65046]]

trial. Once the trial has reached the primary completion date, the 
responsible party must update the Enrollment data element to reflect 
the actual number of human subjects enrolled in the clinical trial.'' 
We expect that the estimated or target enrollment for a clinical trial 
may change before or during the clinical trial (e.g., as recruitment 
continues). Consistent with section 402(j)(4)(C) of the PHS Act and 
Sec.  11.64(a)(1), a responsible party would be required to update the 
Enrollment data element not less than once every 12 months, if the 
anticipated or target enrollment for the clinical trial changes. This 
update would be in addition to the requirement in Sec.  11.64(a), 
described in Section IV.D.3, that a responsible party submit the actual 
enrollment when the clinical trial has reached its primary completion 
date, i.e., when the Primary Completion Date of the trial is changed to 
``actual.'' This requirement is intended to provide users of 
ClinicalTrials.gov with additional information on the total number of 
participants enrolled in the clinical trial, which may differ from the 
target enrollment. (See Sec.  11.64(a) and the discussion of Primary 
Completion Date'' for a discussion of this requirement.) We also note 
that ``enrolled,'' as defined in Sec.  11.10(a) of the final rule, 
means ``a human subject's, or their legally authorized 
representative's, agreement to participate in a clinical trial 
following completion of the informed consent process, as required in 21 
CFR part 50 and/or 45 CFR part 46, as applicable. For the purposes of 
this part, potential subjects who are screened for the purpose of 
determining eligibility for a trial, but do not participate in the 
trial, are not considered enrolled, unless otherwise specified by the 
protocol.'' In addition, we note that in response to comments on the 
update requirements in Sec.  11.64, the Enrollment data element must be 
updated at the time the Primary Completion Date data element is updated 
to ``actual'' instead of at the time after enrollment closes.
    (W) Primary Outcome Measures and (X) Secondary Outcome Measures are 
data elements expressly required by section 402(j)(2)(A)(ii)(I)(ll) of 
the PHS Act to be submitted as part of clinical trial information at 
the time of registration. Definitions of the terms ``outcome measure'', 
``primary outcome measure'', and ``secondary outcome measure'' are 
provided and elaborated on in the preamble and subpart A of the final 
rule. However, section 402(j) of the PHS Act does not specify what 
specific information about primary and secondary outcome measures must 
be submitted to ClinicalTrials.gov at the time of registration. Under 
proposed Sec.  11.28(a)(1)(xxi) and (xxii) of the NPRM, responsible 
parties would be required to submit the information specified in 
proposed Sec.  11.10(b)(19) and (20) for each primary or secondary 
outcome measure in their clinical trials, namely the following: (1) The 
name of the specific outcome measure (e.g., systolic blood pressure), 
(2) a description of the metric used to characterize the specific 
outcome measure (e.g., mean value of systolic blood pressure), and (3) 
the time point(s) at which the measurement is assessed for the specific 
metric used (e.g., 24 weeks after initiation of treatment). We noted in 
the NPRM that these requirements are consistent with the WHO Trial 
Registration Data Set (version 1.2.1), which specifies that each 
outcome include the name of the outcome, the metric or method of 
measurement used, and the time point(s) of primary interest. 
Furthermore, based on our experience in operating ClinicalTrials.gov, 
we expressed our belief that these three elements are key attributes of 
an outcome measure. Not only may certain outcome measures be assessed 
in different ways (e.g., systolic blood pressure can be measured as a 
mean value at a specific time point or as a change from baseline), but 
also a single clinical trial may assess a single attribute at multiple 
points in time (e.g., systolic blood pressure may be measured 3 months, 
6 months, and 12 months after beginning treatment). Each of these would 
be considered a different outcome measure. We noted that ensuring that 
the primary and secondary outcome measures include descriptions of the 
measures and the time points of assessment is therefore necessary for 
differentiating between similar measures and for subsequently ensuring 
that results information is provided for all of them and in a manner 
that is consistent with the way in which they were pre-specified in the 
registry. This approach would also ensure that any changes in the 
outcome measure are recorded as updates to the registration 
information, consistent with the purpose of the data bank ``to track 
subsequent progress of clinical trials,'' section 402(j)(2)(A)(i) of 
the PHS Act (79 FR 69620).
    One commenter cited findings of that commenter's research [Ref. 14] 
and recommended that the final rule require responsible parties to 
submit information on whether each outcome measure is defined in terms 
of a noninferiority, superiority, or equivalence hypothesis and 
associated information about the noninferiority or equivalence margin 
with relevant calculations and justification of margin selection as 
free-text descriptions in a new sub-element associated with each 
reported outcome measure. While we agree with the commenter on the 
potential value of this information, we note that the information 
should be available with the reporting of outcomes with results 
information under Sec.  11.48. We do not believe that the benefits of 
reporting this information at registration outweighs the burden on 
responsible parties for reporting these details at that time. We will 
continue, however, to evaluate ways to accommodate this and other 
information related to the SAP as optional structured data elements in 
ClinicalTrials.gov. Responsible parties are able to submit this 
information voluntarily during registration as part of the Detailed 
Description data element. We also note that, during results reporting 
for any statistical analysis that is considered scientifically 
appropriate, the following information is required to be submitted: 
``for a non-inferiority or equivalence test, a description of the 
analysis that includes, at minimum, the power calculation and non-
inferiority or equivalence margin'' (see Sec.  11.48(a)(3)(v)). After 
considering this comment, we maintain the proposed definition in the 
final rule.
(ii) Recruitment Information
    (A) Eligibility Criteria. In Sec.  11.10(b)(21) of the NPRM, 
Eligibility Criteria was described as ``a limited list of criteria for 
selection of human subjects to participate in the clinical trial, 
provided in terms of inclusion and exclusion criteria and suitable for 
assisting potential human subjects in identifying clinical trials of 
interest.'' Section 402(j)(2)(A)(ii)(II)(aa) of the PHS Act expressly 
requires ``eligibility criteria'' to be submitted for registration on 
ClinicalTrials.gov, but it does not define the term. In the NPRM we 
expressed our belief that the purpose of this data element is to enable 
users of the data bank to determine key characteristics of potential 
participants in the clinical trial and assist prospective participants 
in identifying clinical trials that may be of interest. Consistent with 
the stated objective of section 402(j)(2)(A)(i) of the PHS Act to 
``enhance patient enrollment,'' we interpreted the requirement to 
include an ``Eligibility Criteria'' data element as part of clinical 
trial registration information to refer to information that can be of 
practical use to prospective participants who wish to determine if they 
potentially qualify to participate in

[[Page 65047]]

a clinical trial and who may be interested in seeking additional 
information about a clinical trial. We noted that our proposed 
definition of ``eligibility criteria'' was consistent with ``key 
inclusion and exclusion criteria'' of the WHO Trial Registration Data 
Set (version 1.2.1) (WHO data item #14) and ICMJE registration policies 
[Ref. 2, 73] (79 FR 69621). A few commenters addressed the proposed 
Eligibility Criteria data element. One commenter agreed with the 
proposal that only ``a limited list of criteria'' be provided but 
suggested the need for a disclaimer on the posted record that the data 
element is not intended to represent all eligibility criteria. Although 
we do not believe that a disclaimer about the eligibility criteria data 
element on the record is necessary, particularly because there may be 
cases in which the criteria listed do represent the complete list, we 
will consider displaying on the public record an explanation that the 
listed eligibility criteria represent ``key'' or ``selected'' criteria 
to minimize the potential for confusion. Another commenter suggested 
requiring the use of standardized terminology for describing the 
eligibility criteria to facilitate automated, machine-based screening 
and matching with potential participants. While this is an active area 
of ongoing research, we are not aware of any widely-accepted data 
standards for representing eligibility criteria and the commenter did 
not reference any. Therefore, the final rule does not require the 
submission of eligibility criteria using any particular standardized 
terminology, although we encourage responsible parties to submit such 
information in as structured and standardized a fashion as possible to 
facilitate data reuse. After considering these comments, we maintain 
the proposed definition in the final rule. For submission of 
eligibility criteria information, responsible parties must provide a 
list of inclusion and exclusion criteria (e.g., Inclusion Criteria: 
Clinical diagnosis of Alzheimer's Disease, must be able to swallow 
tablets; Exclusion Criteria: Insulin dependent diabetes, thyroid 
disease). We note that clinical trial protocols typically contain 
lengthy, detailed descriptions of inclusion and exclusion requirements 
for participants, including, for example, specific laboratory test 
result values. The requirements are often complex and must be assessed 
by a clinician or researcher involved in the clinical trial. We believe 
that the submission of all eligibility criteria would be burdensome for 
responsible parties and, instead of helping prospective participants, 
would prove confusing or overwhelming to them. We believe that 
prospective participants are better served by a more limited list of 
inclusion and exclusion criteria in the data bank to assist in 
identifying clinical trials of possible interest. Prospective 
participants who believe they meet the criteria listed in the data bank 
could discuss the clinical trial with their physician or other 
healthcare advisor and contact the facility-specific contact or central 
contact for the clinical trial for more information and a more complete 
assessment of eligibility. We note that for users of the data bank who 
want more detailed information about eligibility criteria for the 
purposes of interpreting clinical trial results information and better 
understanding the population of human subjects studied, the final rule 
requires responsible parties to submit protocols as part of the 
clinical trial results information (see Section III.D. of this 
preamble).
    (B) Sex/Gender. In Sec.  11.10(b)(22) of the NPRM, we defined the 
term ``gender'' to mean, ``the biological sex of the human subjects who 
may participate in the clinical trial.'' Section 
402(j)(2)(A)(ii)(II)(bb) of the PHS Act expressly requires ``gender'' 
to be submitted as clinical trial information at the time of 
registration, but it does not define this term. We also proposed that 
responsible parties would select from the following limited set of 
choices: ``male,'' ``female,'' or ``both.'' Although no ``other'' 
option was proposed, the NPRM explained that responsible parties would 
be able to provide additional, optional free-text information about the 
gender of participants who may participate in the clinical trial (79 FR 
69621).
    Several commenters addressed this data element. A few requested 
that the final rule change the term to ``sex.'' Others stated that use 
of the term ``sex'' would be consistent with FDA's guidance, 
``Evaluation of Sex-Specific Data in Medical Device Clinical Studies,'' 
in which ``sex'' refers to classification by reproductive organ, and 
``gender'' refers to a person's self-representation as male or female 
[Ref. 95]. They also noted that FDA's guidance is based on an IOM 
report, ``Exploring the Biological Contributions to Human Health: Does 
Sex Matter?'' [Ref. 96].
    We agree with the commenters that the proposed definition of 
``gender'' does not align with the cited definitions and usage of the 
distinct terms ``gender'' and ``sex.'' The commenters further suggested 
that we change the data element name from ``Gender'' to ``Sex'' to 
better align with the proposed definition. Although not mentioned 
specifically by commenters, we also note that the WHO Trial 
Registration Data Set (version 1.2.1) describes inclusion and exclusion 
criteria for participant selection, including age and ``sex.''
    To further consider how the terms ``gender'' and ``sex'' are used 
to define recruitment/eligibility criteria in protocols, we evaluated a 
convenience sample of 80 study protocols made available online with 
publication in the Journal of the American Medical Association and the 
New England Journal of Medicine. Our observations suggest that although 
protocols use the terms ``gender'' and/or ``sex,'' it was generally not 
possible to determine whether the usage was appropriate, as definitions 
of those terms were not typically included. Among the protocols 
examined, 23 (29 percent) used the term ``gender'' only, 11 (14 
percent) used ``sex'' only, 32 (40 percent) appeared to use the terms 
``gender'' and ``sex'' interchangeably, and 14 (17 percent) did not use 
either term. We believe it is important for the information on 
ClinicalTrials.gov to accurately represent the individuals who may 
participate in the clinical trial, based on information specified in 
the trial protocol. Based on our evaluation of this sample of protocols 
and the comments received on the NPRM, we have concluded that the data 
element needs to be sufficiently flexible to allow responsible parties 
to submit information about both sex and gender, if those terms are 
applicable to the trial being registered. We have therefore modified 
the proposed name of the data element to ``Sex/Gender'' in Sec.  
11.28(a)(2)(ii)(B) of the final rule to accommodate studies that base 
eligibility on sex (meaning, for purposes of this part, a person's 
classification as male or female based on biological distinctions) and 
gender (meaning, for purposes of this part, a person's self-
representation of gender identity). Similarly, to reflect both terms, 
we have updated the definition of ``Sex/Gender'' to be ``the sex and, 
if applicable, gender of the human subjects who may participate in the 
clinical trial'' in Sec.  11.10(b)(22). The responsible party must 
indicate the sex of the individuals who may participate in the clinical 
trial using the following options available on ClinicalTrials.gov for 
this data element: ``male,'' which indicates that only male 
participants are being studied, ``female,'' which indicates that only 
female participants are being studied, and ``all'' which indicates that 
the recruitment

[[Page 65048]]

criteria do not limit eligibility based on the sex of participants. In 
addition, if eligibility for the clinical trial is based on gender, the 
responsible party may also select from the following options to provide 
details about gender: ``yes'' (meaning eligibility is based on gender) 
or ``no'' (meaning eligibility is not based on gender). If the 
responsible party selects ``yes,'' descriptive information about gender 
criteria may be provided in the optional, additional, free-text 
element. Information on gender is required to be submitted only if 
gender is used as an eligibility/recruitment criterion for the clinical 
trial. We further note that we consider the Sex/Gender data element 
complementary to the limited list of criteria submitted as part of the 
Eligibility Criteria data element, but provision of information on sex/
gender in that data element does not substitute for the requirement to 
provide the Sex/Gender data element.
    (C) Age Limits. In Sec.  11.10(b)(23) of the NPRM, we defined this 
term to mean, ``the minimum and maximum age of human subjects who may 
participate in the clinical trial, provided in relevant units of 
time.'' Section 402(j)(2)(A)(ii)(II)(cc) of the PHS Act expressly 
requires ``age limits'' to be submitted as clinical trial information 
at the time of registration, but it does not define the term (79 FR 
69621). We received no comments and therefore retain the proposed data 
element and definition in the final rule. We clarify, however, that the 
responsible party selects the unit of time from the following limited 
set of choices: ``years,'' ``months,'' ``weeks,'' ``days,'' ``hours,'' 
``minutes,'' and ``N/A'' (i.e., no limit). These structured choices are 
consistent with current practice on ClinicalTrials.gov and facilitates 
more specific searches by age limits (e.g., finding studies recruiting 
children aged 24 to 36 months versus adults aged 24 to 36 years).
    (D) Accepts Healthy Volunteers. In Sec.  11.10(b)(24) of the NPRM, 
we defined the Accepts Healthy Volunteers data element to mean 
``whether human subjects who do not have a disease or condition, or 
related conditions or symptoms, under study in the clinical trial are 
permitted to participate in the clinical trial.'' Section 
402(j)(2)(A)(ii)(II)(dd) of the PHS Act requires the submission of 
information about ``whether the trial accepts healthy volunteers.'' (79 
FR 69621) We received no comments and therefore retain the proposed 
data element and definition in the final rule, except we delete the 
word ``whether'' in the definition for additional clarity. We note that 
we consider any human participant in a clinical trial to be a human 
subject regardless of whether he or she is a healthy volunteer.
    (E) Overall Recruitment Status. Under Sec.  11.10(b)(25) of the 
NPRM, we defined the Overall Recruitment Status data element as ``the 
recruitment status for the clinical trial as a whole, based upon the 
status of the individual sites. If at least one facility in a multi-
site clinical trial has an individual site status of `recruiting,' then 
the overall recruitment status for the trial must be `recruiting.' '' 
Section 402(j)(2)(A)(ii)(II)(ee) of the PHS Act requires ``overall 
recruitment status'' to be submitted as clinical trial information at 
the time of registration, but it does not define the term. To 
facilitate searching for clinical trials by recruitment status and to 
allow information to be compared across clinical trials, we also stated 
in the NPRM that responsible parties would be required to select from 
the following limited set of choices: ``Not yet recruiting'' 
(participants are not yet being recruited); ``Recruiting'' 
(participants are currently being recruited, whether or not any 
participants have yet been enrolled); ``Enrolling by invitation'' 
(participants are being, or will be selected from a predetermined 
population); ``Active, not recruiting'' (study is ongoing, meaning 
participants are being treated or examined, but new participants are 
not currently being recruited or enrolled); ``Completed'' (the study 
has concluded normally; participants are no longer being examined or 
treated, i.e., last patient's last visit has occurred); ``Suspended'' 
(recruiting or enrolling participants has halted prematurely but 
potentially will resume), ``Terminated'' (recruiting or enrolling 
participants has halted prematurely and will not resume; participants 
are no longer being examined or treated), and ``Withdrawn'' (study 
halted prematurely, prior to enrollment of first participant). No 
``other'' option was proposed. We invited public comment on whether the 
proposed options are sufficient to accurately describe the overall 
recruitment status of clinical trials subject to the proposed rule. We 
also noted that the proposed definition of ``overall recruitment 
status'' is consistent with ``recruitment status'' in the WHO Trial 
Registration Data Set (version 1.2.1) (WHO data item #18) and ICMJE 
registration policies [Ref. 2, 73] (79 FR 69621).
    We received no comments and therefore retain the proposed 
definition in the final rule. The final rule requires responsible 
parties to provide and update information for the Overall Recruitment 
Status data element. Such a requirement will provide users of 
ClinicalTrials.gov with an effective means of tracking the progress of 
clinical trials, as required by section 402(j)(2)(A)(i) of the PHS Act. 
However, we clarify the descriptions for the following four choices 
identified in the NPRM for the Overall Recruitment Status data element: 
``Active, not recruiting'' indicates that a ``study is continuing, 
meaning that participants are receiving an intervention or being 
examined, but new participants are not currently being recruited or 
enrolled;'' ``Completed'' indicates that ``the study has concluded 
normally; participants are no longer receiving an intervention or being 
examined, i.e., the last patient's last visit has occurred;'' 
``Suspended'' indicates that a ``study halted prematurely but 
potentially will resume;'' and ``Terminated'' indicates that a ``study 
halted prematurely and will not resume; participants are no longer 
being examined or receiving an intervention.'' These descriptions are 
clearer and more accurate for the data element choices. We remove the 
term ``treated'' from the description of these options and instead use 
the phrase ``receiving an intervention'' for greater accuracy because 
not all clinical trials are conducted to evaluate whether interventions 
are efficacious for the treatment of the disease or condition that is 
the focus of the study. We note that ``receiving an intervention'' 
includes receiving a placebo or receiving no intervention, as assigned 
in the study protocol. The other modifications clarify that the status 
relates to the entire study, not just the aspect of the study that 
involves recruitment. We also note that if a clinical trial is 
registered before it is open to recruitment, we would expect the 
Overall Recruitment Status to be ``Not yet recruiting.'' When the 
clinical trial opens for enrollment, we would expect the Overall 
Recruitment Status to be ``Enrolling by invitation'' if human subjects 
are selected from a predetermined population or ``Recruiting'' if the 
study is open to volunteers who meet the study's eligibility criteria. 
As indicated in the discussion of the Study Start Date data element, 
for this rule, if a clinical trial is registered prior to enrollment of 
the first subject and the clinical trial is subsequently halted before 
the first subject is enrolled, we would expect the responsible party to 
update the Overall Recruitment Status data element to ``Withdrawn.''
    We believe that updating the Overall Recruitment Status data 
element will provide users of ClinicalTrials.gov with

[[Page 65049]]

an effective means of tracking the progress of clinical trials, as the 
data bank is intended to do (see section 402(j)(2)(A)(i) of the PHS 
Act). In the case of a clinical trial that is halted before the first 
subject is enrolled (i.e., a status of Withdrawn), this information 
will explain why no results information can be expected or is required 
to be submitted. In the case of a clinical trial for which recruitment 
is prematurely halted (i.e., a status of Suspended or Terminated), this 
information will allow potential human subjects to determine whether 
enrollment is likely to resume. Such information will also assist in 
the interpretation of results information, for example, by providing an 
explanation of why some clinical trial outcomes were not achieved and/
or enrollment was significantly below the target. We note that when a 
study has reached its study completion date, as defined in Sec.  
11.10(a), the Overall Recruitment Status would be Completed, unless the 
responsible party terminates the study, which would be reflected in a 
status of Terminated.
    (F) Why Study Stopped. Proposed Sec.  11.10(b)(26) of the NPRM 
defined the Why Study Stopped? data element to mean ``for a clinical 
trial that is suspended or terminated or withdrawn prior to its 
completion as anticipated by the protocol, a brief explanation of the 
reason(s) why such clinical trial was stopped.'' We proposed allowing 
responsible parties to enter this information as a free-text response, 
to provide them with the flexibility to explain the reason(s) why a 
clinical trial stopped prematurely. While this information is not 
required for submission by section 402(j) of the PHS Act, we indicated 
that it is important to communicate to users of the data bank why a 
clinical trial was suspended, terminated, or withdrawn (e.g., safety 
concerns, difficulties in recruitment, financial reasons). Such 
information also furthers the statutory objective stated in section 
402(j)(2)(A)(i) of the PHS Act to enable users ``to track subsequent 
progress of clinical trials.'' As we stated in the NPRM, for these 
reasons requiring this information improves and does not reduce the 
clinical trial information available in the data bank, consistent with 
the authority granted to the Agency under section 402(j)(2)(A)(iii) of 
the PHS Act. We also indicated our concern that if such information 
were not required in each instance in which a clinical trial is stopped 
prematurely (i.e., not according to the protocol), it might be 
submitted only for some trials, resulting in inconsistencies in the 
information available for registered clinical trials (79 FR 69622).
    Two commenters requested that for this data element the final rule 
require only the submission of reasons for stopping a study that are 
directly related to safety. These commenters asserted that any other 
reasons would be business reasons, which would be confidential 
commercial information prohibited from disclosure. As we explained in 
the NPRM, we believe it is important for responsible parties to provide 
any reasons for stopping a study, whether or not they relate to safety. 
This increased transparency will assist the public, including patients, 
in understanding the reasons why a trial was stopped. We also note that 
this proposed definition specifies that any explanation provided be 
brief; therefore, we do not believe that a responsible party will need 
to provide any confidential commercial or proprietary information when 
submitting the information for this data element. However, even if the 
summary results information required to be submitted and posted does 
include such proprietary information, as discussed above, section 
402(j) of the PHS Act and this final rule constitute authorization by 
law to disclose the information.
    After considering the comments, we are maintaining the NPRM 
definition in the final rule. We note that Sec. Sec.  11.10(b)(26) and 
11.64(a)(1) specify that a brief explanation for why the clinical trial 
was stopped must be submitted if the Overall Recruitment Status is 
``Suspended,'' ``Terminated,'' or ``Withdrawn.'' In most cases, the 
Overall Recruitment Status of a clinical trial would be other than 
Suspended, Terminated, or Withdrawn at the time of registration (e.g., 
a status of ``Not yet recruiting'' or ``Recruiting''). The responsible 
party would not be required to complete the Why Study Stopped data 
element unless and until there is a change in the Overall Recruitment 
Status to Suspended, Terminated, or Withdrawn. (The Why Study Stopped 
data element would not be available to a responsible party during the 
registration process nor to the public in the posted clinical trial 
record, unless and until the Overall Recruitment Status indicates that 
the clinical trial is Suspended, Terminated, or Withdrawn.) However, if 
a clinical trial is suspended, terminated, or withdrawn, the 
responsible party would be required to update the Overall Recruitment 
Status data element and, consistent with Sec.  11.64(a)(1), submit the 
Why Study Stopped data element not later than 30 calendar days after 
the date of the suspension, termination, or withdrawal of the clinical 
trial to explain why the study stopped.
    (G) Individual Site Status. In proposed Sec.  11.10(b)(28) of the 
NPRM, we defined this data element as ``the recruitment status of each 
participating facility in a clinical trial.'' Section 
402(j)(2)(A)(ii)(II)(ff) of the PHS Act expressly requires ``individual 
site status'' to be submitted as a clinical trial information at the 
time of registration, but it does not define the term. To be consistent 
with the proposed Overall Recruitment Status data element, we also 
stated in the NPRM that responsible parties would be required to 
indicate the individual site status by selecting from the following 
limited set of choices: ``Not yet recruiting,'' ``Recruiting,'' 
``Enrolling by invitation,'' ``Active, not recruiting,'' ``Completed,'' 
``Suspended,'' ``Terminated,'' and ``Withdrawn.'' No ``other'' option 
was proposed. We invited public comment on whether the proposed options 
were sufficient to accurately describe the individual site status of 
clinical trials that would be subject to the proposed rule (79 FR 
69623). Two commenters suggested that the final rule remove the 
proposed requirement for registering and updating the Individual Site 
Status data element for each participating facility in the trial. The 
Individual Site Status data element is required by section 
402(j)(2)(A)(ii)(II)(ff) of the PHS Act. Furthermore, such information 
supports the purpose of ClinicalTrials.gov to enhance patient 
enrollment by assisting potential human subjects who search for 
clinical trials by location and wish to retrieve information about only 
those trials that are open to recruitment in specified locations. We 
clarify that when the Overall Recruitment Status is a status other than 
Recruiting, the Individual Site Status data element no longer needs to 
be updated because the Overall Recruitment Status would apply to each 
individual site. We also note that the update burden for responsible 
parties is reduced by tools available in the PRS that allow the 
Individual Site Status data element to be easily changed (e.g., from 
Recruiting to Active, not recruiting) for many sites at once. After 
considering the comments, we retain the proposed definition in the 
final rule. However, we clarify these descriptions as described for the 
Overall Recruitment Status data element. Specifically, we modify the 
following four choices for the Individual Site Status data element from 
the limited set described in the NPRM: ``Active, not recruiting'' 
indicates that a study is continuing, meaning that participants are 
receiving

[[Page 65050]]

an intervention or being examined, but new participants are not 
currently being recruited or enrolled; ``Completed'' indicates that the 
study has concluded normally and that participants are no longer 
receiving an intervention or being examined, i.e., the last patient's 
last visit has occurred; ``Suspended'' indicates that a study halted 
prematurely but potentially will resume; and ``Terminated'' indicates 
that a study halted prematurely and will not resume and that 
participants are no longer being examined or receiving an intervention. 
We note that when a study has reached its study completion date, as 
defined in Sec.  11.10(a), the Individual Site Status would be 
Completed, unless the responsible party terminates the study, which 
would be reflected as a status of Terminated.
    (H) Availability of Expanded Access. Section 
402(j)(2)(A)(ii)(II)(gg) of the PHS Act specifies that if a drug 
(including a biological product) being studied in an applicable 
clinical trial is not approved under section 505 of the FD&C Act or 
licensed under section 351 of the PHS Act, the responsible party must 
specify (1) ``whether or not there is expanded access to the drug under 
section 561 of the [FD&C Act] for those who do not qualify for 
enrollment in the clinical trial'' and, if so, (2) ``how to obtain 
information about such access.'' As we expressed in the NPRM, we 
believe the purpose of this requirement is to allow prospective human 
subjects and other users of the data bank to readily identify 
unapproved drugs that are available through expanded access under 
section 561 of the FD&C Act and to direct these users to additional 
information about the expanded access. Therefore, we proposed that 
responsible parties meet the requirements of section 
402(j)(2)(A)(ii)(II)(gg) of the PHS Act by indicating in the clinical 
trial record whether expanded access is available for the drug under 
study (i.e., either ``yes'' or ``no'') and, if yes, submitting the 
additional information about the expanded access in the form of an 
expanded access record under proposed Sec.  11.28(c) and including the 
NCT number for the expanded access record in the record of a clinical 
trial that studies the drug.
    In the NPRM, we proposed to require the submission of information 
to create an expanded access record using the statutory authority at 
section 402(j)(2)(A)(iii) of the PHS Act, which allows the Secretary by 
regulation to modify the requirements for clinical trial registration 
information if the Secretary provides a rationale for why such a 
modification ``improves and does not reduce such clinical trial 
information.'' Information about the availability of expanded access 
would be a data element that a responsible party is required to submit 
under section 402(j)(2)(A)(ii)(II) of the PHS Act and, therefore, would 
meet the definition of ``clinical trial information'' in section 
402(j)(1)(A)(iv) of the PHS Act. We indicated that the additional data 
elements describing expanded access availability would improve, and not 
reduce, this clinical trial information by providing users with more 
complete and consistent information about expanded access programs for 
drugs studied in applicable clinical trials than would be available 
pursuant to section 402(j)(A)(ii)(II)(gg) of the PHS Act alone. We 
further concluded that we have the authority to require that the 
clinical trial information required under proposed Sec.  11.28(c) be 
submitted by creating a separate expanded access record in 
ClinicalTrials.gov under section 402(j)(2)(B)(iv) of the PHS Act, as 
the expanded access record would ensure that the public may more easily 
use the data bank to determine whether there is expanded access to a 
drug and compare different expanded access programs.
    The approach we proposed is similar to the one used to submit a 
description of whether, and through what procedure, the manufacturer or 
sponsor will respond to requests for protocol exception, with 
appropriate safeguards, for single-patient and expanded access use of 
the investigational drug, particularly in children, prior to the 
enactment of FDAAA [Ref. 78, 79]. Proposed Sec.  11.28(a)(2)(ix) would 
require the responsible party for an applicable clinical trial of a 
drug that is not approved under section 505 of the FD&C Act to submit 
the Availability of Expanded Access data element, which was defined in 
proposed Sec.  11.10(b)(29) to include ``[a]n indication of whether 
there is expanded access to the drug under section 561 of the [FD&C 
Act] (21 U.S.C. 360bbb) for those who do not qualify for enrollment in 
the applicable clinical trial,'' and, if expanded access is available, 
``the NCT number of the expanded access record.'' The availability of 
expanded access would be indicated by a yes/no designation in 
ClinicalTrials.gov. In addition, if the drug studied in the clinical 
trial is available through expanded access under section 561 of the 
FD&C Act and an expanded access record has not been created, under the 
NPRM the responsible party would be required to create an expanded 
access record consisting of the information specified in proposed Sec.  
11.28(c). The posted expanded access record would be assigned its own 
NCT number and thus would be searchable and retrievable independent of 
the record(s) for the applicable clinical trial(s) of the 
investigational product for which expanded access is available.
    Under the proposed approach, we stated that we would expect the 
sponsor of the expanded access program to be responsible for (1) 
informing the responsible party(ies) for any applicable clinical trials 
that study the drug available under expanded access of the creation of 
an expanded access record and (2) providing them with the NCT number 
for the expanded access record. The responsible party(ies) would be 
required to update the related clinical trial record under proposed 
Sec.  11.64(b) to include the NCT number for the expanded access record 
within 30 calendar days of receipt. Accordingly, a single expanded 
access record could be linked, via the expanded access record NCT 
number, to several applicable clinical trials that study the drug that 
is available via expanded access. If an expanded access record has 
already been completed at the time of registration of an applicable 
clinical trial (e.g., to fulfill the registration or updating 
requirements for a previously registered applicable clinical trial), 
the responsible party would be required to submit the NCT number for 
that expanded access record as part of the Availability of Expanded 
Access data element. The NPRM also noted that expanded access is 
available via treatment INDs, which provide widespread access; expanded 
access for intermediate-size patient populations; and expanded access 
for individual patients (79 FR 69624). As we stated in the NPRM, 
because requests for individual patient access are generally handled on 
a case-by-case basis, a responsible party likely would not be able to 
provide detailed information describing individual patient access at 
the time of registering an applicable clinical trial. For cases in 
which expanded access is only available for individual patients on a 
case-by-case basis, we stated that we would not require the responsible 
party to submit the elements of the expanded access record, as 
described below, and we would expect that users of ClinicalTrials.gov 
would direct inquiries regarding individual patient access to the 
facility contact.
    Commenters addressed issues related to the Availability of Expanded 
Access data element in proposed Sec.  11.28(a)(2)(ix) and its 
definition in proposed Sec.  11.10(b)(29). A few commenters expressed 
support for the

[[Page 65051]]

proposed data element and its definition. A few commenters supported, 
in particular, the proposed requirement that responsible parties for 
applicable clinical trials of drugs available through expanded access 
provide the NCT number for the expanded access record to permit linking 
from clinical trial records to additional information about the 
expanded access program. One commenter opposed the proposed requirement 
for creating expanded access records because of concerns that such 
records may (1) mislead patients into believing that no other 
opportunities to obtain expanded access exist beyond what is described 
in expanded access records because the proposal does not require the 
submission of information about individual patient access and/or (2) 
confuse patients regarding the distinction between clinical trials and 
expanded access programs. We agree with the commenter that requiring 
the submission of registration information for only certain types of 
available expanded access programs, as proposed, could be problematic. 
In addition, section 402(j)(2)(A)(ii)(II)(gg) of the PHS Act broadly 
requires ``specify[ing] whether or not there is expanded access to the 
drug under section 561 of the Federal Food, Drug, and Cosmetic Act'' 
and does not explicitly exclude individual patient expanded access.
    After considering these comments and the statutory provision, in 
the final rule we have revised the requirements regarding the 
information to be submitted about the availability of expanded access 
to investigational drug products (including biological products). We 
have also clarified that ``drug'' means ``drug product.'' Therefore, 
under the final rule, if an investigational drug product (including a 
biological product) is available for any type of expanded access, and 
the responsible party for an applicable clinical trial of that product 
is both the manufacturer of the product and the sponsor of the 
applicable clinical trial, the responsible party must create an 
expanded access record for the investigational product by submitting 
the expanded access data elements specified in Sec.  11.28(c) of the 
final rule. We note that only one expanded access record should be 
created for any given investigational product, even if the 
investigational product is being made available for individual patient 
expanded access (i.e., the responsible party should not create an 
expanded access record for each instance of individual patient access). 
This approach permits users of ClinicalTrials.gov to identify the full 
range of expanded access availability under section 561 of the FD&C Act 
by searching posted expanded access records.
    Another commenter requested that posted clinical trial records be 
made ``separate and distinct'' from expanded access records to avoid 
confusion and suggested that ClinicalTrials.gov provide sponsors with 
the ability to link to their expanded access policy and contact Web 
pages. We recognize the potential for confusion between expanded access 
records and clinical trial records and have sought to help users 
distinguish between them (e.g., prominently displaying Study Type of 
``Expanded Access'' versus ``Interventional Study,'' and Overall 
Recruitment Status displayed as ``Expanded access is currently 
available for this treatment'' versus ``This study is currently 
recruiting participants''). We will continue to explore ways to 
differentiate between the two types of records. With regard to the 
second comment, we note that ClinicalTrials.gov currently permits 
responsible parties to submit URLs of Web sites through the optional 
Links data element.
    One commenter requested that the final rule define ``expanded 
access program'' and clarify for which expanded access programs the 
data elements specified in proposed Sec.  11.28(c) would be required 
under the final rule. In particular, although the preamble of the NPRM 
stated that responsible parties would not be required to create 
expanded access records when expanded access is available only through 
individual patient access, this distinction was not specified in the 
codified section of the NPRM. The commenter suggested that the final 
rule state explicitly which types of expanded access programs require 
the creation of expanded access records, such as by adding a definition 
of expanded access in Sec.  11.10 of the final rule. Another commenter 
suggested that the final rule narrow the proposed definition of 
Availability of Expanded Access to section 561(c) of the FD&C Act, 
thereby limiting the types of expanded access programs ``to 
intermediate-size and large-size treatment INDs with established 
inclusion/exclusion enrollment parameters and exclude[ing] emergency 
situations and individual patient access to INDs intended for serious 
diseases.''
    We agree that the codified section of the proposed rule did not 
provide specificity with respect to the term ``expanded access 
program.'' After considering the issue, in the final rule, we have 
revised the phrase ``expanded access program'' to ``expanded access'' 
for an expanded access record to more accurately characterize the 
mechanism through which a responsible party makes its investigational 
product available under expanded access. This flexibility will 
accommodate both situations in which a responsible party has 
established what it considers to be an expanded access program and 
those in which a responsible party makes its investigational product 
available through expanded access but does not itself characterize that 
availability as a ``program.'' Furthermore, because the statutory 
requirement for providing information about expanded access did not 
explicitly exclude individual patient expanded access, we disagree with 
the commenter that ClinicalTrials.gov should only include information 
on certain types of expanded access. The final rule broadens the scope 
of the proposed rule to include and define all three types of expanded 
access under section 561 of the FD&C Act: (1) For individual patients, 
including emergency use, as specified in 21 CFR 312.310; (2) for 
intermediate-size patient populations as specified in 21 CFR 312.315; 
and (3) under a treatment IND or treatment protocol as specified in 21 
CFR 312.320. Section 11.10(b)(28) of the final rule, which defines the 
Availability of Expanded Access data element, clarifies that if the 
investigational product is available for any of these three types of 
expanded access, the NCT number of a corresponding expanded access 
record must be submitted. As such, the definition of and requirements 
for the Availability of Expanded Access data element in the final rule 
cover all types of expanded access for investigational drug products 
(including biological products) under section 561 of the FD&C Act, 
consistent with the statutory requirements. Additionally, Sec.  
11.28(c) of the final rule, which indicates the data elements that must 
be submitted for an expanded access record, lists the Expanded Access 
Type data element, which is defined as ``[t]he type(s) of expanded 
access for which the investigational drug product is available, as 
specified in Sec.  11.10(b)(28).''
    A few commenters expressed concern that requiring responsible 
parties who are not industry sponsors and manufacturers of the drug to 
create expanded access records could be problematic because only a 
manufacturer would know when expanded access to a drug becomes 
available and would possess the

[[Page 65052]]

information required to be submitted under Sec.  11.28(c) and updated 
under Sec.  11.64. Accordingly, they suggested that the final rule only 
require responsible parties who are industry sponsors of relevant 
trials and manufacturers of the drug to create expanded access records 
for their drugs. Several commenters suggested that the final rule 
require drug manufacturers to notify responsible parties for applicable 
clinical trials when drugs become available through expanded access 
programs and that ClinicalTrials.gov could notify responsible parties 
who are not drug manufacturers when an expanded access record has been 
submitted for the drug being studied in their applicable clinical 
trials. They also requested guidance on whether the Agency would 
recommend that ``investigators of investigator-initiated trials'' seek 
agreements from manufacturers that require notification that an 
expanded access program for a studied drug becomes available. One other 
commenter requested clarification on two issues: (1) How independent 
investigators who are responsible parties for applicable clinical 
trials would know when and what information to submit for an expanded 
access record when the manufacturer makes a drug they are studying 
available through expanded access and (2) whether the proposed rule 
intended for the manufacturer to provide one expanded access record per 
drug and an indication for the purposes of the registration 
requirements.
    We agree with the concerns raised by these commenters and have 
modified the final rule to specify that the requirement to submit 
information for the Availability of Expanded Access data element only 
applies to a responsible party who is both the manufacturer of the 
investigational drug product (including a biological product) and the 
sponsor of the applicable clinical trial for that investigational 
product. We believe that these new requirements will decrease the 
burden on responsible parties who are not the manufacturer without 
impeding access to information posted on ClinicalTrials.gov about the 
availability of investigational drug products (including biological 
products) for expanded access. At the same time, these new requirements 
will ensure that only one expanded access record is created for each 
investigational drug product that is available for expanded access for 
any disease or condition. We wish to emphasize, however, that an 
expanded access record is required to be submitted regardless of 
whether the responsible party registering the applicable clinical 
trial, who is both the sponsor of the applicable clinical trial and the 
manufacturer of the investigational product, itself oversees the 
availability of the investigational product for expanded access (i.e., 
it is required even in situations where the expanded access 
availability is managed by a different entity). If certain data 
elements required for submitting an expanded access record under Sec.  
11.28(c) are unknown to the responsible party because the expanded 
access availability is managed by a different entity, the responsible 
party will need to consult with NIH concerning these data elements 
before submitting the expanded access record. Instructions for 
contacting NIH will be available at https://prsinfo.clinicaltrials.gov 
(or successor site).
    In addition, responsible parties will no longer need to be notified 
by the manufacturer when an investigational drug product (including a 
biological product) is available through expanded access. We note that 
there may be cases in which the sponsor who is the manufacturer of the 
unapproved drug product (including a biological product) may designate 
the principal investigator to be the responsible party of an applicable 
clinical trial of that product. Based on our experience operating 
ClinicalTrials.gov, we expect the designation of a principal 
investigator to be the responsible party by a manufacturer to be a rare 
event. If it does occur, we recommend that the sponsor provide the 
necessary information to the responsible party or, on an optional 
basis, create an expanded access record to allow information about 
expanded access to be shared with individuals who do not qualify for 
enrollment in the clinical trial.
    One commenter suggested that ClinicalTrials.gov provide links 
between applicable drug clinical trial records and expanded access 
records for the studied drugs and provide appropriate caveats about the 
expanded access programs. ClinicalTrials.gov is able to provide the 
appropriate links between matched clinical trial records and expanded 
access records after a responsible party has identified in the clinical 
trial record(s) that the investigational drug product (including a 
biological product) is available through a particular expanded access 
program. Once the responsible party submits the NCT number for the 
relevant expanded access record, ClinicalTrials.gov creates and 
displays a link on the clinical trial record to the related record for 
the expanded access program. We can also provide links from expanded 
access records to the matched clinical trial records. We note that 
ClinicalTrials.gov currently provides links to information about 
expanded access on FDA's Web site (e.g., www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm). As 
suggested by the commenter, we will consider providing additional 
information about expanded access or links on ClinicalTrials.gov.
    Taking into consideration the commenters' suggestions and the 
statutory requirements for providing information about expanded access 
as part of clinical trial registration information, Sec.  
11.28(a)(2)(ii)(H) of the final rule modifies the Availability of 
Expanded Access data element with respect to which responsible parties 
must submit the data element and by expanding the submission 
requirement to include applicable clinical trials for which the 
investigational drug products (including biological products) that are 
being studied are available through individual patient expanded access, 
including for emergency use. The Availability of Expanded Access data 
element as defined in Sec.  11.10(b)(28) and specified in Sec.  
11.28(a)(2)(ii)(H) of the final rule indicates whether the unapproved 
drug product (including a biological product) studied in the applicable 
clinical trial is available for expanded access under section 561 of 
the FD&C Act for those who do not qualify for enrollment in the 
applicable clinical trial (i.e., ``yes,'' ``no,'' or ``unknown''). 
Under the final rule, the requirement to submit the data element is 
limited to a responsible party for an applicable clinical trial of an 
unapproved drug product (including a biological product) who is both 
the manufacturer of the drug product and the sponsor of the trial. 
Therefore, a responsible party for an applicable drug clinical trial 
who is not the manufacturer of the drug product (including a biological 
product) would not be required to submit information for the 
Availability of Expanded Access data element (i.e., response of 
``unknown''). This modification will decrease the burden on responsible 
parties who are not the manufacturer but will still help ensure the 
availability of information about expanded access on 
ClinicalTrials.gov.
    For an investigational drug product (including a biological 
product) that is available through expanded access, including for 
individual patients, the responsible party who is both the manufacturer 
of the investigational drug product (including biological product) and 
the sponsor of an applicable clinical

[[Page 65053]]

trial must provide the NCT number of the expanded access record as part 
of the clinical trial information for that applicable clinical trial. 
If an expanded access record for the investigational drug product 
(including a biological product) has not yet been submitted to 
ClinicalTrials.gov, the responsible party is required to create an 
expanded access record as specified in Sec.  11.28(c). This new 
requirement will provide users of ClinicalTrials.gov with a way to 
obtain information about available expanded access to an 
investigational drug product (including a biological product) as 
required by the statute, including for individual patients.
    We note that even though the expanded access record NCT number is a 
registration data element, a responsible party is not required to 
submit the expanded access data elements under Sec.  11.28(c) and 
obtain an NCT number for that expanded access record prior to the date 
on which clinical trial registration information under Sec.  11.28(a) 
is due for the first applicable clinical trial of that investigational 
product that the responsible party registers. Rather, the responsible 
party is required at the time it submits clinical trial registration 
information for the applicable clinical trial to indicate that expanded 
access is available, submit the applicable data elements required by 
Sec.  11.28(c), and indicate that the NCT number for the expanded 
access record is ``pending.'' As described previously, within 30 
calendar days of receipt of the NCT number for the expanded access 
record, the responsible party is required to update the applicable 
clinical trial record with the NCT number assigned to the expanded 
access record. Finally, we note both that expanded access to an 
investigational drug product (including a biological product) may not 
be available at the time an applicable clinical trial is registered and 
that an expanded access program may be discontinued on a date other 
than the study completion date of an applicable clinical trial. We 
believe that information about changes in the availability of expanded 
access must be conveyed to users of ClinicalTrials.gov in a timely 
manner and therefore Availability of Expanded Access is a data element 
that must be updated more frequently than once every 12 months. 
Accordingly, as explained in further detail in Sec.  11.64, the 
Availability of Expanded Access data element must be updated within 30 
calendar days of expanded access becoming available, consistent with 
Sec.  11.64(a).
(iii) Location and Contact Information
    (A) Name of the Sponsor. In Sec.  11.10(b)(30) of the NPRM, Name of 
the Sponsor is defined as ``the name of the entity or the individual 
that is the sponsor of the clinical trial, as defined in Sec.  
11.10(a).'' Section 402(j)(2)(A)(ii)(III)(aa) of the PHS Act expressly 
requires responsible parties to submit the name of the sponsor as part 
of clinical trial information at the time of registration. In the NPRM, 
the term ``sponsor'' is defined as ``either a `sponsor' or `sponsor-
investigator,' as each is defined in 21 CFR 50.3, or any successor 
regulation.'' As we indicated, if the sponsor is a sponsor-
investigator, we would expect the name of the sponsor to be the name of 
an individual; otherwise the name of the sponsor may be an 
organizational name (79 FR 69624). We received no comments on this data 
element and therefore retain the proposed definition in the final rule, 
however, we made minor grammatical corrections (e.g., changing ``that'' 
to ``who'').
    (B) Responsible Party, by Official Title. Section 11.10(b)(31) of 
the NPRM defined Responsible Party, by Official Title to mean ``(i) 
Indication of whether the responsible party is the sponsor of the 
clinical trial, as that term is defined in 21 CFR 50.3, the sponsor-
investigator, as that term is defined in 21 CFR 50.3, or a principal 
investigator designated pursuant to this part; and (ii) Either: (A) The 
official name of the entity, if the responsible party is an entity; or 
(B) The official title and primary organizational affiliation of the 
individual, if the responsible party is an individual.'' Section 
402(j)(2)(A)(ii)(III)(bb) of the PHS Act expressly requires the 
submission of the ``responsible party, by official title'' as part of 
clinical trial registration information. When an organizational entity 
is the responsible party, we noted our belief that the official name of 
the entity (e.g., company name, university name, government agency 
name) must be included to satisfy the requirement for the Responsible 
Party, by Official Title data element. When the responsible party is an 
individual, we noted our belief that the official job title and the 
organizational affiliation of the individual are necessary (e.g., 
``Director of Clinical Research, Institution X'' or ``Professor of 
Medicine, Institution Y''). In addition, we indicated that we believe 
it is necessary to ask whether the responsible party is the sponsor, 
sponsor-investigator, or a principal investigator designated by the 
sponsor, grantee, contractor, or awardee. Collection of this 
information will help determine what information must be provided for 
the official title and will allow a principal investigator to provide 
an affirmative acknowledgement that he or she has been designated the 
responsible party (79 FR 69624). We received no comments on this data 
element and therefore retain the proposed definition in the final rule. 
We note that an individual who serves as a responsible party and has 
multiple affiliations (e.g., a research university and a teaching 
hospital, a research institution and a private company) would be 
required to submit only one such affiliation, namely, the affiliation 
that the individual considers their primary affiliation. A related data 
element, Responsible Party Contact Information, is defined in Sec.  
11.10(b)(37).
    (C) Facility Information. In Sec.  11.10(b)(32) of the NPRM, we 
defined Facility Information as (1) ``Facility Name, meaning the full 
name of the organization where the clinical trial is being conducted''; 
(2) ``Facility Location, including city, state, country and zip code 
for U.S. locations (including territories of the United States) and 
city and country for locations in other countries,'' and (3) for each 
participating facility either ``a Facility Contact, including the name 
or title, telephone number, and email address of a person to whom 
questions concerning the trial and enrollment at that site can be 
addressed'' or a ``Central Contact Person, including the name or title, 
toll-free telephone number and email address of a person to whom 
questions concerning enrollment at any location of the trial can be 
addressed.'' Section 402(j)(2)(A)(ii)(III)(cc) of the PHS Act expressly 
requires the submission of ``the facility name and facility contact 
information'' as part of clinical trial information at the time of 
registration and describes facility contact information as ``including 
the city, State, and zip code for each clinical trial location, or a 
toll-free number through which such location information may be 
accessed.'' Section 402(j)(2)(B)(i) of the PHS Act requires the 
Director to ensure that the public may search the entries in 
ClinicalTrials.gov by one or more of several enumerated criteria, one 
of which is ``location of the clinical trial.'' In the NPRM, we 
interpreted ``location of the clinical trial'' to mean each location of 
the clinical trial because section 402(j)(2)(A)(ii)(III)(cc) of the PHS 
Act describes ``facility contact information'' as meaning contact 
information ``for each clinical trial location.'' To enable the public 
to search the data bank by the location of the

[[Page 65054]]

clinical trial; in our view, satisfactory searching of the data bank by 
location can only be accomplished if responsible parties submit 
complete facility location information for each clinical trial 
location. Also, in our view, a toll-free telephone number is not a 
substitute for the location information for each facility or site but 
rather is a source of supplementary information about the clinical 
trial overall and an alternative to site-specific contact information 
for each location. Therefore, the Agency proposed to exercise its 
authority under section 402(j)(2)(A)(iii) of the PHS Act as we noted 
our belief that including this information improves and does not reduce 
the clinical trial registration information. We noted that our proposal 
to permit responsible parties to submit Central Contact instead of 
Facility Contact was intended to reduce the burden on responsible 
parties who must submit clinical trial registration information. 
However, the central contact person should be fully informed of, and 
able to respond to, requests for information concerning the clinical 
trial at all of its sites (79 FR 69625).
    Commenters addressed the proposed Facility Information data 
element. One commenter requested that facilities located outside of the 
United States be excluded from the submission requirements. We disagree 
with this comment. As discussed in the preamble of the NPRM, we 
interpret ``location of the clinical trial'' in this context as meaning 
each location of the clinical trial because section 
402(j)(2)(A)(ii)(III)(cc) of the PHS Act describes ``facility contact 
information'' as meaning contact information ``for each clinical trial 
location.'' Because the final rule is not limited to applicable 
clinical trials that are conducted in the United States, and because it 
is important that the database be complete in order to allow users to 
search for registered trials by key characteristics (including where 
they are being conducted), the Facility Information data element must 
include information about all facility locations, including those 
outside the United States. A few commenters suggested that the final 
rule limit the required Facility Contact Information sub-element to 
information about the facility, rather than also requiring information 
about an individual, as proposed. One commenter suggested requiring 
only a toll-free telephone number for the Central Contact Person and 
removing the proposed requirement for a name or title and an email 
address to reduce the reporting burden and the submission of personally 
identifiable information. Another commenter suggested that providing 
contact information for each facility participating in a trial would 
increase the burden on academic sites to respond to inquiries and 
requested confirmation that a toll-free phone number is only required 
for the Central Contact Person, if provided, and not for each study 
facility. One commenter suggested that the final rule clarify that the 
proposed Central Contact Person sub-element defined in Sec.  
11.10(b)(32)(iii)(B) applies to the entire trial. Another commenter 
supported the inclusion of contact information for someone who is 
knowledgeable about the trial at each facility.
    We disagree with these comments and maintain the definition of 
``Facility Information.'' As explained in the preamble of the NPRM, the 
requirement that the responsible party must submit to the data bank the 
location of each facility at which the clinical trial is conducted will 
allow users of ClinicalTrials.gov to search the data bank by each 
clinical trial location (79 FR 69625). We believe that providing ``the 
name or title . . . of a person to whom questions concerning the trial 
and enrollment at that site can be addressed . . .'' helps users 
identify who they can contact for additional information about a trial. 
In addition, we believe that a toll-free telephone number is not a 
substitute for the location information for each facility, but rather 
is a source of supplementary information about the clinical trial 
overall and an alternative to site-specific contact information for 
each location. Because a toll-free phone number in one country may not 
be applicable when a call originates in another country, and given the 
worldwide prevalence of electronic communication, we believe that 
submitting email addresses is necessary to provide an alternate method 
of contacting someone knowledgeable about the trial. Finally, we note 
that proposed Sec.  11.10(b)(32)(iii)(B) already specified ``a person 
to whom questions concerning enrollment at any location of the trial 
can be addressed'' and we believe that this description sufficiently 
indicates that the person must be knowledgeable about all the locations 
for a trial.
    For these reasons, we believe including the information required in 
the final rule improves and does not reduce the clinical trial 
registration information. Under our authority in section 
402(j)(2)(A)(iii) of the PHS Act, we therefore modify in Sec.  
11.28(a)(2)(iii)(C) the requirement in section 
402(j)(2)(A)(ii)(III)(cc) of the PHS Act for ``facility name and 
facility contact information'' to require Facility Information for each 
participating facility in the clinical trial, as defined in Sec.  
11.10(b)(31). As noted above, the Agency intends to exercise its 
authority under section 402(j)(2)(B)(i) of the PHS Act to enable the 
public to search the data bank by the location of a clinical trial; in 
our view, satisfactory searching by location can only be accomplished 
if responsible parties submit complete facility location information 
for each clinical trial location. In addition, the final rule allows, 
but does not require, responsible parties to submit the name or title 
of a person knowledgeable about the clinical trial at each site, along 
with the phone number and email address of that person, which would 
help prospective human subjects obtain additional, specific information 
about a clinical trial at a particular location. Responsible parties 
will also be permitted to submit a Central Contact Person instead of 
Facility Contact, which will reduce the burden on responsible parties 
who must submit clinical trial registration information. As noted in 
the NPRM preamble, the central contact person should be fully informed 
of, and able to respond to, requests for information concerning the 
clinical trial for all its sites (79 FR 69625).
(iv) Administrative Data
    Section 402(j)(2)(A)(ii)(IV) of the PHS Act provides for certain 
``administrative data'' to be submitted by responsible parties as part 
of clinical trial registration information; however, unlike the other 
categories of clinical trial registration information, the statute 
specifies that the Secretary may make administrative data ``publicly 
available as necessary.'' Accordingly, in the NPRM, we indicated 
whether we would make the information publicly available through 
ClinicalTrials.gov.
    (A) Unique Protocol Identification Number. In Sec.  11.10(b)(33) of 
the NPRM, we defined ``unique protocol identification number'' to mean 
``any unique identification number assigned to the protocol by the 
sponsor.'' Section 402(j)(2)(A)(ii)(IV)(aa) of the PHS Act expressly 
requires the submission of ``the unique protocol identification 
number'' as part of clinical trial information at the time of 
registration, but it does not define the term (79 FR 69625). We did not 
receive any comments on this data element, but we are modifying the 
proposed data element in the final rule for accuracy. To clarify that 
the unique protocol identifier need not be a number, Unique Protocol 
Identification Number is defined in the final rule as ``any unique 
identifier assigned to the protocol by the

[[Page 65055]]

sponsor.'' We note that once a unique protocol identifier is entered on 
ClinicalTrials.gov, the same identifier cannot be assigned to another 
protocol for another clinical trial in the sponsor's ClinicalTrials.gov 
account. In cases in which multiple identifiers may have been assigned 
to a clinical trial (e.g., a funding organization's grant number, a 
unique identifier established by another clinical trial registry), 
interpreting this term as an identifier ``assigned by the sponsor'' 
will remove any ambiguity for responsible parties about which 
identifier to submit as the unique protocol identifier for purposes of 
registration on ClinicalTrials.gov. We also expect that the unique 
protocol identifier would be readily available to the responsible 
party, whether the sponsor or a designated principal investigator who 
would have access to the protocol itself and/or be able to obtain the 
unique protocol identifier from the sponsor. Furthermore, these 
identifiers are often used in other clinical trial documentation, which 
will enable cross-referencing of information submitted to different 
data systems. To enable such cross-referencing, this data element will 
be publicly available on ClinicalTrials.gov.
    (B) Secondary ID. In Sec.  11.10(b)(34) of the NPRM, we defined the 
term, in part, as ``[a]ny identification number(s) other than the 
organization's unique protocol identification number or NCT number that 
is assigned to the clinical trial . . .'' Section 
402(j)(2)(A)(ii)(IV)(bb) of the PHS Act expressly requires the 
submission of ``other protocol identification numbers, if any,'' at the 
time of registration, but it does not define the term. We also proposed 
that the Secondary ID include the complete grant or contract number for 
any clinical trial that is funded, in whole or in part, by a U.S. 
Federal Government agency and ``any unique clinical trial 
identification numbers assigned by other publicly available clinical 
trial registries'' (e.g., EudraCT in the EU). This requirement would 
enable users of ClinicalTrials.gov to identify Government-funded 
clinical trials. It also would assist agencies of the Department 
(including NIH, FDA, the Centers for Disease Control and Prevention, 
and the Agency for Healthcare Research and Quality) to verify that 
clinical trial information for each applicable clinical trial for which 
a grantee is the responsible party has been submitted consistent with 
sections 402(j)(2) and (3) of the PHS Act and this part before the 
agency releases any remaining funding for a grant or provides funding 
for a future grant to such grantee as required under section 
402(j)(5)(A)(ii) of the PHS Act of any agency of the Department that 
funds applicable clinical trials. In addition, the inclusion of grant 
and contract numbers for awards from other federal agencies (e.g., 
Department of Veterans Affairs, Department of Defense) would facilitate 
efforts by the Secretary, as required under section 402(j)(5)(A)(iv) of 
the PHS Act, to consult with such other agencies and develop comparable 
procedures for the verification of compliance with the requirements of 
sections 402(j)(2) and (3) of the PHS Act. Finally, in order for users 
to interpret the various types of secondary ID information that might 
be provided in response to this requirement, we proposed to require 
responsible parties to submit ``[a] description of the type of 
Secondary ID'' for each secondary ID submitted. We stated that these 
descriptions should be brief but should clearly indicate the source of 
the identifier, e.g., ``U.S. NIH Grant Number'' or ``[XYZ] Registry 
Identifier.'' To facilitate data entry and improve comparability across 
registered clinical trials, we stated that we would include a list of 
several common identifier types in ClinicalTrials.gov, as well as 
permitting free-text entriesl (79 FR 69626).
    Currently, ClinicalTrials.gov allows responsible parties to select 
from the following options: ``US NIH Grant/Contract Award Number,'' 
``Other Grant/Funding Number,'' ``Registry Identifier,'' ``EudraCT 
Number,'' and ``Other Identifier.'' Responsible parties who select 
``Other Grant/Funding Number,'' ``Registry Identifier,'' or ``Other 
Identifier'' are required to enter the name of the funding organization 
or a brief description of the identifier. One commenter supported the 
proposal to require responsible parties to provide the complete grant 
or contract number for any trial that is funded in whole or part by a 
U.S. Federal Government agency. We modify the proposed data element in 
the final rule for accuracy in a manner similar to the modifications 
made to the Unique Protocol Identification Number. To clarify that a 
secondary identifier need not be a number, Secondary ID is defined in 
the final rule, in part, as ``[a]ny identifier(s) other than the 
organization's unique protocol identifier or NCT number that is 
assigned to the clinical trial, including any unique clinical trial 
identifiers assigned by other publicly available clinical trial 
registries.'' We will post the secondary ID publicly, as this 
information will enable users to locate additional information in other 
clinical trial registries as well as provide grant and contract numbers 
for awards from other Federal agencies.
    (C) U.S. Food and Drug Administration IND or IDE Number. In Sec.  
11.10(b)(35) of the NPRM, we defined the Food and Drug Administration 
IND or IDE Number data element to include an indication whether or not 
there is an IND or IDE for the clinical trial (a yes/no response) and, 
if so, each of the following elements: (1) ``[n]ame or abbreviation of 
the FDA center with whom the IND or IDE is filed''; (2) ``IND or IDE 
number assigned by the FDA center''; and (3) for an IND, ``the IND 
serial number (as defined in 21 CFR 312.23(c), or any successor 
regulation), if any, assigned to the clinical trial.'' Section 
402(j)(2)(A)(ii)(IV)(cc) of the PHS Act expressly requires the ``Food 
and Drug Administration IND/IDE protocol number'' to be submitted to 
ClinicalTrials.gov at the time of registration in ClinicalTrials.gov, 
but it does not define this term. FDA does not issue an ``IND/IDE 
protocol number,'' as referred to in section 402(j)(2)(A)(ii)(IV)(cc) 
of the PHS Act; rather it issues an IND or IDE number. We therefore 
proposed to use the term ``Food and Drug Administration IND or IDE 
number'' to identify this data element on ClinicalTrials.gov. We also 
recognized that not all applicable clinical trials will be conducted 
under an IND or IDE (e.g., because they are exempt). Because Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation 
and Research (CBER), and Center for Devices and Radiological Health 
(CDRH) each issues IND or IDE numbers using a similar format, we 
expressed in the NPRM our belief that, for purposes of registration 
with ClinicalTrials.gov, a complete, unambiguous IND or IDE number must 
include the name of the FDA center that issued it. In addition, if 
several clinical trials are conducted under a single IND, each such 
clinical trial may have a different serial number assigned to it. We 
noted that any such serial number must also be specified to avoid 
confusion. However, the NPRM explained that if multiple serial numbers 
are assigned to a single IND (e.g., to reflect different clinical 
trials, protocols, or protocol amendments), the responsible party 
should submit only the first serial number that corresponds to the 
clinical trial being registered (79 FR 69626).
    Commenters addressed the Food and Drug Administration IND or IDE 
Number data element. One commenter suggested that the final rule remove 
the proposed requirement to provide the name or abbreviation of the FDA 
center

[[Page 65056]]

with which the IND or IDE is filed. Another commenter requested 
clarification on whether submitting an IRB registration number in place 
of an IDE number or the FDA center information would be sufficient for 
clinical trials of nonsignificant risk devices subject to FDA 
abbreviated IDE requirements. We proposed requiring the FDA center name 
as a sub-element of the Food and Drug Administration IND or IDE Number 
data element because CDER, CBER, and CDRH all issue IND or IDE numbers 
using a similar format. We also recognize that not all applicable 
clinical trials will be conducted under an IND or IDE (e.g., ``IND-
exempt'' trials) and therefore would permit a responsible party to 
indicate that a particular trial is not being conducted under an FDA 
IND or IDE (i.e., the responsible party would indicate ``no'' for this 
sub-element). We clarify that the FDA IND or IDE Number only refers to 
the number that is assigned by one of the FDA centers. Because FDA does 
not assign an IDE number for a clinical trial of a non-significant risk 
device subject to FDA-abbreviated IDE requirements nor does it issue an 
IDE for a clinical trial conducted outside of the United States, a 
responsible party for such trials should indicate ``no'' for the U.S. 
Food and Drug Administration IND or IDE Number data element. One 
commenter suggested that the final rule require information on whether 
a trial is being conducted under an IND or BLA for all trials conducted 
in the United States. As proposed under the NPRM, all responsible 
parties would be required to indicate whether an applicable clinical 
trial is being conducted under an IND or IDE, regardless of whether 
trial facility locations are within or outside the United States or 
both. We do not require the submission of information about BLAs for 
this data element because they are submitted to FDA only after trial 
completion, when a manufacturer is seeking to obtain a license for 
marketing a biological product, and so would not be available during 
trial registration. We note, however, that section 402(j)(5)(B) of the 
PHS Act requires submissions of BLAs to FDA to be accompanied by a 
certification (i.e., Form FDA 3674) that all applicable requirements of 
this part have been met and to include a list of appropriate NCT 
numbers for applicable clinical trials used to support the BLA. Another 
commenter suggested that the final rule require the inclusion of an IND 
number or IND-exempt status of a trial to accommodate the determination 
of which trials quality for coverage of routine care costs of clinical 
trials under the Affordable Care Act in 42 U.S.C. 300gg-8. As noted in 
the NPRM, we do not intend to make the Food and Drug Administration IND 
or IDE Number available in the posted record. However, we note that 
this information would be readily accessible in the PRS to a 
responsible party for its own records and could be used by the 
responsible party to support this need. After consideration of these 
comments, we retain the proposed definition in final rule, but we 
clarify that it means ``an indication of whether'' there is an IND or 
IDE for the clinical trial. We also change the name of the data element 
to ``U.S. Food and Drug Administration IND or IDE Number'' for clarity, 
sinces other countries also have governmental agencies named ``Food and 
Drug Administration'' (e.g., Korea).
    (D) Human Subjects Protection Review Board Status. Section Sec.  
11.10(b)(36) of the NPRM defined this data element as ``information to 
indicate whether a clinical trial has been approved by a human subjects 
protection review board or is exempt from human subjects protection 
review board approval. Human Subjects Protection Review Board Status 
must be listed as `approved' if at least one human subjects protection 
review board has approved the clinical trial.'' While submission of 
this information is not required by section 402(j) of the PHS Act, we 
proposed to add this requirement pursuant to the authority given by 
section 402(j)(2)(A)(iii) of the PHS Act to modify the requirements for 
clinical trial registration information if such modification ``improves 
and does not reduce such clinical trial information.'' We expressed in 
the NPRM our belief that submission of the Human Subjects Protection 
Review Board Status to ClinicalTrials.gov would improve, and not 
reduce, clinical trial information by indicating to users of the data 
bank whether a clinical trial registered on ClinicalTrials.gov is 
undergoing or has undergone review by a human subjects protection 
review board. Inclusion of this information would inform potential 
human subjects of whether the clinical trials they find on 
ClinicalTrials.gov have undergone at least one human subjects 
protection review board review, have received the necessary approvals 
for human subjects research from at least one human subjects protection 
review board, or were exempt from such review. We stated in the NPRM 
that the responsible party would be required to select from the 
following limited set of options intended to cover all possible 
statuses: ``Request not yet submitted'' (review board approval is 
required but has not yet been requested); ``Submitted, pending'' 
(review board approval has been requested but not yet granted); 
``Submitted, approved'' (review board approval has been requested and 
obtained); ``Exempt'' (an exemption in accord with applicable law and 
regulation has been granted); ``Submitted, denied'' (review board has 
denied the approval request); and ``Submission not required'' (review 
board approval is not required because the study is not subject to 
laws, regulations, or applicable institutional policies requiring human 
subjects review). No ``other'' option was proposed. We requested 
comments on whether this menu of options adequately captured all 
possible review statuses for clinical trials that would be subject to 
this regulation (79 FR 69627).
    The NPRM stated that the status would be listed as ``approved'' if 
at least one human subjects protection review board has approved the 
clinical trial. To clarify for users that the human subjects protection 
review board status pertains to only one human subjects protection 
review board, we would indicate that fact on ClinicalTrials.gov and 
instruct potential human subjects to communicate with the site-specific 
point-of-contact or the central contact for the clinical trial 
(included as part of the Facility Information data element that is 
submitted as part of clinical trial information under Sec.  
11.28(a)(2)(iii)(C)) in order to determine the status of human subjects 
protection review board review at other sites of interest. We indicated 
that we believe this approach will provide users with important 
information about human subjects review without burdening responsible 
parties with updating information on multiple sites (79 FR 69627). Some 
commenters proposed that the final rule require the submission of more 
detailed information for the Human Subjects Protection Review Board 
Status data element and display that information on the posted record, 
with one suggesting that public access to such information would be 
helpful for patients as well as for promoting the use of central IRBs 
for multicenter trials. As discussed, we believe that the proposed 
approach strikes the appropriate balance by providing users with the 
important information that at least one human subjects protection 
review board has reviewed and approved a trial without burdening 
responsible parties with the need to submit and update more detailed 
information for each board (up to one per facility). Therefore, we 
retain the proposed approach in the final rule.

[[Page 65057]]

We note that an applicable clinical trial could be registered prior to 
human subjects protection review board approval by indicating that the 
status is Request not yet submitted; Submitted, pending; or Exempt. If 
the status subsequently changes, the responsible party would be 
required, consistent with Sec.  11.64(a)(1), to update the Human 
Subjects Protection Review Board Status data element not later than 30 
calendar days after the change. If any IRB is still providing oversight 
for at least one site, the status of the trial would not be suspended 
even if such action is taken in relation to another site. We will 
continue to make available, as optional data elements, more detailed 
information about IRB approval, such as the name of the IRB, to support 
a responsible party's and/or an organization's tracking needs.
    (E) Record Verification Date. Section Sec.  11.10(b)(37) of the 
NPRM defined Record Verification Date as ``the date upon which the 
responsible party last verified the clinical trial information in the 
entire ClinicalTrials.gov record for the clinical trial, even if no 
additional or updated information was submitted at that time.'' This 
data element is required by section 402(j)(2)(A)(ii)(IV)(cc) of the PHS 
Act to be submitted as part of clinical trial information at the time 
of registration, but it does not define the term. In the NPRM, we 
expressed our belief that the record verification date is intended to 
be submitted as a separate data element that indicates to users of the 
data bank how recently the information for a particular clinical trial 
was verified and, hence, whether it may be out of date. We stated our 
intent to collect and post publicly the Record Verification Date data 
element on ClinicalTrials.gov (79 FR 69628).
    We proposed requiring responsible parties to include the Record 
Verification Date data element as part of the initial submission of 
clinical trial registration information to ClinicalTrials.gov and to 
update it any time the responsible party reviews the complete clinical 
trial record for accuracy, such as when making a periodic review of an 
entire clinical trial record. However, if the responsible party submits 
updates to one or more data elements without reviewing the accuracy of 
the rest of the record, the Record Verification Date data element would 
not be updated. We noted that the proposed approach would not require a 
responsible party to review records more frequently or regularly than 
would be needed in order to update submitted information as specified 
in Sec.  11.64 (should the responsible party use this method to help 
ensure that updates are submitted on time), but it would require that 
the Record Verification Date be updated if the complete record was 
reviewed for accuracy during such an update (79 FR 69628).
    One commenter requested that we delete the word ``entire'' from the 
definition so that the responsible party is not required to review all 
data in the record any time the responsible party reviews some of the 
information. We agree with the commenter's point that a responsible 
party is not required to review all data each time a record is 
accessed. We believe, however, that the proposed definition makes it 
clear that the record verification date needs to be updated only when 
the responsible party does review the entire record, not just part of 
the record. This data element allows users to determine when all of the 
data submitted in the record was last reviewed and verified by the 
responsible party. Therefore, we maintain the NPRM definition in the 
final rule, but we note that Sec.  11.64 of the final rule specifies 
that ``Record Verification Date must be updated any time the 
responsible party reviews the complete set of submitted clinical trial 
information for accuracy and not less than every 12 months, even if no 
other updated information is submitted at that time.''
    (F) Responsible Party Contact Information. In Sec.  11.10(b)(38) of 
the NPRM, we described Responsible Party Contact Information as 
``[a]dministrative information to identify and allow communication with 
the responsible party by telephone, email, and regular mail or delivery 
service. Responsible Party Contact Information includes the name, 
official title, organizational affiliation, physical address, mailing 
address, phone number, and email address of the individual who is the 
responsible party or of a designated employee of the organization that 
is the responsible party.'' Section 402(j)(1)(B) of the PHS Act 
requires the Secretary to develop a mechanism ``by which the 
responsible party for each applicable clinical trial shall submit the 
identity and contact information of such responsible party to the 
Secretary at the time of submission of clinical trial information. . . 
.'' Using the authority in section 402(j)(2)(A)(iii) of the PHS Act, we 
proposed to modify the requirements for clinical trial information 
submitted at the time of registration to require responsible parties to 
submit Responsible Party Contact Information. As noted in the NPRM, we 
believe that the addition of this information will improve and not 
reduce clinical trial information by providing a mechanism for the 
Agency to communicate with the responsible party about submitted 
information, which can improve its quality, accuracy, and completeness. 
We noted that we do not intend to post the physical address, mailing 
address, phone number or email address of the responsible party (79 FR 
69628). We received no comments on this data element and therefore 
maintain it in the final rule. In general, we intend to post the name 
of the responsible party if the responsible party is an individual 
(e.g., a sponsor-investigator who holds the IND or IDE for a clinical 
trial or a designated principal investigator). We would post the name 
of the responsible party, along with the Responsible Party, by Official 
Title data element as specified in Sec.  11.28(a)(2)(iii)(B) of the 
final rule, which section 402(j)(2)(A)(ii)(III)(bb) of the PHS Act 
requires to be made publicly available. We believe that the posting of 
the individual's name is necessary to avoid ambiguity; for example, if 
the responsible party is a university professor, there may be a number 
of individuals with the same title and affiliation (professor of 
medicine at ABC University). Posting the name of the individual when an 
individual is the responsible party would also be consistent with 
posting the name of the entity when an entity is the responsible party 
of an applicable clinical trial. The Responsible Party Contact 
Information data element would be required to be updated as specified 
in Sec.  11.64.
    Data elements that were suggested in public comments but not 
incorporated into the final rule are discussed below.
    Bioequivalence and Bioavailability. One commenter requested the 
addition of data elements to identify bioequivalence and 
bioavailability studies and to indicate specific biomarkers relevant to 
the population studied. We note that ClinicalTrials.gov currently 
offers an optional registration data element, Study Classification, 
that includes both ``Bio-equivalence'' and ``Bio-availability'' as 
options. Biomarkers that are the focus of a study may be listed in the 
Primary Disease or Condition Being Studied in the Trial, or the Focus 
of the Study data element specified in proposed Sec.  11.48(a)(1)(ix) 
and defined in proposed Sec.  11.10(b)(9). We also note that biomarkers 
may be described in the context of outcome measures that are evaluated 
in the clinical trial. Otherwise, responsible parties could provide 
such information voluntarily as part of an optional data element (e.g., 
Detailed Description). Because responsible parties can submit

[[Page 65058]]

this information using optional data elements, and consistent with our 
goal to minimize the number of required data elements, we do not 
require the submission of this information in the final rule. We 
understand the growing interest in and research on biomarkers and will 
continue to evaluate this topic and ways to further optimize the 
collection, retrieval, and display of such information.
    Individual Participant Data (IPD) Availability. One commenter 
requested that the final rule include an optional data element for 
indicating whether IPD or CSRs are being made available to others and, 
if so, the location of the data and contact information. In December 
2015, ClinicalTrials.gov added the following optional data elements 
that allow responsible parties to provide information about their plans 
for sharing IPD and to describe where data sets and/or study documents 
are available: Plan to Share Data? and Available Study Data/Documents. 
Because responsible parties can choose to submit this information using 
the optional data elements, and consistent with our goal to minimize 
the number of required data elements, we do not include these data 
elements in the final rule.
    Other Trial Characteristics. Several commenters suggested that 
whether a registered trial is ``for profit'' should be clearly labeled 
on the posted record on ClinicalTrials.gov. We are not aware of any 
standard approaches for defining a trial's profit status (e.g., ``for 
profit'' or ``non-profit'') and the commenters did not suggest any 
operational definitions. In addition, there are many features of a 
trial's sponsor that may be of interest to potential participants, as 
well as those interested in the study's results; ClinicalTrials.gov can 
help identify the trial and its sponsor but cannot provide all 
potentially relevant information. One other commenter recommended 
adding a data element that could be used for searching for trials of 
genetic therapies. We note that the Intervention Type data element 
defined in Sec.  11.10(b)(13) includes a ``genetic'' (including gene 
transfer, stem cell and recombinant DNA) option that a responsible 
party could choose to identify a genetic therapy intervention. For 
these reasons, we are not adding additional data elements to include 
other trial characteristics, but we will consider providing an Advanced 
Search feature in the future that would allow users to search 
ClinicalTrials.gov for registered studies by Intervention Type.
    Schedule of Events. One commenter suggested that the Agency 
consider adding a ``schedule of events'' data element that would 
provide information for participants about the medical care that will 
be covered in a study. While we understand that this information could 
be important for a potential participant, we believe it is more 
appropriate for this information be provided by the study contact at 
the time that potential participants and/or their health care providers 
are seeking further information about the study. Accordingly, we are 
not including this data element in the final rule.
Sec.  11.28(b)--Pediatric Postmarket Surveillance of a Device Product 
That Is Not a Clinical Trial
Overview of Proposal
    (b) Data elements required to register a pediatric postmarket 
surveillance of a device product that is not a clinical trial. Proposed 
Sec.  11.28(b) specified the clinical trial information that must be 
submitted to ClinicalTrials.gov to register a pediatric postmarket 
surveillance of a device that is not a clinical trial, as defined in 
this part, but is required to be registered under proposed Sec.  11.22. 
Section 801(c) of FDAAA recognizes that not all of the clinical trial 
information specified in section 402(j) of the PHS Act or proposed in 
this rule will apply to all pediatric postmarket surveillances of a 
device and directs the Secretary to issue guidance explaining how the 
registration and results information submission provisions of section 
402(j) of the PHS Act apply to a pediatric postmarket surveillance of a 
device that is not a clinical trial. As stated in the NPRM, the Agency 
intended for the discussion of the proposed sections related to 
pediatric postmarket surveillances of a device to provide draft 
guidance. In 21 CFR 822.3, ``postmarket surveillance'' is defined as 
the ``active, systematic, scientifically valid collection, analysis, 
and interpretation of data or other information about a marketed 
device.'' The Agency interpreted a pediatric postmarket surveillance of 
a device as a postmarket surveillance of a device used in a pediatric 
population (i.e., patients who are 21 years of age or younger at the 
time of diagnosis or treatment) (see 21 U.S.C. 360j(m)(6)(c)). The 
clinical trial information specified in proposed Sec.  11.28(a) and 
defined in proposed Sec.  11.10(b) would apply to any pediatric 
postmarket surveillance of a device that is a clinical trial (i.e., 
Study Type would be ``interventional''). However, because not all 
pediatric postmarket surveillances under section 522 of the FD&C Act 
are clinical trials, as defined in this part, many of the data elements 
listed in proposed Sec.  11.28(a) or the definitions proposed in Sec.  
11.10(b) may not apply. Therefore, proposed Sec.  11.28(b) specified a 
more limited set of data elements required to register a pediatric 
postmarket surveillance of a device that is not a clinical trial; 
moreover, it also modified the definitions of certain data elements 
that were defined in proposed Sec.  11.10(b) (79 FR 69629).
    In general, the proposed definitions of these data elements were 
consistent with the definitions of the named data elements in proposed 
Sec.  11.10(b); however, we had modified them, where appropriate, to 
better match the characteristics of pediatric postmarket surveillances 
of a device that are not clinical trials. For example, Study Start 
Date, which was defined in proposed Sec.  11.10(b)(16) for a clinical 
trial as ``the estimated date on which a clinical trial will be open to 
enrollment of human subjects, or the actual date on which the first 
human subject was enrolled,'' was defined in proposed Sec.  
11.28(b)(1)(xi) as the ``date on which FDA approves the postmarket 
surveillance plan, as specified in 21 CFR 822.19(a) (or any successor 
regulation).'' Similarly, the definition of Completion Date in section 
402(j)(1)(A) of the PHS Act and proposed Sec.  11.10(b)(17) generally 
would not apply to a pediatric postmarket surveillance of a device that 
is not a clinical trial; therefore, in proposed Sec.  11.28(b)(1)(xii) 
we proposed to require submission of the Completion Date data element, 
which was defined as ``[t]he estimated date on which the final report 
summarizing the results of the pediatric postmarket surveillance of a 
device is expected to be submitted to FDA. Once the final report has 
been submitted, the actual date on which the final report is submitted 
to FDA.'' The Agency considered the proposed list of required data 
elements for a pediatric postmarket surveillance of a device that is 
not a clinical trial to be the most inclusive set of data elements that 
could be expected to apply to all pediatric postmarket surveillances of 
a device that are not clinical trials, regardless of the design of the 
surveillance. The proposed required information would allow users to 
access records of pediatric postmarket surveillances of a device that 
are not clinical trials by conducting searches using a number of 
relevant criteria, retrieve basic descriptive information about the 
surveillances, and find a point-of-contact for additional information. 
We did not propose the submission of those data elements listed under 
section 402(j)(2)(A)(ii) of the PHS Act that are not expected to apply 
to all

[[Page 65059]]

pediatric postmarket surveillances of a device that are not clinical 
trials. For example, Study Phase is relevant only to clinical trials 
involving drugs. The specific elements of Study Design (e.g., 
Interventional Study Model, Allocation, Masking, Single Arm 
Controlled?) would not apply to most studies that are not 
interventional clinical studies (i.e., clinical trials). Eligibility 
Criteria, Age, and Gender may not be defined specifically for the study 
population in a pediatric postmarket surveillance of a device that is 
not a clinical trial. Enrollment would not be relevant to a pediatric 
postmarket surveillance of a device that takes the form of a literature 
review. We noted that we expect that some information about the study 
design and relevant study population would be included in the brief 
summary of the pediatric postmarket surveillance of a device. We 
invited comments on alternative approaches for specifying the 
registration requirements for a pediatric postmarket surveillance of a 
device that is not a clinical trial (79 FR 69629).
Comments and Response
    One commenter suggested that the registration data elements 
required to be submitted for a pediatric postmarket surveillance of a 
device that is not a clinical trial in proposed Sec.  11.28(b) be 
replaced in the final rule with the same set of data elements required 
for clinical trials as specified in proposed Sec.  11.28(a). The Agency 
disagrees with this suggestion. As described in the preamble, not all 
pediatric postmarket surveillances of a device product under section 
522 of the FD&C Act are clinical trials. For such pediatric postmarket 
surveillances of a device product, many of the data elements for 
clinical trials listed in proposed Sec.  11.28(a) and defined in 
proposed Sec.  11.10(b) would not apply. Therefore, we specified in 
proposed Sec.  11.28(b), and retain in the final rule, a limited set of 
registration data elements that would more likely apply across all 
pediatric postmarket surveillances of a device product, and we modified 
the definitions in proposed Sec.  11.10(b) accordingly.
Final Rule
    Taking into consideration the commenter's suggestions and the 
statutory requirements for what constitutes clinical trial registration 
information, Sec.  11.28(b) of the final rule retains the data elements 
proposed in the NPRM but modifies some of the names and definitions to 
improve clarity and for consistency with the data elements named in 
Sec.  11.28(a) and defined in Sec.  11.10(b) of the final rule. Section 
11.28(b) of the final rule identifies the structured information, or 
data elements, that constitute clinical trial information that a 
responsible party must submit in order to register a clinical trial. 
While the full set of data elements from the NPRM is maintained in the 
final rule, we have modified some of the names and definitions. For 
example, we have clarified that ``device'' means ``device product'' and 
the proposed name of Whether the Study is a Pediatric Postmarket 
Surveillance of a Device data element in Sec.  11.28(b)(1)(v) of the 
NPRM has been renamed ``Pediatric Postmarket Surveillance of a Device 
Product'' throughout the final rule (i.e., in Sec. Sec.  11.10(b)(8), 
11.28(a), 11.28(b), 11.60(b)(2)(i)(B)) for clarity and convenience, but 
the proposed definition is maintained in the final rule. Conversely, 
while the name of the Unique Protocol Identification Number data 
element has been retained, the definition has been modified from ``the 
unique identification number'' to ``the unique identifier'' for 
accuracy (i.e., is not limited to numbers).
    As set forth in Sec.  11.28(b) of the final rule, to register a 
pediatric postmarket surveillance of a device product that is not a 
clinical trial, the responsible party must provide the following data 
elements: (1) Brief Title; (2) Official Title; (3) Brief Summary; (4) 
Study Type; (5) Pediatric Postmarket Surveillance of a Device Product; 
(6) Primary Disease or Condition Being Studied, or the Focus of the 
Study; (7) Intervention Name(s); (8) Other Intervention Name(s); (9) 
Intervention Description; (10) Intervention Type; (11) Study Start 
Date; (12) Primary Completion Date; (13) Name of the Sponsor; (14) 
Responsible Party, by Official Title; (15) Contact Information; (16) 
Unique Protocol Identification Number, if any; (17) Secondary ID; (18) 
Human Subjects Protection Review Board Status; (19) Record Verification 
Date; and (20) Responsible Party Contact Information. Consistent with 
the elaboration of these data elements in Section IV.B.4 of the 
preamble, for a pediatric postmarket surveillance of a device product 
that is not a clinical trial the Study Type must be designated as 
``observational'' and Pediatric Postmarket Surveillance of a Device 
Product must indicate ``yes.''
    In addition, for a pediatric postmarket surveillance of a device 
product that is not a clinical trial, we recommend that the responsible 
party submit any other registration information data elements that are 
consistent with the surveillance design and are capable of being 
accepted by ClinicalTrials.gov. For example, for a pediatric postmarket 
surveillance of a device product that takes the form of a prospective 
observational study, information such as the location(s) of the 
surveillance, its eligibility criteria, the recruitment status, and its 
outcome measures would also be relevant and should be submitted. We 
believe the public would be best served if additional descriptive 
information about these pediatric postmarket surveillances of a device 
product were included in the data bank, but, given the lack of 
experience to date, we cannot at this time specify what additional 
information would be relevant to a particular type of pediatric 
postmarket surveillance of a device product that is not a clinical 
trial.
Sec.  11.28(c)--Expanded Access Records
Overview of Proposal
    (c) Data elements required to create expanded access records. 
Proposed Sec.  11.28(c) described the clinical trial information that 
must be submitted to ClinicalTrials.gov to create an expanded access 
record when a responsible party registers an applicable drug clinical 
trial that studies an unapproved drug or unlicensed biological product 
that is available via an expanded access program under section 561 of 
the FD&C Act to those who do not qualify for enrollment in the clinical 
trial. However, because expanded access programs do not share all of 
the characteristics of clinical trials, as defined in this part, many 
of the data elements listed in proposed Sec.  11.28(a) or their 
definitions in proposed Sec.  11.10(b) do not apply. Therefore, 
proposed Sec.  11.28(c) specified a limited set of data elements 
required to create an expanded access record; moreover, it also 
modified the definitions of certain data elements in proposed Sec.  
11.10(b). Overall, in the NPRM we considered the proposed set of data 
elements required to create an expanded access record to be the most 
inclusive that would be relevant to all expanded access programs (other 
than individual-patient access), regardless of design, and helpful to 
users of ClinicalTrials.gov who wish to determine whether they may be 
eligible to receive an investigational drug through an expanded access 
program and to obtain additional information about such access. The 
descriptions of the data elements in the NPRM generally paralleled the 
definitions of the data elements in proposed Sec.  11.10(b) that are 
required to be submitted when registering a clinical trial under 
proposed Sec.  11.28(a), but were modified in proposed Sec.  11.28(c) 
to refer to expanded access programs rather than

[[Page 65060]]

clinical trials and to be limited to expanded access programs for drugs 
and biologics. One data element that was not defined in proposed Sec.  
11.10(b) but is required to be submitted for expanded access records 
only is the Expanded Access Status data element. We invited comments on 
whether the proposed list of options for this data element was 
sufficient to describe the status of an expanded access program (79 FR 
69630).
    We proposed requiring the submission of information to create an 
expanded access record using the statutory authority in section 
402(j)(2)(A)(iii) of the PHS Act, which allows the Secretary by 
regulation to modify the requirements for clinical trial registration 
information if the Secretary provides a rationale why such a 
modification ``improves and does not reduce such clinical trial 
information.'' Information about the availability of expanded access is 
a data element that a responsible party is required to submit under 
section 402(j)(2)(A)(ii)(II) of the PHS Act and thus meets the 
definition of ``clinical trial information'' as that term is used in 
section 402(j)(1)(A)(iv) of the PHS Act. We noted in the NPRM that we 
think these additional data elements describing expanded access would 
improve and not reduce clinical trial information by providing users 
with more complete and consistent information about expanded access 
programs for drugs studied in applicable clinical trials than would be 
available pursuant to section 402(j)(A)(ii)(II)(gg) of the PHS Act 
alone. We further concluded that the clinical trial information 
required under proposed Sec.  11.28(c), to be submitted by creating a 
separate expanded access record in ClinicalTrials.gov, under section 
402(j)(2)(B)(iv) of the PHS Act would help ensure that the public can 
more easily use the data bank to determine whether there is expanded 
access to a drug and to compare different expanded access programs. In 
addition, this approach was consistent with the practice followed prior 
to the enactment of FDAAA, when those registering trials in compliance 
with FDAMA submitted expanded access information in the form of 
expanded access records on ClinicalTrials.gov. We proposed that in the 
rare instance in which an expanded access program for a drug met all of 
the elements of an applicable drug clinical trial, the expanded access 
program would have to be registered as an applicable drug clinical 
trial (79 FR 69630). In developing the NPRM, we considered alternative 
approaches, such as requiring the responsible party to submit the name, 
phone number, and email address of a point-of-contact or Web site for 
information about the expanded access program for each clinical trial 
of a drug that has such a program. However, we concluded that this 
approach would not ensure that complete information is available and, 
by including such information as part of clinical trial registration 
information, we can better ensure that the information is kept up-to-
date as required in proposed Sec.  11.64. Another alternative we 
considered was to require responsible parties to enter the additional 
data elements describing expanded access with every applicable clinical 
trial of a drug or biological product for which expanded access is 
available. Under our proposal, however, in situations in which multiple 
applicable clinical trials study the same drug that is available via 
the expanded access program, the expanded access record would be 
submitted only once. Thereafter, any responsible party could link the 
expanded access record to the clinical trial record(s) using the NCT 
number assigned to the expanded access record, thereby reducing the 
burden a responsible party faces when providing information about 
expanded access for multiple records (79 FR 69631).
    As explained in Section IV.B.4 of the NPRM, in the discussion of 
the Availability of Expanded Access data element, the expanded access 
record generated on ClinicalTrials.gov pursuant to the submission of 
the data elements at proposed Sec.  11.28(c) would be assigned its own 
NCT number and would be searchable and retrievable independent of the 
record(s) for the clinical trial(s) that study(ies) the drug or 
biological product for which expanded access is offered. To allow 
ClinicalTrials.gov to establish a link between the expanded access 
record and the clinical trial record(s), the responsible party(ies) for 
any applicable clinical trials of the drug available via expanded 
access would be required to include the NCT number that is assigned to 
the expanded access record as part of the registration information 
submitted for that clinical trial. In this way, the expanded access 
record could be linked in this fashion to multiple applicable clinical 
trials that study the drug or biological product that is available via 
the expanded access program. We sought comments on this proposed 
approach.
    We also proposed that expanded access information for a medical 
device that was studied in an applicable device clinical trial could be 
submitted voluntarily under section 402(j)(4)(A) of the PHS Act to 
create an expanded access record for the device. (79 FR 69630) We 
further proposed that if a responsible party chose to submit this 
information, the responsible party would be required to submit all of 
the data elements that are required for expanded access to a drug in 
Sec.  11.28(c), and that such expanded access records for 
investigational devices would be required to be updated in accordance 
with Sec.  11.64(b)(1)(v).
Comments and Response
    We received comments addressing the proposed content of an expanded 
access record. A commenter suggested that NIH and FDA should streamline 
and standardize expanded access information for patients and that NIH 
should collect and post the results obtained through expanded access 
programs on ClinicalTrials.gov. A commenter proposed linking expanded 
access records to the FDA application forms for expanded access 
programs. Section 11.28(c) of the NPRM represented our efforts to 
develop a streamlined and standardized approach to presenting 
information on ClinicalTrials.gov about expanded access programs. The 
proposed set of data elements represents, for the most part, a subset 
of the registration data elements required for an applicable clinical 
trial of a drug under proposed Sec.  11.28(a). These proposed data 
elements were selected to represent key information that would 
generally apply across all expanded access programs. We stated in the 
NPRM that these data elements would allow ClinicalTrials.gov to display 
a structured summary about each expanded access program in a consistent 
format that would allow users to review important information quickly 
and easily (e.g., eligibility criteria, disease or condition, 
intervention name and description). Regarding the suggestion to require 
the submission of results from expanded access use, as discussed in 
Section IV.A.5, we have concluded that use of an investigational drug 
product (including a biological product) under expanded access will not 
be considered an applicable clinical trial. Therefore, no expanded 
access use of an investigational drug product (including a biological 
product) will be subject to the results information submission 
requirements of this rule. We will consider providing links to 
additional resources about expanded access such as FDA application 
forms on the ClinicalTrials.gov public Web site, as suggested.

[[Page 65061]]

Final Rule
    Taking into consideration the commenters' suggestions and the 
statutory requirements for what constitutes clinical trial registration 
information, Sec.  11.28(c) of the final rule modifies the set of data 
elements from the NPRM that a responsible party must submit in order to 
create an expanded access record as required in Sec.  
11.28(a)(2)(ii)(H) of the final rule. Some of the data elements in 
Sec.  11.28(c) that have been modified from what was proposed address 
the modification described in section IV.B.4 of this preamble in the 
discussion of the Availability of Expanded Access data element, which 
requires submission of an expanded access record for all expanded 
access types, including when expanded access is available for 
individual patients, including emergency use. Other modifications 
include some of the names and definitions of the proposed data elements 
to improve clarity and consistency with the data elements named in 
Sec.  11.28(a) and defined in Sec.  11.10(b) of the final rule, 
including the clarification that ``drug'' means ``drug product'' and 
that ``device'' means ``device product''. In addition, we provide 
further elaboration on the purpose of some data elements and how a 
responsible party can meet the data element requirements. Section 
11.28(c) of the final rule also clarifies that expanded access records 
are only required to be created and updated by a responsible party who 
is both the manufacturer of the investigational drug product (including 
biological product) that is available through expanded access and the 
sponsor of an applicable clinical trial of that investigational drug 
product (including biological product), as specified in Sec. Sec.  
11.10(b)(28) and 11.28(a)(2)(ii)(H) of the final rule. Finally, we 
exclude from the final rule the proposed provision regarding the 
voluntary submission of expanded access information for a medical 
device under section 402(j)(4)(A) of the PHS Act, and we provide a 
further explanation below.
    The Expanded Access Type data element, which was not proposed in 
the NPRM, is defined in Sec.  11.28(c)(1)(x) of the final rule as 
``[t]he type(s) of expanded access for which the investigational drug 
product (including a biological product) is available as specified in 
Sec.  11.10(b)(28).'' For this data element, responsible parties would 
be required to select one or more options from the following limited 
set: ``individual patient'' (i.e., expanded access for individual 
patients, including for emergency use, as specified in 21 CFR 312.310), 
``intermediate'' (i.e., expanded access for intermediate-size patient 
populations, as specified in 21 CFR 312.315), or ``treatment use'' 
(i.e., expanded access for widespread treatment use under a treatment 
IND or treatment protocol, as specified in 21 CFR 312.320). As 
described in section IV.B.4 of this preamble, in the discussion of the 
Availability of Expanded Access data element, the final rule expands 
the proposed requirement to provide expanded access records for all 
types of expanded access available for an unapproved drug product 
(including a biological product). In light of this expansion, the 
Expanded Access Type data element is required to indicate the 
particular type(s) of expanded access under which an investigational 
drug product (including a biological product) is available. 
Additionally, the submission of certain expanded access record data 
elements specified in Sec.  11.28(c)(2) are not required if the 
Expanded Access Type indicates that expanded access is available only 
for individual patients, including for emergency use. Thus, the 
Expanded Access Type data element facilitates identifying which 
information must be provided, specific to the type of availability of 
expanded access. For these reasons, this new registration data element 
is authorized by section 402(j)(2)(A)(ii) of the PHS Act because 
requiring it improves and does not reduce the clinical trial 
information.
    While the other required data elements from the NPRM are maintained 
in the final rule, we have modified some of the names and definitions 
to be consistent with other modifications throughout this final rule. 
For example, the proposed Gender data element in Sec.  11.28(c)(2)(ii) 
of the NPRM is renamed ``Sex/Gender'' here and throughout the final 
rule to be consistent with the same modification described in section 
IV.B.4 of this preamble and Sec.  11.28(a)(2)(ii) of the final rule. 
Conversely, while the name of the Unique Protocol Identification Number 
data element is maintained, the definition has been modified from ``the 
unique identification number'' to ``the unique identifier'' for 
accuracy (i.e., is not limited to numbers) and the explanation modified 
to explain it can also be an identifier of the expanded access record. 
Specifically, if the sponsor did not assign a unique identifier to the 
availability of its investigational drug product (including a 
biological product) for expanded access use, an identifier for the 
expanded access record must be provided. This identifier is composed of 
numbers and/or letters and is needed to uniquely identify an expanded 
access record in the PRS prior to submission and assignment of an NCT 
number. The Agency will provide additional instructions at https://prsinfo.clinicaltrials.gov (or successor site) to assist sponsors in 
creating a unique identifier for the expanded access record if the 
sponsor did not assign an identifier to the expanded access. Similarly, 
instructions will also be available at https://prsinfo.clinicaltrials.gov (or successor site) for sponsors needing to 
create a Brief Title as specified in Sec.  11.28(c)(1)(i), which is 
used for identification of the expanded access record in the PRS and on 
the publicly posted study record.
    As set forth in Sec.  11.28(c) of the final rule, if expanded 
access is available for an intermediate-size patient population as 
specified in 21 CFR 312.315) or through a treatment IND or treatment 
protocol (as specified in 21 CFR 312.320), a responsible party who is 
both the manufacturer of an investigational drug product (including a 
biological product) that is available through expanded access and the 
sponsor of an applicable clinical trial of that investigational product 
must provide the following data elements to create an expanded access 
record: (1) Brief Title; (2) Official Title; (3) Brief Summary; (4) 
Study Type (which is ``expanded access'' for this type of record); (5) 
Primary Disease or Condition; (6) Intervention Name(s); (7) Other 
Intervention Name(s); (8) Intervention Description; (9) Intervention 
Type (which is typically ``drug''), (10) Expanded Access Type; (11) 
Eligibility Criteria; (12) Sex/Gender; (13) Age Limits; (14) Expanded 
Access Status; (15) Name of the Sponsor; (16) Responsible Party, by 
Official Title; (17) Contact Information; (18) Unique Protocol 
Identification Number; (19) Secondary ID; (20) U.S. Food and Drug 
Administration IND Number; (21) Record Verification Date; and (22) 
Responsible Party Contact Information.
    If expanded access is only available for individual patients, 
including for emergency use as specified in 21 CFR 312.310, then only 
the following data elements are required: (1) Brief Title; (2) Brief 
Summary; (3) Study Type; (4) Intervention Name; (5) Intervention Type; 
(6) Expanded Access Type; (7) Expanded Access Status; (8) Name of 
Sponsor; (9) Responsible Party, by Official Title; (10) Contact 
Information; (11) Unique Protocol Identification Number; (12) U.S. Food 
and Drug Administration IND number, if

[[Page 65062]]

applicable; (13) Record Verification Date; and (14) Responsible Party 
Contact Information. This more limited set of expanded access 
information is sufficiently detailed to address the availability of an 
investigational drug product (including biological product) under 
individual patient expanded access.
    If information necessary to complete certain data elements required 
for submitting an expanded access record under Sec.  11.28(c)(1)-(4) 
are unknown to the responsible party because the expanded access 
availability is managed by a different entity, the responsible party 
will need to consult with NIH concerning those data elements before 
submitting the expanded access record, Instructions for contacting NIH 
will be available at https://prsinfo.clinicaltrials.gov (or successor 
site). We also note that the definition of Official Title specified in 
Sec.  11.28(c)(1)(ii) has been clarified to indicate it only needs to 
be provided if one exists (i.e., if there is an official title then it 
must be provided; if there is not an official title, the data element 
does not need to be provided). Similarly, the U.S. Food and Drug 
Administration IND Number data element has been modified to allow a 
responsible party to specify whether the expanded access is being 
conducted under an IND, but to allow for certain elements related to 
the IND to be provided ``if applicable''.
    Expanded Access Status is another data element that is required to 
be submitted only for expanded access records and is not defined in 
Sec.  11.10(b). It is defined in Sec.  11.28(c)(2)(iv) of the final 
rule to mean ``[t]he status of availability of the investigational drug 
product (including a biological product) through expanded access.'' 
When submitting this data element, responsible parties are required to 
select from the following limited set of options for describing the 
current status of availability of the investigational drug product 
through the expanded access program: ``Available'' (expanded access is 
currently available), ``No longer available'' (expanded access was 
available previously but is not currently available and is not expected 
to be available in the future), ``Temporarily not available'' (expanded 
access was previously available, is not currently available, but is 
expected to be available in the future), and ``Approved for marketing'' 
(expanded access was available previously but is not currently 
available because the drug or device has been approved, licensed, or 
cleared by FDA).
    We have further considered the proposal regarding the voluntary 
submission of expanded access information under section 402(j)(4)(A) of 
the PHS Act for unapproved or uncleared device products that are 
studied in an applicable device clinical trial and have decided not to 
include this provision in the final rule under Sec.  11.60. The 
Availability of Expanded Access data element defined in Sec.  
11.10(b)(28) and specified in Sec.  11.28(a)(2)(ii)(H) of the final 
rule is a data element that is specific to the availability of expanded 
access for an applicable drug clinical trial of an investigational drug 
product (including a biological product). Similarly, the obligations in 
Sec.  11.28(c) to create an expanded access record are, consistent with 
section 402(j)(2)(A)(ii)(II)(gg) of the PHS Act, are specific to the 
provision of information when expanded access to an investigational 
drug product (including a biological product) is available under 
section 561 of the FD&C Act and 21 CFR 312.310 (for individual 
patients, including for emergency use), 21 CFR 312.315 (for an 
intermediate-size patient population), or 21 CFR 312.320 (under a 
treatment IND or treatment protocol). Therefore, for the purposes of 
the voluntary submission of expanded access information under section 
402(j)(4)(A) of the PHS Act and Sec.  11.60 for unapproved or uncleared 
device products that are studied in an applicable device clinical 
trial, ``complete clinical trial information'' does not include 
information about the availability of expanded access for the 
investigational device product.
    We note that a responsible party for an applicable device clinical 
trial could choose to create an expanded access record for the 
investigational device product being studied in that trial if the 
investigational product is being made available under section 561 of 
the FD&C Act and 21 CFR 812.36. We intend to provide additional 
information at https://prsinfo.clinicaltrials.gov (or successor site) 
to clarify which data elements would apply in such a situation.
5. 11.35--By when will the NIH Director post clinical trial 
registration information submitted under Sec.  11.28?
Overview of Proposal
    According to section 402(j)(2)(D)(i) of the PHS Act, for applicable 
clinical trials, NIH is to post registration information not later than 
30 days after the information is submitted. In the NPRM, we proposed in 
Sec.  11.35(a) that NIH will post publicly the clinical trial 
registration information, except for certain administrative data, ``not 
later than 30 calendar days after the responsible party has submitted 
such information in accordance with Sec.  11.24 of this part'' (79 FR 
69631).
    For an applicable device clinical trial of a device that was 
previously cleared or approved by FDA, section 402(j)(2)(D)(ii)(II) of 
the PHS Act requires registration information to be posted ``not later 
than 30 days after'' results information is required to be posted. The 
Agency interpreted section 402(j)(2)(D)(ii)(II) of the PHS Act as 
providing a deadline by which such registration information must be 
posted. The Agency considered the requirement to post registration 
information ``not later than 30 days after [results information] is 
required to be posted'' to be the last possible date on which it may 
post registration information and that it is permissible to post 
registration information prior to the deadline. The NPRM at Sec.  
11.35(b)(1) proposed that for an applicable device clinical trial of a 
device that was previously approved or cleared, NIH will publicly post 
the clinical trial registration information, except for certain 
administrative data, not later than 30 calendar days after clinical 
trial results information is required to be posted in accordance with 
proposed Sec.  11.52 (79 FR 69631).
    Section 402(j)(2)(D)(ii)(I) of the PHS Act stipulates that for an 
applicable device clinical trial of a device that has not previously 
been cleared or approved, registration information must be posted 
publicly not earlier than the date of clearance or approval of the 
device and not later than 30 days after such date. Proposed Sec.  
11.35(b)(2) reflected this statutory provision by stating that for an 
applicable device clinical trial of a device that has not been 
previously approved or cleared, ``NIH will post publicly at 
ClinicalTrials.gov the clinical trial registration information, except 
for certain administrative data, not earlier than the date of FDA 
approval or clearance of the device, and not later than 30 calendar 
days after the date of such approval or clearance.'' In the NPRM, we 
acknowledged that while postponing the posting of clinical trial 
registration information for applicable device clinical trials for a 
device that previously has not been approved or cleared may protect the 
commercial interests of device manufacturers, there are a number of 
situations in which those who conduct such clinical trials may prefer 
to make such information publicly available in the data bank prior to 
the time frames specified by section 402(j) of the PHS Act. Therefore, 
we invited comments from the public on how, given the statutory 
language of Section 402(j)(2)(D)(ii)(I) of the PHS Act,

[[Page 65063]]

the Agency may address the concerns of sponsors and responsible parties 
who wish to have clinical trial registration information for applicable 
device clinical trials of devices that previously have not been 
approved or cleared made publicly accessible in ClinicalTrials.gov when 
the responsible party so chooses (79 FR 69576).
    In order to help NIH meet the posting deadline and identify the set 
of applicable device clinical trials for which registration information 
must be posted after approval or clearance of a device, the NPRM 
included a requirement in proposed Sec.  11.64(b)(2) for the 
responsible party to update the U.S. FDA Approval, Licensure, or 
Clearance Status data element not later than 15 calendar days after a 
change in status has occurred. The responsible party would be required 
to update that data element for all applicable device clinical trials 
that study a device that was approved or cleared (79 FR 69631).
Comments and Response
    We received comments on the specific question of when NIH should 
post clinical trial registration information. Some commenters supported 
and some opposed the proposed approach to determining which devices 
would be able to take advantage of the delayed posting available to 
devices that have not been previously approved or cleared. This topic 
is addressed in more detail in Section IV.B.4 of this preamble.
    Some commenters indicated they did not support the delayed posting 
of registration information for devices that have not been previously 
cleared or approved. Delayed posting is outlined in Section 
402(j)(2)(D)(ii)(I) of the PHS Act, which says that the Agency may not 
post publicly clinical trial registration information before the date 
of clearance or approval for an applicable device clinical trial of a 
device that was not previously cleared or approved. Section 11.35(b)(2) 
of the NPRM, and the final rule at Sec.  11.35(b)(2)(i), reflect this 
limit. Other commenters argued that the delayed posting of clinical 
trial registration information provision in the statute should not be 
understood as a bar to consensual disclosure of such information if a 
device sponsor wishes to waive the right to delayed posting. The 
commenters noted that under circumstances where a party wishes to waive 
a statutory right, and that waiver would not frustrate the public 
purpose of that statute, courts have acknowledged that statutory rights 
intended to protect individual rights may be waived by the persons for 
whom the statute provides protection.
    We agree with views expressed by commenters that because the 
delayed posting of registration information benefits the responsible 
party, the responsible party should be able to choose to authorize the 
Agency to make registration information available earlier. There may be 
any number of reasons a responsible party would wish to opt out of the 
delayed posting of registration information, such as to enhance patient 
enrollment or to meet the requirements for consideration by a journal 
abiding by ICMJE policy [Ref. 2]. Although Section 402(j)(2)(D)(ii)(I) 
of the PHS Act provides that the Director of NIH ``shall'' ensure that 
clinical trial information for an applicable device clinical trial of 
an unapproved or uncleared device is not posted on ClinicalTrials.gov 
earlier than the date of clearance or approval of the device, section 
402(j)(2)(A)(iii) of the PHS Act gives the Secretary authority to 
modify by regulation the requirements for clinical trial information 
under paragraph (2), which includes the delayed posting provision in 
402(j)(2)(D)(ii), so long as a rationale is provided for why the 
modification improves and does not reduce such clinical trial 
information. The Agency believes that allowing the responsible party to 
authorize that clinical trial registration information that would 
otherwise fall under the delayed posting provision be publicly posted 
prior to approval or clearance of the product would improve and not 
reduce such clinical trial information by making it accessible to the 
public earlier. This approach would strike the proper balance between 
affording the statutory protections of delayed disclosure to those 
responsible parties that would like to take advantage of it while 
promoting transparency of clinical trial registration information by 
allowing responsible parties to authorize earlier posting.
    Pursuant to section 402(j)(2)(A)(iii) of the PHS Act, we are adding 
a new provision at Sec.  11.35(b)(2)(ii) to incorporate this option for 
a responsible party to authorize early posting as well as a specific 
data element in Sec.  11.28(a)(2)(i)(Q) that will be the mechanism 
through which a responsible party can indicate to the Director that it 
is authorizing the Director to publicly post its clinical trial 
registration information prior to U.S. FDA approval or clearance of the 
device product. See further discussion in this Section describing the 
final rule as well as in Section IV.B.4 of this preamble.
Final Rule
    We have taken into consideration the commenters' suggestions and 
the statutory requirements for posting registration information in 
developing Sec.  11.35 of the final rule. Section 11.35(a) states that 
the Director will post publicly at ClinicalTrials.gov the clinical 
trial registration information for an applicable drug clinical trial 
not later than 30 calendar days after the responsible party has 
submitted such information, as specified in Sec.  11.24.
    Section 11.35(b)(1), which covers posting of registration 
information for an applicable device trial of a device product that has 
been previously approved or cleared, has been modified from the NPRM 
for clarity. We have added the phrase ``as soon as practicable'' to 
indicate that NIH will post registration information for an applicable 
device clinical trial of a device product that previously was approved 
or cleared ``as soon as practicable, but not later than'' the statutory 
deadline outlined in section 402 (j)(2)(D)(ii)(II) or successor 
statute. Section 402(j)(2)(D)(ii)(II) stipulates that clinical trial 
registration information for an applicable device clinical trial of a 
device that was previously cleared or approved will be posted ``not 
later than 30 days after the clinical trial information under paragraph 
(3)(C) is required to be posted by the Secretary.'' The information 
referred to by ``in paragraph (3)(C)'' is basic results information. 
The additional phrase of ``as soon as practicable'' clarifies in the 
regulatory language the NIH's intent, described in the NPRM, to post 
registration information for such applicable device clinical trials as 
soon as practicable after submission, but not later than 30 calendar 
days after clinical trial results information is required to be posted. 
Posting this information prior to the deadline is consistent with the 
objectives of expanding the registry and results data bank by 
rulemaking, facilitating enrollment in clinical trials, and providing a 
mechanism to track subsequent progress of clinical trials. Conversely, 
waiting to post registration information for applicable device clinical 
trials of device products that were previously approved or cleared 
until after results information is required to be posted would delay 
access to information about such clinical trials and would eliminate 
the possibility for the data bank to be used to facilitate enrollment 
in such trials and to allow the public to track such trials while they 
are ongoing. We have also clarified that ``device'' means ``device 
product.''
    Section 11.35(b)(2) covers posting of registration information for 
an applicable device trial of a device product that has not been 
previously

[[Page 65064]]

approved or cleared. Proposed Sec.  11.35(b)(2) has been separated in 
the final rule into Sec.  11.35(b)(2)(i) and Sec.  11.35(b)(2)(ii). In 
these sections, we have clarified that ``device'' means ``device 
product.'' Additionally, Sec.  11.35(b)(2)(i) adds a reference to the 
exception in Sec.  11.35(b)(2)(ii) for earlier posting of registration 
information by the Director if authorized by the responsible party.
    New Sec.  11.35(b)(2)(ii) allows a responsible party for an 
applicable clinical trial that is initiated on or after the effective 
date of the rule to indicate to the Director, prior to the date of 
approval or clearance of the device product, that it is authorizing the 
Director to publicly post its clinical trial registration information 
that would otherwise be subject to delayed posting as specified in 
paragraph (b)(2)(i) prior to the date of FDA approval or clearance of 
the device product. Upon notification, in the form of the responsible 
party's submission of the Post Prior to U.S. FDA Approval or Clearance 
data element under Sec.  11.28(a)(2)(i)(Q), the Director will post the 
clinical trial registration information, except for certain 
administrative data, as soon as practicable. Additionally, the Director 
intends to follow the timelines established by section 402(j)(2)(D)(i) 
of the PHS Act of posting the clinical trial registration information 
not later than 30 days after such submission. While this section of the 
statute refers to applicable drug clinical trials, it establishes a 
clear timeline between the submission of clinical trial registration 
information and its posting.
    Two additional issues directly related to posting of registration 
information are briefly described further: (1) The administrative data 
elements that the Agency does not intend to post publicly and (2) the 
relationship of posting and quality control described in Section IV.D.3 
of this preamble. First, section 402(j)(2)(A)(ii)(IV) of the PHS Act 
specifies that the Secretary ``may make publicly available as 
necessary'' administrative data that are submitted as part of clinical 
trial registration information. We interpret this provision to permit 
the Secretary to not post certain administrative data in the data bank 
if the data are not considered necessary for understanding the clinical 
trial or for recruitment. As noted for each data element discussed in 
Section IV.B.4 of this preamble, we do not believe it is necessary to 
make public the following administrative data and currently do not 
intend to post them publicly in ClinicalTrials.gov for any applicable 
clinical trials: (1) Food and Drug Administration IND or IDE Number and 
(2) Responsible Party Contact Information other than the name of the 
responsible party if the responsible party is an individual (as opposed 
to an entity). Second, as described in further detail in Section IV.D.3 
of this preamble, we intend to continue a form of quality control 
review at the time of clinical trial information submission that is 
similar to the procedures we have been using for the past several 
years. We note here, however, that, because the quality control review 
process does not affect the statutory deadlines for submitting or 
publicly posting submitted clinical trial information, there will be 
cases in which submitted clinical trial information is posted even 
though the quality control review process has not concluded. Although 
we will post clinical trial registration information not later than 30 
calendar days after submission, we will not assign an NCT number until 
the quality control review process has concluded. Thus, the clinical 
trial registration information will be posted to the ClinicalTrials.gov 
Web site without an NCT number. In addition, the clinical trial record 
will contain information that will be visible to those viewing the 
record on ClinicalTrials.gov to make it clear that the quality control 
review process has not concluded for the posted registration 
information.
    Reflecting section 402(j)(2)(C) of the PHS Act, as codified in 
Sec.  11.22, the timelines in Sec.  11.35 apply only to clinical trials 
that are required to register with ClinicalTrials.gov. If a clinical 
trial is registered with ClinicalTrials.gov as a voluntary submission 
as specified in Sec.  11.60, the registration information will be 
posted as soon as practicable after it has been submitted and reviewed 
as part of quality control review procedures.
C. Subpart C--Results Information Submission
    Subpart C sets forth requirements and procedures related to the 
submission of results information. In addressing what constitutes 
results information, subpart C does not specify what results 
information must be collected while the applicable clinical trial or 
other clinical trial is being conducted, but rather spells out which 
elements of the collected data must be submitted and in what required 
format. Subpart C also specifies when NIH will post results information 
in ClinicalTrials.gov and what procedures may be used to request a 
waiver of any applicable requirements for results information 
submission. Below, we summarize each section of subpart C, summarizing 
its statutory basis, what we proposed in the NPRM, any public comments 
received on the proposal, and the approach we take in the final rule.
1. Sec.  11.40--Who must submit clinical trial results information?
Overview of Proposal
    Proposed Sec.  11.40 required that the responsible party for an 
applicable clinical trial specified in proposed Sec.  11.42 submit 
clinical trial results information for that clinical trial. This 
approach is consistent with section 402(j)(3)(E)(i) of the PHS Act (79 
FR 69632).
Comments and Response
    No comments were received on this section.
Final Rule
    The final rule maintains Sec.  11.40 as proposed.
2. Sec.  11.42--For which applicable clinical trials must clinical 
trial results information be submitted?
Overview of Proposal
    In the NPRM, Sec.  11.42 detailed the applicable clinical trials 
for which results information would be required to be submitted in 
accordance with subpart C to ClinicalTrials.gov, unless the requirement 
is waived under proposed Sec.  11.54 (79 FR 69632). Pursuant to section 
402(j)(3)(D)(ii)(I) of the PHS Act, Sec.  11.42 proposed to require the 
submission of results information for specified: (1) Applicable 
clinical trials of drugs that are approved under section 505 of the 
FD&C Act or licensed under section 351 of the PHS Act; and (2) 
applicable clinical trials of devices that are cleared under section 
510(k) of the FD&C Act or approved under section 515 or 520(m) of the 
FD&C Act. Proposed Sec.  11.42 also would have required the submission 
of results information for specified applicable clinical trials of 
drugs or devices that are not approved, licensed, or cleared for any 
indication (regardless of whether the sponsor seeks approval, 
licensure, or clearance). We noted that proposed Sec.  11.42 pertains 
to section 402(j)(3)(D)(ii)(II) of the PHS Act, which directs that the 
Secretary establish through regulation whether or not results 
information must be submitted for applicable clinical trials of drugs 
and devices that have not been approved, licensed, or cleared by FDA, 
whether or not approval, licensure, or clearance is sought (79 FR 
69632).
    In the NPRM, Sec.  11.42 proposed to require responsible parties to 
submit

[[Page 65065]]

results information for applicable clinical trials that are required to 
be registered with ClinicalTrials.gov under Sec.  11.22 and that met 
one of the following criteria: (a) The completion date is on or after 
the rule's effective date (Sec.  11.42(a)); or (b) the completion date 
is prior to the effective date of this rule, the applicable deadline 
established by Sec.  11.44 is on or after the effective date of the 
rule, and clinical trial results information is submitted on or after 
the effective date of the rule, consistent with the applicable deadline 
established by Sec.  11.44 (Sec.  11.42(b)) (79 FR 69632). The NPRM 
also stated in the discussion of the effective date/compliance date 
(Section III.D) that for results information due prior to the rule's 
effective date under section 402(j)(3)(C) of the PHS Act, if the 
responsible party did not in fact submit these results by the effective 
date, then the responsible party would be required to submit the 
clinical trial results information specified by Sec.  11.48 (79 FR 
69593).
    In addition, the NPRM proposed how the rule would handle an 
applicable clinical trial of a drug or device under study that was not 
approved, licensed, or cleared by FDA and reached its completion date 
prior to the effective date of the rule, but the product is 
subsequently approved, licensed, or cleared by FDA after the effective 
date. We proposed that responsible parties for such applicable clinical 
trials be required to submit clinical trial results information 
specified in Sec.  11.48 by the earlier of 1 year after the completion 
date or 30 calendar days after the date of initial FDA approval, 
licensure, or clearance (79 FR 69594).
Comments and Response
    We received a few comments on the issues specifically covered by 
proposed Sec.  11.42. Those commenters suggested that results 
information submission should not be required for trials with results 
published in a peer-reviewed journal and that a hyperlink from 
ClinicalTrials.gov to the published study and lay summary of results 
would suffice. While results information submission to 
ClinicalTrials.gov is required by section 402(j) of the PHS Act 
independently of publication, ClinicalTrials.gov currently provides a 
number of optional data elements such as Citations and Links, which can 
be used to link a record to relevant trial results cited in 
publications or available at another Web site, respectively [Ref. 97]. 
We anticipate that these optional data elements will continue to be 
available on ClinicalTrials.gov.
    We also received comments on issues relevant to proposed Sec.  
11.42. Several commenters suggested that the rule should require 
results information for applicable clinical trials completed at any 
time, in order to ensure public access to such results information for 
completed trials of drugs that are currently on the market. Applicable 
clinical trials initiated on or before September 27, 2007, or completed 
before December 26, 2007, are not required to register or submit 
results information under section 402(j) of the PHS Act. As discussed 
here and furthermore in Section III.B Submission of Results Information 
for Applicable Clinical Trials of Unapproved, Unlicensed, or Uncleared 
Products for Any Use and Section IV.F Effective Date, Compliance Date, 
and Applicability of Requirements in this Part in the preamble, in the 
final rule, the NIH requires results information submission from 
applicable clinical trials of products that were unapproved, 
unlicensed, or uncleared before the primary completion date but 
subsequently approved, licensed, or cleared after the primary 
completion date when the primary completion date is on or after the 
effective date of the final rule. That is, with this rule, we require 
results information from trials completed after the effective date, 
regardless of whether approval, licensure, or clearance of the studied 
product is sought. A related suggestion in comments was to require 
submission of results information from applicable clinical trials 
completed since the year 2000. The submission of results information 
pursuant to these regulations, from trials with a primary completion 
date before the effective date of the regulations, is not required. 
Submission of basic results information (as defined in 402(j)(3)(C) of 
the PHS Act) from applicable clinical trials has been a statutory 
requirement since September 27, 2008, however, and is required for 
applicable clinical trials with a primary completion date before the 
effective date of the final rule.
    Finally, some commenters opposed the NPRM requirement that 
responsible parties who previously submitted results information for 
outcome measures would be required to comply with the final rule, 
anissue discussed in more depth in Section IV.F. of the preamble, 
Effective Date, Compliance Date, and Applicability of Requirements in 
this Part. As discussed in Section IV.F., the results information 
submission requirements that apply to an applicable clinical trial are 
determined by the date on which the trial reaches its actual primary 
completion date rather than when a responsible party submits results 
information.
Final Rule
    Taking into consideration these submitted comments as well as the 
statutory requirements, we have modified Sec.  11.42 in the final rule. 
We clarify which applicable clinical trials must submit results 
information according to the final rule and, consistent with the 
discussion in Section IV.F. of the preamble, we have made revisions and 
have restructured Sec.  11.42 to address the differing requirements 
that apply to applicable clinical trials (and, if voluntarily 
submitted, other clinical trials). Section 11.42(a) applies to 
applicable clinical trials for which the studied product is approved, 
licensed, or cleared by FDA. If the primary completion date for such 
trial is before the effective date of the final rule, Sec.  11.42(a)(1) 
requires clinical trial results information submission as specified in 
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act. If the primary 
completion date for such trial is on or after the effective date of the 
final rule, Sec.  11.42(a)(2) requires clinical trial results 
information submission as specified in Sec.  11.48. As discussed 
further in Section IV.F. on Effective Date, Compliance Date, and 
Applicability of Requirements in this Part, results information 
submission requirements are determined by the date on which the trial 
reaches its actual primary completion date. Thus, for trials that reach 
their primary completion date before the effective date of the final 
rule, results information submission is required as specified in 
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act, and for trials 
that reach their primary completion date on or after the effective date 
of the final rule, results information submission is required as 
specified in this final rule.
    Section 11.42(b) applies to applicable clinical trials for which 
the studied product is not approved, licensed, or cleared by FDA. As 
discussed in Section III.B Submission of Results Information for 
Applicable Clinical Trials of Unapproved, Unlicensed, or Uncleared 
Products for Any Use and Section IV.E. Effective Date, Compliance Date, 
and Applicability of Requirements in this Part, such applicable 
clinical trials are not subject to results information submission 
requirements until the effective date of the final rule. Thus, Sec.  
11.42(b) only applies to applicable clinical trials for which the 
studied product is not approved, licensed, or cleared if those trials 
have a primary completion date on or after the effective date of the 
final rule. For such trials,

[[Page 65066]]

clinical trial results information is required to be submitted as 
specified in Sec.  11.48.
    We note that proposed Sec.  11.42(b) had outlined scenarios in 
which the completion date of the trial is prior to the effective date 
of the rule and results information was required to be submitted 
according to the proposed rule. Under the simplified approach taken in 
the final rule, as discussed in Section IV.F., because determination of 
results information submission requirements relies on the primary 
completion date in relation to the effective date, proposed Sec.  
11.42(b) is no longer necessary. That is, there will be no scenarios in 
which the primary completion date is prior to the effective date of the 
rule and results information is required to be submitted according to 
the rule. We also note that the requirement to submit results 
information for applicable clinical trials with a primary completion 
date that is on or after the effective date, as specified in Sec.  
11.48, applies regardless of whether any results information, including 
for primary outcome measure(s), has been submitted before the effective 
date.
3. Sec.  11.44--When must results information be submitted for 
applicable clinical trials subject to Sec.  11.42?
Overview of Proposal
    Proposed Sec.  11.44 specified the deadlines for submitting results 
information for applicable clinical trials, implementing section 
402(j)(3)(E) of the PHS Act. Proposed Sec.  11.44(a) specified the 
standard submission deadlines for applicable clinical trials that are 
clinical trials subject to proposed Sec.  11.42. Proposed Sec.  
11.44(b) and (c) described procedures for delaying the standard 
submission deadlines with certification when seeking approval, 
licensure, or clearance of a new use or initial approval, licensure, or 
clearance, respectively, of a drug (including a biological product) or 
device studied in an applicable clinical trial. Proposed Sec.  11.44(d) 
specified the procedures for submitting partial results information, 
while Sec.  11.44(e) described the process for requesting an extension 
of the results information submission deadline for good cause. Finally, 
proposed Sec.  11.44(f) established the timeline for submitting results 
of a pediatric postmarket surveillance of a device that is not a 
clinical trial (79 FR 69632). Below we discuss each part of Sec.  11.44 
separately.
Sec.  11.44(a) Standard Submission Deadline
Overview of Proposal
    Proposed Sec.  11.44(a)(1) specified that, in general, the deadline 
for submitting results information for an applicable clinical trial 
would be 1 year after the completion date of the clinical trial. As 
explained in the NPRM, sections 402(j)(3)(E)(i)(I) and (II) of the PHS 
Act specify that results information is to be submitted not later than 
1 year after the ``earlier of'' the estimated completion date or the 
actual completion date (79 FR 69632). Under proposed Sec.  11.64(b)(1), 
however, responsible parties would be required to update the estimated 
completion date not later than 30 calendar days after a change to the 
estimated completion date has occurred or after the applicable clinical 
trial has reached its actual completion date. Therefore, submission 1 
year after the actual completion date would then always reflect the 
``earlier of'' 1 year after the estimated completion date or the actual 
completion date. Thus, under proposed Sec.  11.44(a)(1), results 
information would be due not later than 1 year after the actual 
completion date of the applicable clinical trial. This proposed 1 year 
standard submission deadline would apply to applicable clinical trials 
of drugs and devices in order to simplify results information 
submission procedures and provide consistency between the deadlines for 
applicable clinical trials, regardless of the approval status of the 
products under study. Section 402(j)(3)(D)(iv)(III) of the PHS Act 
requires the Secretary to determine by regulation ``the date by which . 
. . clinical trial [results] information [for applicable clinical 
trials of unapproved, unlicensed, or uncleared products] shall be 
required to be submitted . . .'' Applicable clinical trials of 
unapproved, unlicensed, or uncleared drugs and devices, and of 
approved, licensed, or cleared drugs and devices that are studied for a 
new use may, however, qualify for delayed submission of results 
information, as described below. As we noted in the NPRM, although 
section 402(j)(3)(D)(iv)(I) of the PHS Act requires the Secretary to 
determine whether to increase the standard submission deadline for 
results information submission from 1 year to ``a period not to exceed 
18 months'' after the earlier of the estimated or actual primary 
completion date, the Agency chose not to propose extending the general 
results information submission deadline to as long as 18 months (79 FR 
69633).
    Proposed Sec.  11.44(a)(2) specified that the deadline for 
submitting results information for any applicable clinical trial of an 
FDA-regulated drug (including a biological product) or device that is 
unapproved, unlicensed, or uncleared as of its completion date would be 
by the earlier of 1 year after the completion date, or 30 calendar days 
after FDA approves, licenses, or clears the drug or device for any 
indication studied in the applicable clinical trial (79 FR 69633).
Comments and Response
    Comments on proposed Sec.  11.44 expressed different opinions. 
While one commenter expressed overall support for the proposal, others 
suggested modifications to various parts. Others raised concerns that 
the overall proposed submission and public posting timelines for trial 
results information could lead to premature dissemination of 
confidential commercial information, especially if posted prior to 
peer-reviewed publication or review by the FDA.
    As we explained in the NPRM, we did not propose to require the 
submission of detailed information about clinical trial results (such 
as required for inclusion in an NDA submitted to FDA), but only summary 
results data typically found as tables or figures in journal articles, 
scientific abstracts, and press releases. As mandated by section 
402(j)(3) of the PHS Act and established in the final rule Sec.  11.48, 
responsible parties are required to submit at minimum a standard set of 
data elements needed to understand the findings from an applicable 
clinical trial for all prespecified primary and secondary outcome 
measures and serious adverse events in a structured manner. Further, 
results information submissions are required for all applicable 
clinical trials subject to the final rule according to deadlines 
established by the final rule, regardless of product approval status, 
to ensure consistent and timely public access to comprehensive summary 
results for all relevant clinical trials, thereby mitigating the 
prevalent problems of selective results reporting and negative results 
publication bias [Ref. 21, 22].
    One commenter suggested that the results information submission 
time frames prescribed in the final rule should conform to those 
outlined in the 2015 IOM report on sharing clinical trial data [Ref. 
47] to minimize the administrative burden on sponsors and responsible 
parties. Another commenter suggested that results information should be 
made available as it is created (i.e., real time submission). The

[[Page 65067]]

requirements in the final rule are consistent with the Agency's 
authority in section 402(j) of the PHS Act and represent the Agency's 
determination, consistent with that authority, as to the appropriate 
results information submission deadlines for applicable clinical trials 
of unapproved products.
    Regarding the standard results information submission deadline 
following initial approval, licensure, or clearance, described in 
proposed Sec.  11.44(a)(2), one commenter recommended that, for 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products for which the collection of pre-specified secondary outcome 
measures continues past the completion date, the standard results 
information submission deadline should be extended to the date of final 
data collection for all pre-specified secondary outcome measures (i.e., 
at LPLV). The commenter also suggested that such a change would be 
consistent with results information submission deadlines established 
under the EU's Clinical Trials Regulation [Ref. 70]. Section 
402(j)(D)(iv)(I) of the PHS Act authorizes the Agency to increase by 
regulation the standard results information submission deadline from 1 
year following the completion date described in 402(j)(3)(E)(i) of the 
PHS Act ``to a period not to exceed 18 months.'' The statutorily-
mandated definition of completion date (here referred to as primary 
completion date; see preamble Section IV.A.5 and Sec.  11.10(a)) is 
determined by the status of data collection for solely the primary 
outcome measure(s), as is the basis for determining the standard 
results information submission deadline from the statutorily-mandated 
primary completion date. The final rule permits the responsible party 
to delay submission of results information for applicable clinical 
trials for up to 2 additional years by submitting a certification under 
Sec.  11.44(b) if the manufacturer is the sponsor and is seeking 
approval, licensure, or clearance for a new use or under Sec.  11.44(c) 
if the sponsor is seeking initial approval, licensure, or clearance. 
Such delays provide up to 2 additional years to complete data 
collection for pre-specified outcome measures and/or additional adverse 
event information.
    Further, the final rule specifies timelines in Sec.  11.44(d) for 
submitting partial results information by the date on which results 
information is due even if data collection for secondary outcome 
measure(s), or the pre-specified time frame for collecting additional 
adverse events information, has not been completed. These timelines 
provide submission deadlines for additional partial results information 
of not later than 1 year after the date on which final data collection 
for secondary outcome measure(s) or the pre-specified time frame for 
collecting additional adverse event information is completed, or on the 
date on which results information for primary outcome measure(s) is due 
following delayed certification, as specified in Sec.  11.44(b) and 
(c). In addition, this approach ensures timely submission of results 
information for the primary outcome measure(s), but permits delays for 
the submission of other results information to allow time for the final 
collection and analysis of secondary outcome measure(s) and/or 
additional adverse event information. We note that, in situations in 
which the submission of results information for the primary outcome(s) 
of an applicable clinical trial would impair or otherwise bias the 
ongoing collection, analysis, and/or interpretation of data for 
secondary outcome(s) (e.g., need to maintain masking in a trial), 
responsible parties may request an extension of the results information 
submission deadline for good cause by following the procedures 
specified in Sec.  11.44(e).
    A few other commenters suggested modifying proposed Sec.  
11.44(a)(2), which addressed results information submission for 
applicable clinical trials of products not approved, licensed, or 
cleared as of the completion date, but that receive FDA approval, 
licensure, or clearance thereafter. These commenters asserted that the 
proposal is inconsistent with the statutory language. In particular, 
they asserted the proposed regulatory language stating that results 
information submission is required ``by the earlier of'' (i) 1 year 
after the completion date or (ii) 30 calendar days after FDA approval, 
licensure, or clearance of the product contradicts section 
402(j)(3)(E)(i) of the PHS Act, which states ``not later than 1 year, 
or such other period as may be provided by regulation.'' The commenters 
suggested that to be consistent with the statute, the standard results 
information submission deadline should be changed to ``by the later 
of'' in the final rule. As discussed in Section IV.F below, we have 
reconsidered the approach described in the NPRM (79 FR 69593) with 
respect to determining whether an applicable trial involves an 
approved, licensed, or cleared product, or whether it involves an 
unapproved, unlicensed, or uncleared product. For purposes of this 
final rule, the marketing status of a product will be determined based 
on its marketing status on the primary completion date. Thus, if a drug 
product (including a biological product) or a device product is 
approved, licensed, or cleared for any use as of the primary completion 
date, we will consider that applicable clinical trial to be a trial of 
an approved, licensed, or cleared product. Similarly, if a drug product 
(including a biological product) or a device product is unapproved, 
unlicensed, or uncleared for any use as of the primary completion date, 
regardless of whether it is later approved, licensed, or cleared, we 
will consider that applicable clinical trial to be a trial of an 
unapproved, unlicensed, or uncleared product. Furthermore, as noted in 
the preamble section discussing Sec.  11.42(b) and in Section III.B 
Submission of Results Information for Applicable Clinical Trials of 
Unapproved, Unlicensed, or Uncleared Products for Any Use and Section 
IV.F. Effective Date, Compliance Date, and Applicability of 
Requirements in this Part, applicable clinical trials of an unapproved, 
unlicensed, or uncleared product are not subject to results information 
submission requirements until the effective date of the final rule. 
Thus, whether results information submission is required for an 
applicable clinical trial of an unapproved, unlicensed, or uncleared 
product depends on whether the primary completion date for that trial 
falls before, on, or after the effective date of the rule. Results 
information submission, therefore, is not required for applicable 
clinical trials of products not approved, licensed, or cleared for any 
use as of the primary completion date but receive FDA approval, 
licensure, or clearance thereafter when the primary completion date is 
before the effective date of the rule.
    Other commenters suggested that results information submission 
should be required earlier than the proposed standard submission 
deadline (i.e., earlier than 1 year after the completion date) whenever 
a responsible party publicly discloses results information for a 
clinical trial elsewhere, such as in a publication. Some commenters 
also suggested that the deadline for submission of results information 
in this circumstance should be 30 days after the date of public 
disclosure.
    The Agency disagrees with the suggestion that we should make the 
date of any public disclosure of trial results a ``trigger'' for 
mandatory early results information submission. Sponsors and 
researchers publicly disclose trial results for many reasons, including 
compliance with other federal laws or policies (e.g., disclosure 
requirements to the U.S. Securities and Exchange

[[Page 65068]]

Commission that may contain information about trial results). The final 
rule is consistent with section 402(j)(3)(E)(i) of the PHS Act, which 
provides up to 1 year from the completion date for results information 
submission. For the purpose of describing mandatory results information 
submission deadlines under this section, a triggering event refers to 
any of the events specified in paragraphs (b)(1)(i), (ii), and (iii) 
and paragraphs (c)(1)(i) and (ii) of this section that prompt results 
information submission for a clinical trial with a certification for 
delayed results information submission. The responsible party has 30 
calendar days from the date of a triggering event to submit results 
information. We note that the definition of ``primary completion date'' 
in Sec.  11.10(a) refers to the definition of ``completion date'' in 
Sec.  11.10(a), which is ``for a clinical trial, including an 
applicable clinical trial, the date that the final subject was examined 
or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded 
according to the pre-specified protocol or was terminated. In the case 
of clinical trials with more than one primary outcome measure with 
different primary completion dates, this term refers to the date on 
which data collection is completed for all of the primary outcomes. For 
a pediatric postmarket surveillance of a device product that is not a 
clinical trial, completion date means the date on which the final 
report of the pediatric postmarket surveillance of the device product 
is submitted to FDA. For purposes of this part, completion date will be 
referred to as `primary completion date.' '' In the case that data 
collection is completed for at least one primary outcome measure (but 
not yet for all primary outcome measures), clinical trial results 
information as specified in Sec.  11.48(a) may be submitted before the 
primary completion date of the clinical trial.
Final Rule
    Taking into consideration the commenters' suggestions and the 
statutory requirements for results information submission deadlines, 
the final rule modifies the approach proposed in Sec.  11.44(a) by 
deleting proposed Sec.  11.44(a)(2), which would have required results 
information submission for a clinical trial of a product that is 
unapproved, unlicensed, or uncleared for any use as of its completion 
date by the earlier of 1 year after the completion date or 30 calendar 
days after the date FDA approves, licenses, or clears the drug or 
device for any indication studied in the applicable clinical trial.
    As noted above and discussed in Section IV.F on Effective Date, 
Compliance Date, and Applicability of Requirements in this Part, the 
Agency has reconsidered its approach with respect to determining 
whether an applicable clinical trial involves an approved, licensed, or 
cleared product, or whether it involves an unapproved, unlicensed, or 
uncleared product. For purposes of this final rule, the marketing 
status of a product will be determined based on its marketing status as 
of the primary completion date. With this approach, under section 
402(j)(3)(C) of the PHS Act, results information submission is not 
required for clinical trials of a product that is unapproved, 
unlicensed, or uncleared for any indication as of its primary 
completion date where the primary completion is before the effective 
date. Further, as discussed in Section III.B Submission of Results 
Information for Applicable Clinical Trials of Unapproved, Unlicensed, 
or Uncleared Products for Any Use and Section IV.F Effective Date, 
Compliance Date, and Applicability of Requirements in this Part of the 
preamble, when the primary completion date is on or after the effective 
date of the final rule, the rule requires results information 
submission from applicable clinical trials of all products that were 
unapproved, unlicensed, or uncleared for any indication before the 
primary completion date. For trials of unapproved, unlicensed, or 
uncleared products completed after the effective date, results 
submission is generally required in accordance with the standard 
submission deadline. Thus, it is not necessary for final Sec.  11.44(a) 
to contain separate subparagraphs to account for the approval, 
clearance, or licensure status of the product studied by the applicable 
clinical trial.
    Final Sec.  11.44(a) retains the proposed standard submission 
deadline of 1 year after the primary completion date regardless of 
product approval, clearance, or licensure status. We clarify that Sec.  
11.44(a) applies to applicable clinical trials subject to Sec.  11.42 
and that the results information required is specified in either 
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or in Sec.  
11.48, as appropriate. As discussed in Section IV.F Effective Date, 
Compliance Date, and Applicability of Requirements in this Part, below, 
whether a responsible party is required to submit either results 
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the 
PHS Act or the results information specified in Sec.  11.48 will depend 
on whether the primary completion date of the applicable clinical trial 
is before, on, or after the effective date of the final rule.
Sec.  11.44(b) and (c)--Delayed Submission of Results Information With 
Certification
Overview of Proposal
    Proposed Sec.  11.44(b) and (c) established procedures whereby 
responsible parties may delay submission of results information for a 
particular applicable clinical trial beyond the standard submission 
deadline specified in proposed Sec.  11.44(a)(1) (i.e., 1 year after 
the completion date) (79 FR 69633).
Delayed Submission of Results Information With Certification If Seeking 
Approval, Licensure, or Clearance of a New Use
    Consistent with sections 402(j)(3)(E)(iii) and (v) of the PHS Act, 
we proposed in Sec.  11.44(b) to allow a delay in the submission of 
results information if the responsible party certifies that an 
applicable clinical trial meets the following criteria: (1) The drug 
(including biological product) or device studied in the applicable 
clinical trial previously has been approved, licensed, or cleared by 
FDA; (2) the sponsor of the applicable clinical trial is the 
manufacturer of the product; and, (3) the manufacturer has filed, or 
will file within 1 year, an application or premarket notification 
seeking approval, licensure, or clearance of the use being studied in 
the applicable clinical trial (and is not included in the labeling of 
the approved, licensed, or cleared drug or device). As proposed, the 
responsible party would need to submit this certification to 
ClinicalTrials.gov before the standard submission deadline specified in 
proposed Sec.  11.44(a)(1) (i.e., 1 year or less after the completion 
date). We also proposed to indicate on the posted record for the 
clinical trial that results submission has been delayed, but would not 
specify the particular reason for the delay (79 FR 69633).
    As we explained in the NPRM, in accordance with section 
402(j)(3)(E)(v) of the PHS Act, once a certification has been submitted 
to ClinicalTrials.gov, proposed Sec.  11.44(b)(2) would permit a delay 
in the submission of results information of up to 2 years after the 
date on which the certification is submitted, unless one of the 
following events occurs: (1) FDA approves, licenses, or clears the drug 
or device for the use studied in the applicable clinical trial; (2) FDA 
issues a letter that

[[Page 65069]]

ends the regulatory review cycle for the application or submission 
(e.g., a complete response letter, a not substantially equivalent 
letter, or a not approvable letter) but does not approve, license, or 
clear the drug or device for the use studied in the applicable clinical 
trial; or, (3) the manufacturer, which is also the sponsor of the 
applicable clinical trial, withdraws the application or premarket 
notification seeking approval, licensure, or clearance of the new use 
and does not resubmit it within 210 calendar days. In the event that 
any one of these triggering events occurs, the proposed rule said that 
the responsible party would be required to submit results information 
for the applicable clinical trial for which a certification had been 
submitted under proposed Sec.  11.44(b)(1) not later than 30 calendar 
days after the earliest of the triggering events occurred, consistent 
with section 402(j)(3)(E)(v)(I) of the PHS Act (79 FR 69633).
    As we noted, proposed Sec.  11.44(b)(3) implemented section 
402(j)(3)(E)(v)(II) of the PHS Act, which specifies that if a 
responsible party who is both the manufacturer of the drug or device 
studied in the applicable clinical trial and the sponsor of the 
applicable clinical trial submits a certification to delay submission 
of results information because the manufacturer is seeking or will seek 
within 1 year approval, licensure, or clearance of a new use for a drug 
or device, that responsible party must submit such a certification for 
each applicable clinical trial that meets the following criteria: (i) 
The applicable clinical trial is required to be submitted in an 
application or premarket notification for seeking approval, licensure, 
or clearance of a new use; and, (ii) the applicable clinical trial 
studies the same drug or device for the same use as studied in the 
applicable clinical trial for which the initial certification was 
submitted (79 FR 69633).
Delayed Submission of Results With Certification If Seeking Initial 
Approval, Licensure, or Clearance
    Proposed Sec.  11.44(c) described requirements for delayed 
submission of results information with certification when seeking 
initial approval, licensure, or clearance of a drug or device. As we 
explained in the NPRM, section 402(j)(3)(D)(iv)(III) of the PHS Act 
required that, when proposing to require the submission of results 
information for trials of unapproved, unlicensed, or uncleared 
products, we take into account the certification process in section 
402(j)(3)(E)(iii) of the PHS Act ``when approval, licensure, or 
clearance is sought,'' and that we determine ``whether there should be 
a delay of submission when approval, licensure or clearance will not be 
sought'' (79 FR 69634).
    We proposed in Sec.  11.44(c) to allow a delay in the submission of 
results information if the responsible party certifies that an 
applicable clinical trial meets the following criteria: (1) The drug 
(including biological product) or device studied in the applicable 
clinical trial was not approved, licensed, or cleared by FDA for any 
use before the completion date of the clinical trial; and, (2) the 
sponsor of the applicable clinical trial intends to continue with 
product development and is seeking, or may at a future date seek, FDA 
approval, licensure, or clearance of the drug or device under study. As 
proposed, this certification would be required to be submitted to 
ClinicalTrials.gov before the standard submission deadline specified in 
proposed Sec.  11.44(a)(1) (i.e., 1 year or less after the completion 
date). The record for the clinical trial would indicate that results 
submission has been delayed, but would not specify the particular 
reason for the delay (79 FR 69634).
    As proposed in Sec.  11.44(c), submission of a certification would 
permit a delay in the submission of results information of up to 2 
years after the date on which the certification is submitted to 
ClinicalTrials.gov, unless either of the following events occurs: (1) 
FDA approves, licenses, or clears the drug or device studied in the 
applicable clinical trial for any indication that is studied in the 
clinical trial; or, (2) the application or premarket notification is 
withdrawn without resubmission for not less than 210 calendar days. The 
responsible party would be required to submit results information not 
later than 30 calendar days after the one of these triggering events 
occurs. We explained that the Agency included the second event (i.e., 
withdrawn without resubmission for not less than 210 calendar days) 
because we believe that this situation represents a significant enough 
interruption to product development to trigger the submission of 
results information. Unlike delayed results information submission with 
certification under proposed Sec.  11.44(b), which applies when the 
sponsor (which is the manufacturer) of the applicable clinical trial is 
seeking approval, licensure, or clearance of a new use, we did not 
propose to require the submission of results information 30 calendar 
days after FDA issues a letter not approving, not licensing, or not 
clearing the product under study for delayed results information 
submission with certification seeking initial approval, licensure, or 
clearance because the issuance of such a letter does not necessarily 
indicate abandonment of product development (79 FR 69634).
Two-Year Limitation of Delay
    As we discussed in the NPRM, with regard to the maximum 2-year 
delay pursuant to a certification submitted under section 
402(j)(3)(E)(iii) of the PHS Act, we had considered establishing the 
maximum available delay with certification when seeking initial 
approval, licensure, or clearance to be 3 years from the completion 
date of the applicable clinical trial, regardless of when during the 1-
year period following the completion date the certification is 
submitted. Such a provision would have accomplished the same objective 
as the statutory provision for delayed submission when seeking 
approval, licensure, or clearance of a new use by allowing responsible 
parties to delay results submission by as long as 3 years beyond the 
completion date of a clinical trial, but without creating a 
disincentive to submit the certification early. As we explained in the 
NPRM, measuring the 2-year period from the date on which the 
certification is submitted may result in responsible parties submitting 
certifications as close as possible to the standard results submission 
deadline under proposed Sec.  11.44(a)(1) to obtain the full 3-year 
delay after the completion date. Section 402(j)(3)(D)(iv)(III) of the 
PHS Act expressly authorizes the Secretary to establish the date by 
which clinical trial information for applicable clinical trials of 
unapproved products must be submitted to ClinicalTrials.gov. Thus, in 
order to maintain the same maximum delay for results information 
submission whether seeking initial approval, licensure, or clearance or 
seeking approval, licensure, or clearance of a new use, we did not 
propose that the maximum 3-year delay apply regardless of when during 
the 1-year period following the completion date the certification is 
submitted. We invited public comments on establishing different maximum 
timelines for results information submission under the two delayed-
results-with-certification provisions and on alternative approaches to 
encourage early submission of certifications that would be consistent 
with the statute, without causing a responsible party to have to submit 
results information earlier than the latest deadline they could have 
under the statute (79 FR 69635).

[[Page 65070]]

Explanation of ``initial approval,'' ``initial clearance,'' and 
``approval of a new use,'' or clearance of a new use''
    For purposes of proposed Sec.  11.44(b) and (c), we interpreted the 
term ``drug'' in sections 402(j)(3)(E)(iv) and 402(j)(3)(E)(v) of the 
PHS Act to mean ``drug product'' or ``biological product,'' referring 
to a finished product that is approved or licensed for marketing, and 
not to the active ingredient or active moiety in such a product. We 
concluded that this is the most appropriate interpretation of the 
statutory term and that this interpretation is consistent with the 
statutory intent to draw a distinction between applicable drug clinical 
trials that are ``completed before the drug is initially approved'' 
(see section 402(j)(3)(E)(iv) of the PHS Act) and those pertaining to 
uses ``not included in the labeling of the approved drug'' (see section 
402(j)(3)(E)(v) of the PHS Act). Accordingly, we interpreted ``initial 
approval'' to pertain to the approval or licensure of an original NDA, 
ANDA or BLA, and ``new use'' to pertain to the approval or licensure of 
a supplemental NDA, ANDA, or BLA for an additional use for that 
particular drug product or biological product. Similarly, we 
interpreted ``initial approval'' of a device under sections 515 or 
520(m) of the FD&C Act to pertain to the approval of an original PMA or 
HDE and ``new use'' to pertain to the approval of a supplemental PMA 
for an additional use for that particular device. In addition, for 
purposes of proposed Sec.  11.44(c), we considered the first 510(k) 
cleared for a particular device type as the ``initial clearance'' of 
the device. Consequently, for purposes of proposed Sec.  11.44(b), all 
other 510(k)s cleared for a device type, other than the first one, 
would have been considered ``clearance of a new use.'' We solicited 
comments on whether these are appropriate interpretations and 
distinctions for purposes of proposed Sec.  11.44(b) and (c) (79 FR 
69635).
Comments and Response
    Commenters addressed delayed submission of results with 
certification in proposed Sec.  11.44(b) and (c). While one commenter 
supported the proposed delay of results submission for up to 2 years 
following the date of submission of a certification in proposed Sec.  
11.44(c), another commenter proposed simplifying the approach for 
calculating the deadline for this maximum delay by uniformly allowing 
up to 3 years after the primary completion date, regardless of when a 
certification is submitted. This commenter, however, did not explain 
how the statute allows for this proposed approach. As noted previously 
here and in the proposed rule, the statute does not permit changing by 
rulemaking when the 2-year maximum available delay for results 
submission would begin for submitted certifications seeking approval, 
licensure, or clearance of a new use for the studied drug or device. 
Section 402(j)(3)(E)(v)(III) of the PHS Act states that the time period 
begins on the date that the certification is submitted. While the 
statute provides greater flexibility for establishing the timelines for 
certifications seeking initial approval, licensure, or clearance for a 
studied drug or device, we have decided to keep the same approach for 
determining the maximum delay under both types of certifications, for 
reasons discussed in the NPRM. As such, the final rule retains the 
proposed approach (i.e., ``not later than 2 years after the date on 
which the certification was submitted'').
    One commenter proposed allowing an additional year to delay the 
submission of results for purposes of journal publication. Another 
commenter suggested that the Agency provide a new certification-like 
mechanism for delaying the submission of results of applicable clinical 
trials of approved, licensed, or cleared products for up to 2 years (as 
permitted for unapproved, unlicensed, or uncleared products) to allow 
academic researchers to prepare for journal publication. Several 
commenters proposed that the final rule routinely provide delayed 
submission of results for other reasons, such as publication prior to 
public posting on ClinicalTrials.gov. The statutory provision that 
pertains to delayed submission of results with certification is in 
section 402(j)(3)(D)(iv)(III) of the PHS Act, which explicitly directs 
the Agency to take into account during rulemaking the delayed 
submission of results with certification provisions when proposing to 
require the submission of results for applicable clinical trials of 
unapproved, unlicensed, or uncleared products, whether or not approval, 
licensure, or clearance is sought. In response to this mandate, the 
Agency proposed permitting delayed submission of results in proposed 
Sec.  11.44(c) for applicable clinical trials of unapproved, 
unlicensed, or uncleared products undergoing product development. 
However, the NPRM proposed at Sec.  11.44(a) to require the standard 
submission deadline for trials of unapproved, unlicensed, or uncleared 
products for which product development has been abandoned (see Section 
III.B of this preamble).
    The Agency does not agree that submission of results information 
should be delayed for purposes of journal publication. Moreover, we 
note that the ICMJE clinical trial registration policy recognizes the 
results reporting obligations under section 402(j) of the PHS Act and 
states that ``the ICMJE will not consider results data posted in the 
tabular format required by ClinicalTrials.gov to be prior publication'' 
[Ref. 98]. Therefore, we do not expect that the requirements of the 
final rule for submission of results information will interfere with 
journal publication of articles about applicable clinical trials.
    One commenter proposed requiring submission of results information 
for applicable device clinical trials only after the manufacturer has 
declared product development to be abandoned. This commenter noted 
further that receipt of an initial non-approval or not substantially 
equivalent finding from the FDA does not necessarily indicate that 
product development has stopped and suggested that the final rule 
provide for additional delays for results submission until the 
manufacturer has declared product development to be abandoned. As 
discussed in more detail in Section III.B of this preamble, the Agency 
has decided to maintain the requirement of results information 
submission for applicable clinical trials of drug and device products 
that are not approved, licensed, or cleared by the FDA for any use, 
regardless of whether approval, licensure, or clearance is sought. We 
continue to believe that this approach is consistent with the express 
statutory purpose of the expanded data bank ``[t]o provide more 
complete results information and to enhance patient access to and 
understanding of the results of clinical trials'' (see section 
402(j)(3)(D)(i) of the PHS Act). As discussed previously, Sec.  
11.44(c) mitigates concerns about potential competitive harm resulting 
from disclosure of results information from applicable clinical trials 
of products that are not approved, licensed, or cleared by delaying the 
results submission deadline for applicable clinical trials of products 
that are still under development. Thus, we do not agree with commenters 
who suggested that results submission for applicable device clinical 
trials (or for applicable drug clinical trials) should be limited to 
trials of abandoned products. Consistent with section 
402(j)(3)(E)(v)(I)(bb) of the PHS Act, Sec.  11.44(b)(1)(ii) of the 
final rule provides that the issuance of a letter by the FDA including 
``a complete response letter, not approving the

[[Page 65071]]

submission or not clearing the submission, a not approvable letter, or 
a not substantially equivalent letter for a new use of the drug or 
device'' that ends the regulatory review cycle for the application or 
submission but does not approve, license, or clear the product for the 
use studied in the applicable clinical trial, requires the responsible 
party to submit within 30 calendar days clinical trial results 
information for an applicable clinical trial, which had previously been 
subject to delayed submission of results information.
    One commenter suggested that confidential commercial or proprietary 
information should not need to be submitted as part of the 
certification process. We clarify that to obtain a certification for 
delayed results information submission, a responsible party will need 
to indicate that a particular applicable clinical trial meets the 
requirement for delayed submission with certification in accordance 
with Sec.  11.44(b) or (c) and provide the name(s) of the drug 
product(s), biological product(s), or device product(s), to which the 
certification applies. This information is necessary to demonstrate 
that the certification requirement has been met. No additional 
information will be required as part of this process.
    One commenter suggested that we should post the reason a 
responsible party has been granted a certification for delayed results 
submission or extension. As noted above in the discussions of Sec.  
11.44(b) and (c), for applicable clinical trials that have been granted 
a certification for delayed results information submission or 
extension, the posted record will indicate only that the results 
information submission has been delayed but it will not specify the 
particular reason for the delay.
    Finally, a few commenters disagreed with the Agency's 
interpretation that only the first 510(k) cleared for a particular 
device type be considered ``initial clearance.'' They asserted that 
every 510(k) clearance should be considered ``initial clearance,'' 
which would result in a potentially longer delay in submitting results 
information, rather than considered clearance of a ``new use'' because 
the trigger for submitting results information in proposed Sec.  
11.44(b)(1)(ii) is not found in proposed Sec.  11.44(c). The 
commenters' arguments appear to be rooted in a concern that premature 
disclosure of clinical trial results information would enable 
competitors to shorten the time and expense to develop and market a 
similar device. The commenters' proposal would result in treating all 
510(k) clearances as ``initial clearance'' under section 
402(j)(3)(E)(iv) regardless of whether or not the 510(k) submission is 
an original submission by a manufacturer to obtain initial clearance of 
a device product as compared with a subsequent application by the same 
manufacturer to obtain clearance of the same device product for a 
different use. The Agency disagrees with the commenters' proposal 
because, by considering every 510(k) clearance to be an ``initial 
clearance'' under section 402(j)(3)(E)(iv) of the PHS Act, and 
considering no 510(k) clearances to be clearance of a ``new use'' under 
section 402(j)(3)(E)(v) of the PHS Act, such an interpretation would 
deprive section 402(j)(3)(E)(v) of the PHS Act of any meaning with 
respect to 510(k)s. Accordingly, the commenters' approach would 
contravene the principle of statutory construction that courts should 
give effect, if possible, to every clause and word of a statute, so as 
to avoid rendering any statutory language superfluous.
    For NDA, ANDA, BLA, and PMA approvals, the NPRM focused on a 
manufacturer's particular ``product'' rather than on the ``type'' when 
determining whether a trial would be considered seeking ``initial 
approval,'' as specified in section 402(j)(3)(E)(iv), or ``approval of 
a new use,'' as specified in section 402(j)(3)(E)(v). In contrast, for 
510(k)s, the NPRM focused on the device ``type'' rather than the device 
``product'' for making such a determination. Under the NPRM, only the 
first 510(k) cleared for a device type was considered ``initial 
clearance'' and all other 510(k)s cleared for a device type were 
considered ``clearance of a new use.'' As a result, the NPRM approach 
resulted in disparate treatment of 510(k)s compared with the treatment 
of all other types of applications, including device PMAs.
    To avoid disparate treatment of 510(k) submissions as compared with 
the treatment of all other types of applications, including PMA 
applications, in the final rule, the Agency is focusing on the device 
``product'' rather than the device ``type'' when determining which 
510(k) clearances are considered ``initial clearance'' versus 
``clearance of a new use.'' That is, in the final rule, we interpret 
``initial clearance'' to pertain to the clearance of a manufacturer's 
original 510(k) submission for a particular device product whereas 
``clearance of a new use'' of a device pertains to the clearance of the 
same manufacturer's subsequent 510(k) submission for an additional use 
for the same device product. ``Manufacturer'' means a manufacturer who 
is the sponsor for the applicable clinical trial. The final rule, thus, 
treats 510(k)s in the same way it treats NDAs, ANDAs, BLAs, and PMAs by 
consistently basing its determination on the ``product'' rather than 
the ``type'' when determining whether a trial is seeking ``initial'' 
approval, licensure, or clearance, or approval, licensure, or clearance 
of a ``new use.'' This represents a middle-ground approach between the 
NPRM approach and the approach advocated by the commenters.
    For the purposes of this final rule only, we interpret ``use'' to 
include ``indication.'' For the purposes of this final rule, 
``indication'' means ``the disease or condition the product is intended 
to diagnose, treat, prevent, cure, or mitigate.''
    Thus, for purposes of the final rule, the Agency interprets the 
first 510(k) clearance of a device ``product'' rather than the first 
510(k) clearance of a device ``type'' as ``initial clearance'' under 
section 402(j)(3)(E)(iv) of the PHS Act. Any subsequent clearance of an 
``initially cleared'' 510(k) device product for a different use will be 
considered a ``clearance of a new use'' under section 402(j)(3)(E)(v) 
of the PHS Act.
    This interpretation in the final rule allows a responsible party 
for an applicable clinical trial of a 510(k) device product that is 
uncleared on the primary completion date to seek delayed submission of 
results information by submitting a certification that it is seeking 
``initial clearance'' of its device product under Sec.  11.44(c), 
rather than ``clearance of a new use'' under final Sec.  11.44(b). With 
regard to FDA's issuance of a letter that ends the regulatory review 
cycle but does not approve, license, or clear the product for the use 
studied in the applicable clinical trial, as described in Sec.  
11.44(b)(1)(ii), we note, first, that it does not trigger results 
information submission within 30 calendar days of the event under Sec.  
11.44(c)(1) and, second, that there are no ``additional requirements'' 
in Sec.  11.44(c) for responsible parties who are both the manufacturer 
of the product and the sponsor of the applicable clinical trial to 
submit certifications for each additional applicable clinical trial 
that studies the same product for the same use and is required to be 
submitted in a premarket notification for that use (as required in 
Sec.  11.44(b)(3)).
    We also note that this interpretation has implications for the 
registration requirements in the final rule because the concepts of 
``initial clearance'' and ``clearance of a new use'' also appear in the 
registration provisions of the statute. This interpretation subjects 
clinical trial

[[Page 65072]]

registration information for more applicable clinical trials of 
unapproved or uncleared devices to delayed posting under section 
402(j)(2)(D)(ii)(I) as compared with the NPRM approach because each 
individual device manufacturer seeking initial clearance of its device 
product would be subject to delayed posting of its clinical trial 
registration information, as specified in final Sec.  11.35(b)(2)(i), 
rather than only the first manufacturer to obtain clearance for the 
device type. We note, however, that under final Sec.  11.35(b)(2)(ii), 
a responsible party for an applicable device clinical trial that is 
initiated on or after the effective date of the rule may choose to 
indicate to the Director that it is authorizing the Director to 
publicly post its clinical trial registration information, that would 
otherwise be subject to delayed posting, as specified in Sec.  
11.35(b)(2)(i), prior to the date of FDA approval or clearance of the 
device product.
Final Rule
    Final Sec.  11.44(b)(1) retains the proposed procedure to allow a 
responsible party to delay results information submission with a 
certification indicating that the manufacturer, who is also the sponsor 
of the applicable clinical trial, is or will be seeking approval, 
licensure, or clearance of a new use for the studied drug product 
(including biological product) or device product, but clarifies that 
``drug'' means ``drug product'' and ``device'' means ``device 
product.'' To obtain such a delay, the responsible party would need to 
submit a certification to ClinicalTrials.gov before the standard 
submission deadline specified in Sec.  11.44(a) (i.e., 1 year or less 
after the primary completion date). The responsible party would need to 
certify that (1) an applicable clinical trial involves an FDA-regulated 
drug product (including biological product) or device product that 
previously has been approved, licensed, or cleared by the FDA; (2) for 
which the manufacturer is the sponsor of the applicable clinical trial; 
and, (3) for which an application or premarket notification seeking FDA 
approval, licensure, or clearance of the use being studied in the 
applicable clinical trial, which is not included in the labeling of the 
approved, licensed, or cleared drug product (including a biological 
product) or device product, has been filed or will be filed within 1 
year with FDA. The posted record for the applicable clinical trial 
would indicate that results information submission has been delayed, 
but would not specify the particular reason for the delay. For purposes 
of this part, we interpret ``manufacturer'' to mean a manufacturer who 
is the sponsor of the applicable clinical trial. Note that if the 
manufacturer designates a principal investigator as the responsible 
party as provided for at Sec.  11.4(c)(2), the designated principal 
investigator would be required to submit the certification for delayed 
submission of clinical trial results information.
    The deadline for the delayed submission of results information 
under Sec.  11.44(b) would be 30 calendar days after the earliest of: 
(1) FDA approval, licensure, or clearance of the drug product 
(including a biological product) or device product for the use studied 
in the applicable clinical trial; (2) FDA issuance of a letter ending 
the regulatory review cycle for the application or submission without 
product approval, licensure, or clearance for the use studied in the 
applicable clinical trial (e.g., a complete response letter, a not 
substantially equivalent letter, or a not approvable letter); or, (3) 
withdrawal of the application or premarket notification without 
resubmission within 210 calendar days (i.e., 240 calendar days after 
submission of the withdrawal request). Final Sec.  11.44(b)(2) provides 
a maximum deadline for delayed results information submission of 2 
years after the date of submission of the certification, except to the 
extent that Sec.  11.44(d) applies. Final Sec.  11.44(b)(3) provides an 
additional requirement that any responsible party who is both the 
manufacturer of the drug product (including a biological product) or 
device product studied and the sponsor of an applicable clinical trial, 
and who submits a certification for the delayed submission of results 
under Sec.  11.44(b)(1) for that applicable clinical trial, must also 
submit such a certification for each applicable clinical trial for 
which the manufacturer of the drug product (including a biological 
product) or device product studied is the sponsor and which is required 
to be submitted in an application or premarket notification seeking 
approval, licensure, or clearance of a new use studied in the clinical 
trial.
    We note that if the sponsor of an applicable clinical trial for 
which a ``new use certification'' has been submitted is also the 
manufacturer the drug product (including a biological product) or 
device product studied in the applicable clinical trial, but has 
designated the principal investigator as the responsible party, then 
the manufacturer may need to notify the responsible party of the 
occurrence of a triggering event in order to help ensure that the 
responsible party is aware of the results information submission 
deadline. As discussed in Sec.  11.4(c)(2)(i) (see Section IV.A.2 of 
this preamble), the sponsor may designate a principal investigator as 
the responsible party only if, among other things, the principal 
investigator ``[h]as the ability to meet all of the requirements for 
submitting and updating clinical trial information as specified in this 
part.'' Accordingly, a responsible party who is not the manufacturer of 
the drug product (including a biological product) or device product 
studied will only be able to comply with the results information 
submission requirements subsequent to a certification under sections 
402(j)(3)(E)(iii) and (v) if notified by the manufacturer when one of 
these triggering events occurs. If a manufacturer is not willing or 
able to provide the principal investigator with this information, the 
conditions for designation under Sec.  11.4(c)(2) cannot be met and the 
manufacturer would become the responsible party until the manufacturer 
assigns a new responsible party (see Sec.  11.4(c)(3)).
    We also note that the maximum delay of 2 years specified in Sec.  
11.44(b)(2) would apply to clinical trial results information specified 
in sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or Sec.  
11.48, as applicable. With respect to applicable clinical trials for 
which data collection for any secondary outcome measures and/or 
additional adverse event information extends beyond the primary 
completion date, the deadlines for submission of these clinical trial 
results information are discussed under final Sec.  11.44(d).
    We recognize that in some cases a responsible party may not know 
whether a particular applicable clinical trial will be used to support 
an original NDA, ANDA, BLA, PMA, or HDE for initial approval or 
licensure of a product as opposed to a supplemental NDA, ANDA, BLA, or 
PMA for approval or licensure of a new use. Similarly, a responsible 
party may not know whether a clinical trial will be used to support a 
510(k) seeking ``initial clearance'' of a device product as opposed to 
a 510(k) seeking ``clearance of a new use.'' Responsible parties should 
use their best judgment based on information available at the time of 
certification in order to determine whether certification under Sec.  
11.44(c) (initial approval, licensure, or clearance) or Sec.  11.44(b) 
(approval, licensure, or clearance of a new use) is appropriate.
    As discussed above, the Agency interprets ``initial clearance'' in 
the final rule to apply to the clearance of a manufacturer's original 
510(k) submission for a device product for purposes of this part and 
any

[[Page 65073]]

subsequent clearance of that device product by that manufacturer for a 
different use would be considered ``clearance of a new use.'' By making 
this change, the final rule focuses on the device product, rather than 
the device type, to determine whether an applicable clinical trial of a 
510(k) device will be considered as seeking ``initial clearance'' 
versus ``clearance of a new use.'' This means that under the final 
rule, 510(k) device product trials will be considered not by whether 
the type of device has ever been cleared before, but by whether the 
particular manufacturer's device product has ever been cleared.
    Final Sec.  11.44(c)(1) retains the proposed procedure to allow a 
responsible party to delay results information submission with a 
certification indicating that the sponsor is seeking initial approval, 
licensure, or clearance for the drug product (including a biological 
product) or device product, but clarifies that ``drug'' means ``drug 
product'' and ``device'' means ``device product.'' To obtain such a 
delay, the responsible party will need to submit a certification to 
ClinicalTrials.gov before the standard deadline specified in proposed 
Sec.  11.44(a) (i.e., 1 year or less after the primary completion 
date). The responsible party would need to certify that an applicable 
clinical trial (1) studies a drug product (including a biological 
product) or device product that was not approved, licensed, or cleared 
by FDA for any use before the primary completion date of the clinical 
trial; and, (2) the sponsor of the applicable clinical trial intends to 
continue product development and is seeking or intends to seek FDA 
approval, licensure, or clearance of the drug product (including a 
biological product) or device product under study. Certifications 
cannot be submitted for applicable clinical trials of products that the 
sponsor has no intention of marketing or for which product development 
has been abandoned.
    When a certification for delay is submitted, the posted record for 
the clinical trial will indicate that results information submission 
has been delayed, but will not specify the particular reason for the 
delay. The deadline for delayed submission of results information under 
Sec.  11.44(c) will be 30 calendar days after the earlier of: (1) FDA 
approval, licensure, or clearance of the drug product (including a 
biological product) or device product for the use studied in the 
applicable clinical trial; or, (2) withdrawal of the application or 
premarket notification by the sponsor of the applicable clinical trial 
without resubmission within 210 calendar days (i.e., 240 calendar days 
after submission of the withdrawal request). We believe that this 
latter situation represents a significant enough interruption to 
product development to trigger the submission of results information. 
Final Sec.  11.44(c)(2) retains a maximum deadline for delayed results 
information submission of 2 years after the date of certification 
submission. The Agency expects that a delay of an additional 2 years 
beyond the date the certification is submitted (i.e., up to 3 years 
after the primary completion date of the clinical trial, assuming that 
the certification is submitted 1 year after the primary completion 
date) is sufficient to address any confidentiality concerns that may be 
expressed by responsible parties. This time frame allows a sponsor or 
manufacturer to decide whether to initiate another clinical trial or 
submit a marketing application or premarket notification to the FDA. A 
subsequent pre-market clinical trial of a drug product (including a 
biological product) would likely be an applicable clinical trial that 
would be registered at ClinicalTrials.gov, making public information 
about the sponsor's intention to pursue product development. Thus, the 
total delay in disclosure of results information of up to 3 years after 
the completion date of the trial would provide sponsors with 
significant lead time in product development over potential 
competitors. As discussed further in Section III.B of this preamble, we 
conclude that any competitive disadvantage that may be caused by the 
disclosure of summary results information for clinical trials of 
products that have not been approved, licensed, or cleared for any use 
3 years or more after the primary completion date of the trial is 
limited and, in any case, outweighed by the public health benefits of 
making such information publicly available. Furthermore, as discussed 
above, even if such summary results information were to contain trade 
secret and/or confidential commercial information, the requirement that 
such information be posted on ClinicalTrials.gov is authorized by law 
for the purposes of the U.S. TSA.
    Section 11.44(c) permits delayed submission of results information 
only if the responsible party certifies that the sponsor of the 
applicable clinical trial is continuing to study the product with an 
expectation of seeking future initial approval, licensure, or 
clearance. While we recognize it may be difficult for the sponsor of 
the applicable clinical trial to know early on in the product 
development process whether it will seek future initial approval, 
licensure, or clearance for a product studied in an applicable clinical 
trial, we would, in general, view further development of a product 
through subsequent clinical trials as an indication that the product 
development process is continuing and may lead to seeking initial 
approval, licensure, or clearance. A responsible party who is not the 
sponsor of the applicable clinical trial cannot submit a certification 
to delay results information submission unless the responsible party 
can obtain such information from the sponsor. If a principal 
investigator who has been designated as the responsible party by the 
sponsor cannot obtain such information, then the conditions for 
designation under Sec.  11.4(c)(2) cannot be met and the responsible 
party will not be able to submit a certification for delayed results 
information submission. If a triggering event occurs, the responsible 
party who is not the sponsor (i.e., a responsible party who is a 
principal investigator) will only be able to comply with the results 
information submission requirements under Sec.  11.44(c)(2) if notified 
by the sponsor. In a situation in which the sponsor is not willing or 
able to provide the principal investigator with this information, the 
conditions for designation under Sec.  11.4(c)(2) cannot be met and the 
responsible party will not be able to submit a certification for 
delayed results information submission.
    As discussed with respect to Sec.  11.44(b)(2), the maximum delay 
of 2 years specified in Sec.  11.44(c)(2) would apply to clinical trial 
results information specified in Sec.  11.48. In the event that data 
collection for any secondary outcome measure(s) will not be completed 
as of the primary completion date of the trial or the time frame for 
additional adverse event collection extends beyond the primary 
completion date, clinical trial results information for such secondary 
outcome measure(s) and additional adverse events information shall be 
due by the later of (1) the deadline for delayed submission of results 
with certification established by either final Sec.  11.44(b) or (c) or 
(2) the submitting partial results deadlines established in final Sec.  
11.44(d)(1).
    We also note that after a certification for delayed results 
information submission has been submitted under either Sec.  11.44(b) 
or (c) for an applicable clinical trial, the final rule does not permit 
submission of an additional certification under Sec.  11.44(b) to 
extend the results information submission deadline established by the 
existing certification for the same trial (see

[[Page 65074]]

Sec.  11.44(c)(2)). For example, a responsible party who has submitted 
a certification seeking ``initial approval'' under Sec.  11.44(c) must 
submit results information by the earlier of 30 calendar days of the 
first triggering regulatory event (Sec.  11.44(c)(1)) or 2 years after 
the date of certification (Sec.  11.44(c)(2)), and cannot submit a 
certification seeking ``approval of a new use'' for that same trial, 
even if it studied both uses. Similarly, a responsible party who has 
submitted a certification seeking approval of a ``new use'' under Sec.  
11.44(b) must submit results information by the earlier of 30 calendar 
days of the first event described (Sec.  11.44(b)(1)) or 2 years after 
the date of certification (Sec.  11.44(b)(2)), and cannot submit 
another certification seeking approval of a ``new use'' for the same 
trial. We note that in certain situations, as discussed below in this 
section of the preamble, a responsible party may be able to request an 
extension for good cause under Sec.  11.44(e).
Sec.  11.44(d)--Submitting Partial Results Information
Overview of Proposal
    Proposed Sec.  11.44(d) specified procedures for submitting results 
information when required results information, as specified in proposed 
Sec.  11.48, has not been collected for all secondary outcome measures 
by the date on which results information is due. Since the definition 
of completion date in proposed Sec.  11.10(a) is determined by the 
status of data collection solely for the primary outcome measure(s), an 
applicable clinical trial may therefore still be collecting data for 
the secondary outcome measure(s) after it has reached its completion 
date. In this situation, the responsible party would be required to 
submit results information for the primary outcome measure(s) by the 
required due date specified in proposed Sec.  11.44(a), (b), or (c), as 
applicable. Under proposed Sec.  11.44(d)(1)(i), if a certification to 
delay results information submission had not been submitted under 
proposed Sec.  11.44(b) or (c), results information for each remaining 
secondary outcome measure would be due not later than 1 year after the 
date on which the final subject is examined or receives an intervention 
for the purposes of final collection of data for that secondary outcome 
measure, whether the clinical trial was concluded according to the pre-
specified protocol or was terminated. If the responsible party had 
submitted a certification to delay results information submission, 
results information for the secondary outcome measures could be 
submitted by the later of the date specified in proposed Sec.  
11.44(d)(1)(i) or the date on which the primary outcome measure(s) 
would be required to be submitted under proposed Sec.  11.44(b) or (c) 
as specified in proposed Sec.  11.44(d)(1)(ii). We noted that in either 
situation, if data collection for a secondary outcome measure is 
completed as of the completion date, results information for that 
secondary outcome measure would be required to be submitted on the same 
date as results information for the primary outcome measure(s) (79 FR 
69635).
    We also clarified in proposed Sec.  11.44(d)(2) the process to 
handle results information submission if results information related to 
the primary outcome(s) was submitted prior to the effective date of the 
final rule, but results information for the secondary outcome(s) is 
required to be submitted after the effective date. In such cases, the 
responsible party would be required to provide results information for 
all primary and secondary outcome(s) as specified in Sec.  11.48 of the 
proposed rule. We indicated that, because we believe consistent data 
must be provided for all outcome measures in a single clinical trial, 
the requirements of proposed Sec.  11.48 would apply to all clinical 
trial results information submitted for a trial (79 FR 69636).
    With respect to adverse event information, considered to be part of 
clinical trial results information described under proposed Sec.  
11.48, a responsible party would be required to submit information 
summarizing serious and frequent adverse events recorded to-date each 
time results information for a secondary outcome is submitted until all 
the adverse event information required by this part has been submitted. 
We indicated that we believe such an approach would provide a better 
mechanism for handling submission of adverse event information than 
extending the general results submission deadline for all applicable 
clinical trials up to 18 months after the completion date. It would 
ensure that key results information for primary outcome measures is 
submitted to ClinicalTrials.gov within 1 year of the completion date, 
while allowing subsequent data collection to continue as planned (79 FR 
69636).
Comments and Response
    Commenters addressed Sec.  11.44(d). One commenter suggested that 
the final rule require the submission of data for additional adverse 
event information on an annual basis, rather than during each deadline 
for the submission of partial results information involving secondary 
outcomes for which data collection was incomplete by the completion 
date. The Agency believes that requiring additional adverse event 
information data to be submitted annually rather than by the proposed 
partial results deadlines would potentially be more burdensome for 
responsible parties with few benefits for the public. For example, if a 
study protocol pre-specified time frames for both a secondary outcome 
measure and adverse events collection 5 years after the completion 
date, under the approach proposed in Sec.  11.44(d), the responsible 
party would only need to submit results information once for the 
secondary outcome measure as well as data for additional adverse event 
information not later than 1 year after the date of final data 
collection (i.e., up to 6 years after the completion date). Under the 
approach proposed by the commenter, however, that responsible party 
would also need to submit four datasets of additional adverse event 
information for this trial, once per year after the completion date 
until submission of results for the secondary outcome measure. In 
addition, protocols might not pre-specify that data for adverse event 
information will be analyzed annually, placing additional burden on the 
responsible party to prepare adverse event information for submission 
to the data bank. Thus, the Agency retains the proposed approach with 
respect to submission of adverse event information each time results 
information for a secondary outcome is submitted and extends the 
requirement until all additional adverse event information collected in 
accordance with the time frame for collecting adverse events pre-
specified in the protocol are submitted, even after submission of data 
for all secondary outcomes.
    Reporting of adverse event information is required as part of Sec.  
11.48(a)(4), yet the time frame for reporting of partial adverse event 
information was not specified in proposed Sec.  11.44(d). After 
reviewing proposed Sec.  11.44(d) in response to this comment, we 
identified the need to specify explicitly the deadline for submitting 
partial results information when the pre-specified time frame for 
collecting data for additional adverse event information is not 
completed by the primary completion date. We clarify that the final 
rule addresses this situation by specifying that a responsible party 
submitting partial results information under Sec.  11.44(d) must submit 
additional adverse event

[[Page 65075]]

information by the later of either 1 year after the date of data 
collection for additional adverse event information or the date on 
which results information for the primary outcome measures is due if a 
certification to delay results information submission has been 
submitted under Sec.  11.44(b) or (c). Further, we have added the Study 
Completion Date data element, defined in final Sec.  11.10 and 
discussed in Section IV.A.5 of this preamble, to clinical trial 
registration information specified in Sec.  11.28.
    The Study Completion Date is needed to assist responsible parties 
and viewers of the posted record to help identify when the final rule 
requirements for results information submission and obligations for 
updates and corrections in Sec.  11.64 are fulfilled. Note that even 
though a responsible party for a trial may need to submit partial 
results information several times in order to meet different deadlines 
(i.e., because of different dates for final data collection for primary 
and/or secondary outcome measures or for the pre-specified time frame 
for collecting adverse events), that responsible party's obligation 
under subpart C continues until all required results information is 
submitted not later than 1 year following the Study Completion Date.
    Several additional commenters opposed proposed Sec.  11.44(d)(2), 
which required that results for primary and secondary outcomes 
submitted prior to the effective date of the final rule be resubmitted 
in accordance with final Sec.  11.48 by the deadline for reporting 
partial results information for secondary outcome measures specified in 
proposed Sec.  11.44(d)(1). The Agency agrees with these comments. The 
final rule specifies that if any results information is submitted for a 
clinical trial under sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS 
Act prior to the effective date, those results do not need to be 
resubmitted in accordance with final Sec.  11.48. In addition, partial 
results submitted for that trial after the effective date are also not 
subject to Sec.  11.48 of the final rule, but are subject to the 
results data elements established by sections 402(j)(3)(C) and 
402(j)(3)(I) of the PHS Act, in order to ensure that results data are 
displayed in a consistent format on the posted record.
Final Rule
    The final rule substantively revises the proposed approach to Sec.  
11.44(d) in three ways. First, final Sec.  11.44(d)(1)(ii) adds a 
partial results information submission deadline when adverse event 
information required in Sec.  11.48(a)(4) has not been collected by the 
primary completion date. Under the final rule, data collected for 
additional adverse event information after the primary completion date 
through the pre-specified adverse event collection time frame must be 
submitted by the later of 1 year after the date of data collection for 
additional adverse event information or the date on which results 
information is due if a certification to delay results information 
submission has been submitted under Sec.  11.44(b) or (c). Second, the 
final rule modifies Sec.  11.44(d)(2) to specify that, if any partial 
results information for a clinical trial is submitted prior to the 
effective date of the final rule, any remaining results information 
required to be submitted for that trial after the effective date will 
be subject to the results requirements established by sections 
402(j)(3)(C) and 402(j)(3)(I) of the PHS Act [42 U.S.C. 282(j)(3)(C) 
and 282(j)(3)(I)], not by the final rule (Sec.  11.48). Third, the 
final rule adds Sec.  11.44(d)(3) to require (i) the submission of a 
copy of any revised protocol and/or statistical analysis plan, as 
described in Sec.  11.48(a)(5), if any amendments were made to the 
protocol and/or statistical analysis plan since the previous submission 
of partial results information and (ii) the submission of results 
information about certain agreements between the principal investigator 
and the sponsor as described in Sec.  11.48(a)(6)(ii) if that 
information has changed since the previous submission of partial 
results information.
    Final Sec.  11.44(d)(1) describes the partial results information 
submission deadlines when all clinical trial results information 
required in Sec.  11.48 has not been collected by the primary 
completion date. In such cases, results information for secondary 
outcome measures must be submitted by the later of 1 year after the 
date on which the final subject is examined or receives an intervention 
for the purposes of final collection of data for that secondary outcome 
measure or the date on which results information is due if a 
certification to delay results information submission has been 
submitted under Sec.  11.44(b) or (c). Furthermore, as discussed above, 
data collected for additional adverse event information after the 
primary completion date through the pre-specified adverse event 
collection time frame must be submitted by the later of 1 year after 
the date of data collection for additional adverse event information or 
the date on which results information is due if a certification to 
delay results information submission has been submitted under Sec.  
11.44(b) or (c).
    We clarify that when submitting partial results information 
(pending completion of data collection for secondary outcomes and/or 
the pre-specified time frame for collecting additional adverse event 
information), the responsible party is required to submit the clinical 
trial results information as specified in Sec.  11.48 that is otherwise 
available when submitting partial results information. This means that, 
with respect to adverse event information (considered to be part of 
clinical trial results information described under Sec.  11.48), each 
time results information for a secondary outcome is submitted, a 
responsible party would be required to submit results information 
summarizing serious and frequent adverse events and all-cause mortality 
recorded to that date until all the adverse event information required 
by this part has been submitted. If adverse event information was not 
planned to be collected and reported in the same time frame(s) as 
secondary outcome measures, then it does not need to be reported each 
time information for a secondary outcome measure(s) is submitted. 
However, as specified in Sec.  11.48(a)(4)(i)(A), the Time Frame must 
clearly indicate the time period over which adverse information is 
reported and describe any additional time periods over which adverse 
event information will be submitted, as pre-specified. It is important 
to reiterate that this provision would not impose requirements on the 
design or conduct of the clinical trial or on the data that must be 
collected during the clinical trial.
    Final Sec.  11.44(d)(2) specifies that if any results information 
is submitted for a clinical trial under sections 402(j)(3)(C) and 
402(j)(3)(I) of the PHS Act prior to the effective date, the 
responsible party is not required to resubmit those results in 
accordance with Sec.  11.48. In addition, subsequent partial results 
information as specified in Sec.  11.44(d)(1) submitted for the same 
trial after the effective date is also not required to be submitted in 
accordance with final Sec.  11.48, but in accordance with the results 
data elements established by sections 402(j)(3)(C) and 402(j)(3)(I) of 
the PHS Act. Final Sec.  11.44(d)(3)(i) specifies that the responsible 
party is required to also submit a copy of the revised protocol and/or 
statistical analysis plan when submitting partial results information 
if the protocol and/or statistical analysis plan was amended since the 
previous submission of partial results information for that clinical 
trial. Final Sec.  11.44(d)(3)(ii) specifies that the

[[Page 65076]]

responsible party is required to submit information to reflect any 
changes in the status of certain agreements between the principal 
investigator and the sponsor if that information has changed since the 
previous submission of partial clinical trial results information.
Sec.  11.44(e)--Extensions for Good Cause
Overview of Proposal
    Proposed Sec.  11.44(e) outlined procedures for requesting 
extensions of the deadline for submitting results information for good 
cause. Section 402(j)(3)(E)(vi) of the PHS Act authorizes the Director 
to ``provide an extension of the deadline for submission of clinical 
trial [results] information . . . if the responsible party for the 
trial submits to the Director a written request that demonstrates good 
cause for the extension and provides an estimate of the date on which 
the information will be submitted.'' We interpreted this authority as 
allowing the Director to grant an extension of any results information 
submission deadline that may be in effect for a given applicable 
clinical trial specified in proposed subpart C (e.g., the general 12 
month results information submission deadline); a delayed submission 
deadline established by the submission of an appropriate certification 
under section 402(j)(3)(E)(iii) of the PHS Act; or an extended deadline 
established by a previously granted extension. As for the latter, 
section 402(j)(3)(E)(vi) of the PHS Act explicitly allows the Director 
to ``grant more than one extension for a clinical trial.'' (79 FR 
69636)
    Section 402(j)(3)(E)(vi) of the PHS Act does not define ``good 
cause.'' Similarly, the proposed rule did not contain specific 
proposals for determining which situations would and would not be 
considered good cause for an extension. Instead, we indicated our 
intention to develop guidance (which would be subject to public 
comment) as the Agency gained more experience with extension requests 
and to communicate with the regulated community via other channels, 
including the ClinicalTrials.gov Web site. We intend to issue guidance 
on what might be considered ``good cause'' under particular 
circumstances as soon as practicable. In order to assist responsible 
parties who are considering submitting an extension request, we stated 
our intention to prepare, update periodically, and post on 
ClinicalTrials.gov a non-exhaustive list of reasons that the Agency 
generally will consider to be ``good cause'' and not ``good cause'' for 
granting an extension under section 402(j)(3)(E)(vi) of the PHS Act and 
proposed Sec.  11.44(e). Such a list would contain those reasons that 
we consider would serve as useful examples for responsible parties of 
other applicable clinical trials. We also indicated that all extension 
requests would be considered on a case-by-case basis, and any 
generalizable conclusions that can be drawn from the granting or denial 
of a request may be added to the list of good causes and not-good 
causes for granting extensions (79 FR 69636).
    In general, we indicated that there are likely to be only a few 
situations that would constitute good cause under section 
402(j)(3)(E)(vi) of the PHS Act and proposed Sec.  11.44(e) and listed 
the two situations that we have identified to date that we proposed 
would constitute good cause:
    (1) The need to preserve the scientific integrity of an applicable 
clinical trial for which data collection is ongoing, including 
situations in which the submission of results information for the 
primary outcome(s) of an applicable clinical trial would impair or 
otherwise bias the ongoing collection, analysis, and/or interpretation 
of data for secondary outcome(s). We indicated our belief that an 
extension should be granted only in those situations in which the 
following could be demonstrated: Data collection for the secondary 
outcome(s) of interest extends more than 1 year beyond the completion 
date, the secondary outcome(s) is pre-specified in the protocol or SAP, 
and the planned analysis of the outcome measure is also described in 
the protocol or SAP. We noted that the responsible party could provide 
this information either by voluntarily submitting copies of the 
protocol or statistical analysis plan with the extension request or 
describing them in the extension request itself.
    (2) Emergencies that would prevent timely submission of clinical 
trial results information, including situations in which one or more 
data collection sites were affected by natural disasters or other 
catastrophes outside the responsible party's or sponsor's control. In 
such cases, we indicated that we would generally expect to grant the 
responsible party an initial extension of up to 6 months, after which 
time additional extensions could be granted, as necessary. We generally 
would not consider events that might reasonably have been avoided or 
anticipated through standard contingency planning (e.g., transition 
planning for key staff members who leave an organization) to constitute 
good cause for an extension under section 402(j)(3)(E)(vi) of the PHS 
Act or proposed Sec.  11.44(e) (79 FR 69637).
    To clarify what we believed would not ordinarily constitute good 
cause, we discussed two scenarios in the proposed rule's preamble. 
First we pointed out that a request containing only a general statement 
without any specific reason for a delay in data analysis (e.g., ``data 
could not be analyzed fully within 12 months'') would not be a good 
cause. Second, we indicated that ``awaiting journal publication'' would 
not constitute a good cause. We noted that the ICMJE has stated that 
results information submission to ClinicalTrials.gov in compliance with 
section 402(j) of the PHS Act will not be considered ``prior 
publication'' and will not preclude future publication [Ref. 2, 98]. We 
invited public comment on these specific situations and on more general 
criteria that could be used to determine what constitutes good cause 
for an extension (79 FR 69637).
    Proposed Sec.  11.44(e)(1) specified that a responsible party may 
submit a request for an extension to ClinicalTrials.gov at any time 
before any results information submission deadline established in 
proposed Sec.  11.44(a), (b), or (c), if the relevant certification has 
been submitted; or Sec.  11.44(f), for a pediatric postmarket 
surveillance of a device that is not a clinical trial. Consistent with 
section 402(j)(3)(E)(vi) of the PHS Act, our proposal would require an 
extension request to include a complete description of the reason(s) 
why results information cannot be provided according to the applicable 
deadline and an estimated date on which results information will be 
submitted. The submitted extension request would be reviewed by an 
Agency official designated by the Director (79 FR 69637).
    Proposed Sec.  11.44(e)(2) indicated that the Agency would notify 
the responsible party electronically whether the request has been 
granted and, if granted, the Agency-specified extended deadline by 
which results information must be submitted. If the extension request 
is denied, the responsible party may either submit an appeal to the 
Director or would submit results information by the later of the 
original deadline or 15 calendar days after the date the Agency sends 
the electronic notice of the denial to the responsible party (79 FR 
69637).
    Proposed Sec.  11.44(e)(3) specified that a responsible party may 
appeal a denied extension request or the Agency-specified extended 
deadline by which results information must be submitted not later than 
15 calendar days after the date the Agency sends the electronic notice 
of the denial. Responsible parties are required to submit a description 
of the reasons for the appeal with

[[Page 65077]]

sufficient detail to allow for evaluation. If the appeal is granted, 
the responsible party must submit results information by the revised 
deadline set by the Director in the electronic notification. If the 
appeal is denied, the responsible party must submit results information 
by the later of the following: The original deadline, the Agency-
specified extended deadline provided in the electronic notification, or 
15 calendar days after the date the Agency sends the electronic notice 
of denial of the appeal to the responsible party (79 FR 69637).
    We also noted that extensions would apply only in the context of 
applicable clinical trials subject to the results information 
submission requirements of section 402(j)(3) of the PHS Act because the 
extension provision specifically refers to results information 
submission under 402(j)(3)(E)(i) of the PHS Act. Accordingly, 
extensions do not apply to clinical trial results information that is 
submitted under section 402(j)(4)(A) of the PHS Act (i.e., voluntarily 
submitted trials (see final rule Sec.  11.60(a)(1)) and triggered 
trials (see final rule Sec.  11.60(a)(2)(ii))) (79 FR 69636).
Posting of Information About Certifications for Delayed Submission and 
About Extensions for Good Cause
    In the proposed rule, we suggested that there would be value in 
posting information on the ClinicalTrials.gov Web site about the 
specific mechanism that had been used to delay the submission of 
clinical trial results information for a particular applicable clinical 
trial (i.e., an extension request had been granted under proposed Sec.  
11.44(e) or the responsible party had submitted a certification for 
delayed submission, specifying either proposed Sec.  11.44(b) or (c)). 
Doing so would provide a way to track the progress of clinical trials 
by informing users why clinical trial results information is not yet 
publicly available. Without such an indication, users who view a posted 
clinical trial record that contains no results information more than 1 
year after the primary completion date might be led to believe, 
incorrectly, that the responsible party has not complied with the 
results information submission requirements of this proposed rule or 
that the Agency has failed to post such information. However, we 
recognized that information about the specific mechanism used to delay 
results information submission might in some circumstances be 
considered confidential (e.g., the fact that the manufacturer had 
submitted or was planning to submit within 1 year a marketing 
application or premarket notification to FDA for a new use of a drug or 
device that was studied in the applicable clinical trial prior to any 
public statement by the or manufacturer about its plans).
    In order to balance the competing interests, we proposed posting 
only minimal information about delayed results information submissions 
in these circumstances. That is, whether a responsible party delayed 
results information submission via certification or is granted an 
extension of the deadline, we would indicate in the posted record only 
that results information submission has been delayed, but not which 
mechanism had been used. As described previously, we proposed posting 
and updating periodically on the ClinicalTrials.gov Web site a 
generalized list of reasons for which extensions have and have not been 
granted (without information that might allow a user to identify a 
specific applicable clinical trial) to provide responsible parties with 
insight into the types of reasons that have and have not been 
considered to constitute good cause for an extension (79 FR 69638).
    We invited public comments on our overall proposed approach and on 
the advantages and disadvantages of providing more specific information 
about extension requests (e.g., whether submission was delayed via 
extension or certification), including alternative approaches that we 
could take that would provide more information to the public about the 
reasons for delayed submissions of clinical trial results information. 
We also invited public comment on whether extension requests could be 
submitted without containing any information that would be considered 
confidential (79 FR 69638).
Comments and Response
    Commenters addressed the proposed approach for implementing 
extensions of the results information submission deadline in Sec.  
11.44(e). One commenter suggested that 15 calendar days do not provide 
sufficient time for a responsible party either to submit a written 
letter to appeal a denial for an extension request or to submit results 
information following notification that an appeal has been denied as 
proposed in Sec.  11.44(e)(3)(i) and (vi), respectively. We note that 
several other commenters requested more broadly that the 15 calendar 
day deadlines proposed in the proposed rule be changed to 30 calendar 
day deadlines in the final rule (see discussion of Sec.  11.64 in 
Section IV.D.3 of this preamble). The Agency generally agrees with the 
commenters and has changed, where possible, the 15 calendar day 
deadlines in the proposed rule to 30 calendar day deadlines in the 
final rule (see Section IV.D.3 of this preamble).
    One commenter requested clarification that extension requests are 
not subject to any limitations in time, in contrast to the 2-year 
limitation for delayed submission of results with certification as 
specified in proposed Sec.  11.44(b)(2) and (c)(2). We clarify that 
requests for extensions of the results information submission deadline 
are not subject to a time limit and may include estimated submission 
dates over 2 years after the date of the request. However, all 
submitted requests must provide a sufficient description of the 
reason(s) for proposing the particular estimated submission date. We 
also note that, because the statute and final rule permit the Director 
to grant more than one extension, a final extended results information 
submission deadline may exceed more than 2 years, even if the initial 
extension did not.
    Several commenters suggested additional good cause reasons, such as 
for trials of device products that have received either a non-
substantially equivalent or non-approval letter from the FDA, for 
preparation and analysis of data from large and complex trials, and for 
pending publication of trial results. One commenter requested 
clarification regarding the circumstances under which a sponsor of an 
applicable clinical trial of an unapproved, unlicensed, or uncleared 
product could request an extension. Another commenter proposed limiting 
the situations that would be considered ``good cause'' to national 
emergencies or catastrophic events. As stated in the proposed rule and 
this preamble, the Agency plans to prepare and periodically update a 
public, non-exhaustive list of reasons that it considers to be ``good 
cause'' and ``not good cause.'' At present, we have identified only two 
general situations that we believe would constitute good cause: (1) The 
need to preserve the scientific integrity of a trial; and, (2) 
emergencies outside the control of a responsible party that would 
prevent timely submission, such as natural disasters or other 
catastrophes. In addition, we reiterate that we generally believe that 
pending publication and delays in data analysis for unspecified causes 
would not be considered good cause. We also note that requests for good 
cause may be submitted to extend any type of results information 
submission deadline, including the standard submission deadlines in 
Sec.  11.44(a) (i.e., 1 year after the primary completion date).
    One commenter proposed that responsible parties submitting requests

[[Page 65078]]

for extensions not be required to include confidential commercial or 
proprietary information. This commenter also requested that 
ClinicalTrials.gov provide a way for the public to distinguish between 
applicable clinical trials with missing results submissions because of 
missed regulatory deadlines (i.e., late submissions) and those for 
which an extension has been granted, as required in Sec.  11.44(e). 
Although we do not believe that confidential commercial or proprietary 
information will generally need to be submitted, the responsible party 
must provide in a submitted request for an extension ``sufficient 
detail to allow for the evaluation of the request'' as stated in final 
Sec.  11.44(e)(1)(ii)(A). The Agency will not post detailed information 
about the request publicly and retains its plan to post minimal 
information on posted records to notify users when results information 
submission has been delayed without specifying whether a certification 
or extension mechanism was used. The Agency believes this approach will 
provide sufficient and appropriate information to the public to explain 
the reason for delay (see discussion above on Sec.  11.44(b), (c), and 
(e)).
    One commenter suggested that the final rule provide members of the 
public, including third-party researchers, the ability to appeal any 
reasons given for delaying the submission of results and that any such 
appeals be made publicly available with contact information. The Agency 
does not agree with this approach. We do plan, as proposed, to post 
publicly a list of general reasons provided in requests for extensions 
which the Agency considers to be ``good cause'' and ``not good cause.''
    Regarding the proposal to post on ClinicalTrials.gov a list of 
general reasons the Agency will consider to be ``good cause'' and ``not 
good cause'' for granting extensions, one commenter requested that the 
actual reasons cited in extension requests submitted by responsible 
parties not be posted while two other commenters suggested that all 
submitted justifications and estimated submission dates be posted 
publicly for greater transparency. Another commenter proposed requiring 
the posting of submitted information for extension requests no later 
than 30 calendar days after receipt. As stated in the proposed rule and 
in this preamble above, the generalized list of reasons for which 
extensions have and have not been granted that is to be posted and 
updated periodically on ClinicalTrials.gov will not include any 
information that might allow a user to identify a specific applicable 
clinical trial. The intent is to provide responsible parties and 
members of the public with insight into the types of reasons that have 
and have not been considered to constitute good cause for an extension. 
We believe that this approach provides sufficient information about the 
process for requesting extensions for good cause.
Final Rule
    Final Sec.  11.44(e) largely retains the proposal outlined in the 
NPRM with the following exceptions. First, the final rule replaces the 
15 calendar day deadlines (e.g., for submission of results information 
or an appeal after a request is denied) as proposed in the proposed 
rule with 30 calendar days in the final rule in response to public 
comments. Second, the final rule clarifies that some applicable 
clinical trials may be subject to section 402(j)(3)(E)(vi) of the 
Public Health Service Act. Third, the final rule adds Sec.  11.44(e) to 
the list of provisions in Sec.  11.44(e)(1)(i) and Sec.  
11.44(e)(2)(ii) regarding the submission deadlines that would otherwise 
apply. Fourth, formatting changes are made for consistency and clarity. 
Final Sec.  11.44(e)(1) stipulates that extension requests must be 
submitted to the Agency via direct electronic submission to 
ClinicalTrials.gov prior to the date on which results information would 
otherwise be due in accordance with the results information submission 
deadlines, including one for a previously-granted extension request. 
Responsible parties are required to submit a description of the reasons 
that they believe constitute good cause to justify an extension and an 
estimated extended results information submission date with sufficient 
detail to allow for evaluation of both requested components.
    Under Sec.  11.44(e)(2), a response to the extension request will 
be communicated electronically via ClinicalTrials.gov to the 
responsible party, providing notice as to whether or not the requested 
extension has been granted. If a request is granted because it 
demonstrates good cause, a revised deadline for results information 
submission will be communicated in the notice. If a request is denied, 
the deadline for submitting results is the later of the deadline (e.g., 
1 year after the primary completion date or the delayed submission 
deadline if a certification has been filed under subparts (b) or (c)) 
or 30 calendar days after the date the electronic notice of the denial 
of the request is sent to the responsible party.
    Section 11.44(e)(3) specifies that a responsible party who appeals 
a denied extension request must submit the appeal to the Director in 
the format specified at https://prsinfo.clinicaltrials.gov/ (or 
successor site) not later than 30 calendar days after the date on which 
electronic notification of the granting or denial of the request was 
sent to the responsible party. The appeal must explain why, in the view 
of the responsible party, the initial decision to deny an extension 
request or to grant an extension request with a shorter deadline than 
requested by the responsible party should be overturned or revised 
(e.g., by providing further elaboration of the grounds for the request 
or by highlighting factors that justify an extension). Generally, new 
information should not be submitted upon appeal. The submitted appeal 
will be considered by the Director or his delegate. If an appeal is 
granted, a revised deadline for results information submission will be 
set by the Director and provided to the responsible party in an 
electronic notification. If the appeal is denied, the deadline for 
submitting results information will be the later of the original 
submission deadline or 30 calendar days after the electronic 
notification of the denial of the appeal is sent to the responsible 
party. If the appeal of an extension request that was granted with a 
shorter deadline than was originally requested is denied, the deadline 
for submitting results information is the later of the deadline 
specified in the notification granting the extension request or 30 
calendar days after the electronic notification of the denial of the 
appeal is sent to the responsible party.
    We note that if the estimated primary completion date is earlier 
than the actual (or current estimated) primary completion date, a 
responsible party must update the estimated primary completion date in 
the clinical trial record to reflect the actual (or revised estimated) 
primary completion date within 30 calendar days, as required by Sec.  
11.64(a)(1)(ii)(I), but should not request an extension based on the 
outdated primary completion date. The fact that the responsible party 
has updated the primary completion date will be reflected in 
ClinicalTrials.gov, consistent with the handling of all updates under 
Sec.  11.64.
    Posted records of trials that have been granted certification for 
delayed submission or extension will indicate that results information 
submission has been delayed by displaying minimal information. This 
will provide significant information for users to know whether a trial 
has met the requirements for results information

[[Page 65079]]

submission under the final rule. As soon as practicable, we will post 
on the ClinicalTrials.gov Web site, and periodically update, a list of 
reasons for which extensions have and have not been granted to provide 
responsible parties and the public with insight into the types of 
reasons that have and have not been considered to constitute good cause 
for an extension. We note that entries on this list will not contain 
any information that might allow a user to identify a specific 
applicable clinical trial.
Sec.  11.44(f)--Pediatric Postmarket Surveillance of a Device That Is 
Not a Clinical Trial
Overview of Proposal
    We proposed in Sec.  11.44(f) that results information for a 
pediatric postmarket surveillance of a device that is not a clinical 
trial be submitted not later than 30 calendar days after the date that 
the final report is submitted to FDA. We believe that 30 calendar days 
provide sufficient time to allow the responsible party to format and 
submit the information as required by this part.
    We noted in the NPRM that we recognize that the proposed deadlines 
for submitting clinical trial results information under proposed Sec.  
11.44(a)-(d) are not well adapted to a pediatric postmarket 
surveillance of a device that is not a clinical trial. Such 
surveillances generally do not have a completion date that can be 
easily measured by the date that the final subject was examined or 
received an intervention for the purposes of final collection of data 
for the primary outcome. However, these surveillances will have a date 
on which a final report must be sent to the FDA, as specified in the 
approved postmarket surveillance plan (79 FR 69638).
Comments and Response
    One commenter addressed proposed Sec.  11.44(f) and suggested that 
the timeline submission requirement should apply as to Sec.  11.44(a)-
(d). We note that any pediatric postmarket surveillance of a device 
that is also a clinical trial would be subject to the results 
information submission deadlines that apply to clinical trials (e.g., 
standard submission deadline in proposed Sec.  11.44(a)). For a 
pediatric postmarket surveillance of a device that is not a clinical 
trial the proposed deadlines Sec.  11.44(a)-(d) are not well adapted. 
Therefore, the final rule retains the deadline specified in proposed 
Sec.  11.44(f).
Final Rule
    Aside from clarifying that ``device'' means ``device product'' and 
that some surveillances that are not clinical trials may be subject to 
section 402(j)(C)(3) of the PHS Act, no changes were made in Sec.  
11.44(f) of the final rule, which requires the submission of results 
information not later than 30 calendar days after the date on which the 
final report of the approved pediatric postmarket surveillance of a 
device product as specified in 21 CFR 822.38 is submitted to FDA (i.e., 
the primary completion date as defined in Sec.  11.10(a)).
4. Sec.  11.48--What constitutes clinical trial results information?
Overview of Proposal
    Section 11.48(a) of the NPRM proposed the general requirements for 
clinical trial results information that would apply to an applicable 
clinical trial other than a pediatric postmarket surveillance of a 
device that is not a clinical trial. Proposed Sec.  11.48(b) described 
the requirements for a pediatric postmarket surveillance of a device 
that is not a clinical trial. In specifying the results information 
that must be submitted for a clinical trial, proposed Sec.  11.48(a) 
separated the data elements into the following general categories of 
information: (1) Participant flow, (2) demographic and baseline 
characteristics, (3) outcomes and statistical analyses, (4) adverse 
event information, (5) administrative information, and (6) additional 
results information for applicable device clinical trials of unapproved 
or uncleared devices. The proposal also indicated that whenever 
possible ClinicalTrials.gov will use information submitted during 
registration to pre-populate the column and row names of the tables of 
information that are required as part of results submission. We noted 
that doing so reduces the data entry burden on responsible parties and 
minimizes the possibility of clerical errors. However, in all cases, 
the responsible party is required to revise the information, as needed, 
so that the results information appropriately and accurately reflects 
the way that data were collected and analyzed in the clinical trial. 
Each of the categories of results information that are required to be 
submitted are addressed, in order, below (79 FR 69638).
Comments and Response
    Numerous commenters addressed the requirements for clinical trial 
results information that would apply to an applicable clinical trial. 
The specific comments are described in the sections of Sec.  11.48 to 
which they apply. We received one general comment in support of the 
proposed requirements for results information. We also received one 
general comment requesting that the Agency minimize the number of 
fields and amount of data required for clinical trial results 
information in order to provide responsible parties with more 
flexibility in reporting the results of different types of trials. 
Based on more than 7 years of experience operating the results 
database, we recognize the need for flexibility and generally agree 
with the commenter. The final rule represents our attempt to balance 
the statutory requirements with the minimum information needed to 
understand study results in a way that is consistent across clinical 
trials and with existing reporting standards, such as the CONSORT 
statement [Ref. 93] which are used to guide the publication of trial 
results in peer-reviewed literature.
Sec.  11.48(a)(1)--Participant Flow
Overview of Proposal
    Proposed Sec.  11.48(a)(1) addressed the statutory requirement for 
the submission of specified participant flow information as part of 
clinical trial results information. Section 402(j)(3)(C)(i) of the PHS 
Act specifies that a responsible party must submit ``[a] table of . . . 
data collected overall and for each arm of the clinical trial to 
describe the patients who participated in the clinical trial, including 
the number of patients who dropped out of the clinical trial and the 
number of patients excluded from the analysis, if any.'' Consistent 
with this section of the PHS Act and pursuant to our authority under 
section 402(j)(3)(D)(iii)(IV) of the PHS Act, we proposed in Sec.  
11.48(a)(1) to require the submission of the following participant flow 
information: (1) Participant Flow Arm Information, (2) Pre-assignment 
Information, and (3) Participant Data. This information permits the 
construction of a table that shows the number of participants starting 
the clinical trial and the flow through completion of the trial. In our 
proposed approach, information about the number of participants 
excluded from the analysis would not be contained in the participant 
flow but would be submitted as part of the information about outcome 
measures specified and described in proposed Sec.  11.48(a)(3). We also 
described how we intend to continue to provide responsible parties with 
a means of providing, on an optional basis, additional details about 
the participant flow in a manner consistent with CONSORT guidelines 
[Ref. 93] (79 FR 69639). We invited public comments on

[[Page 65080]]

the value of providing additional information describing study periods 
(e.g., wash-out, consecutive cycles of the intervention), particular 
milestones, and reasons for non-completion on ClinicalTrials.gov as 
well as comments on approaches for collecting this information.
Comments and Response
    Commenters addressed specific aspects of the proposed requirements 
for participant flow information in Sec.  11.48(a)(1). One commenter 
suggested requiring the submission of information on the number of 
participants that are enrolled and who complete the trial at the time 
that the trial ends (instead of at the time of clinical trial results 
submission). We agree with the commenter that the actual number of 
participants enrolled in the trial must be provided in a timely manner 
as specified in Sec. Sec.  11.28 and 11.64. However, the number of 
participants completing the trial is considered clinical trial results 
information that must be submitted in accordance with section 
402(j)(3)(C)(i) of the PHS Act and Sec.  11.24. Another commenter 
suggested requiring the submission of information on the number of 
participants not completing the trial by sex and gender and in a 
standardized format, citing associated scientific principles. While we 
agree with the commenter on the potential value of such information, 
requirements regarding which data must be collected during a clinical 
trial are outside the scope of this rule. We therefore are not 
proposing to make submitting the requested participant flow information 
a requirement, but we do intend to evaluate ways to accommodate the 
submission of any such available information. We did not receive any 
comments on the value of providing additional information for 
describing study periods, milestones, and reasons for non-completion on 
ClinicalTrials.gov or on approaches for collecting this information. 
However, one commenter provided general support for providing Pre-
assignment Information.
Final Rule
    Taking into consideration the comments, as well as the statutory 
requirements for clinical trial results information, we are generally 
maintaining the approach for participant flow information described in 
the NPRM. However, we are providing clarification on certain aspects of 
the requirements, based on our operational experience and routine 
queries received from users. First, we provide additional elaboration 
to clarify the information that is required to be provided as part of 
the brief description of each arm. Second, we clarify the definition of 
Pre-assignment Information in Sec.  11.48(a)(1)(ii). The proposed 
definition indicated that Pre-assignment Information consists of ``[a] 
description of significant events affecting the number of human 
subjects enrolled in the clinical trial but not assigned to an arm, if 
any.'' The phrase ``affecting the number of'' may incorrectly imply 
that the actual number of human subjects enrolled changes based on a 
pre-assignment event. Instead, the intent is to describe events that 
occur between enrollment and assignment to an arm that are planned as 
part of the study design and other events that lead to differences in 
the number of human subjects enrolled and the number of human subjects 
assigned to an arm. Third, we explain the terms ``started'' and 
``completed,'' which are used to describe Participant Data in Sec.  
11.48(a)(1)(iii). Fourth, we address requirements for clinical trials 
that assign participants to arms based on units other than participants 
(e.g., lesions, eyes, implants). While the NPRM included a proposal for 
how such information is specified when reporting an outcome measure in 
Sec.  11.48(a)(3)(ii), Analysis Population Information, it did not 
address similar information in Sec.  11.48(a)(1), Participant flow and 
Sec.  11.48(a)(2) Demographic and baseline characteristics.
    Final Sec.  11.48(a)(1) requires the submission of the following 
participant flow information: (1) Participant Flow Arm Information, 
consisting of ``[a] brief description of each arm used for describing 
the flow of human subjects through the clinical trial, including a 
descriptive title used to identify each arm''; (2) Pre-assignment 
Information, consisting of ``[a] description of significant events in 
the clinical trial that occur after enrollment and prior to assignment 
of human subjects to an arm, if any''; and (3) Participant Data, which 
is ``[t]he number of human subjects that started and completed the 
clinical trial, by arm. If assignment is based on a unit other than 
participants, also include a description of the unit of assignment and 
the number of units that started and completed the clinical trial, by 
arm.'' This information permits the construction of a table that shows 
the flow of participants through the clinical trial, with each 
participant represented in only one arm. Information about the number 
of participants excluded from the analysis is not contained in the 
participant flow; it is submitted as part of the information about 
outcome measures (Sec.  11.48(a)(3), Outcomes and statistical 
analyses). ClinicalTrials.gov will use the Arm Information, 
Intervention Name, and Intervention Description data elements 
(submitted as part of clinical trial registration information) to 
provide the responsible party with an option for pre-populating table 
column names and descriptions for Participant Flow Arm Information. The 
responsible party will review and edit the information as needed to 
ensure that it appropriately and accurately reflects the participant 
flow for the clinical trial, or the responsible party may instead 
define new arms to reflect how participants were assigned to arms. In 
general, the Participant Flow Arm Information must include all arms to 
which participants were assignedand must contain sufficient details to 
understand the arms to which participants were assigned and the 
intervention strategy used in each arm. The amount and level of detail 
are similar to what is described in Sec.  11.10(b) for the arm and 
intervention data elements that are used to pre-populate Participant 
Flow Arm Information.
    Pre-assignment Information is collected in a free text field to 
allow the responsible party to explain significant events that occur 
between the enrollment of human subjects and their assignment to an 
arm. These events may be planned as part of the study design or 
unplanned. An example of a significant event that is planned as part of 
the study design is a run-in period during which all participants 
receive an intervention, which may result in identifying participants 
who are not eligible to continue in the study or may otherwise 
influence assignment to an arm. An example of an unplanned event is the 
voluntary withdrawal of a participant prior to assignment to an arm. 
Either event may result in the number of human subjects starting the 
trial (e.g., assigned to an arm) being fewer than the total number of 
human subjects enrolled. Pre-assignment Information is where the 
responsible party describes any such differences. As part of 
Participant Data, the responsible party provides the number of human 
subjects that started and completed each arm. The number of 
participants that ``started'' the clinical trial means the number of 
participants assigned to the arm (regardless of whether these 
participants received the assigned intervention). The meaning of the 
number of participants that ``completed'' the arm may vary, based on 
the specific context of the clinical trial. However, if there is more 
than one

[[Page 65081]]

period (e.g., a discrete stage) in the clinical trial, the meaning of 
the number of participants starting and completing is in the context of 
initial assignment and the specific period. Specifically, ``started'' 
in the first period (and the overall clinical trial) means the number 
of participants assigned to each arm, and ``started'' in subsequent 
periods (if any) means the number of participants initiating each 
period of the clinical trial in each arm. In order to retain the 
flexibility desired by responsible parties in reporting results, we do 
not intend to define this further. However, we will implement an 
optional data element to allow responsible parties to explain the 
meaning of ``started'' and/or ``completed'' in the context of their 
specific clinical trial. If the assignment of participants to an arm is 
based on a unit other than human subjects (e.g., lesions, eyes, 
implants), the responsible party must also provide, in addition to 
participants, the type and number of units that started and completed 
the clinical trial, by arm. Based on our experience with submitted 
results information and routine queries from users of 
ClinicalTrials.gov, this information is necessary for accurately 
representing the assignment strategy and for interpreting similar 
information on the units analyzed in Analysis Population Information 
for Demographic and baseline characteristics in Sec.  11.48(a)(2)(ii) 
and Outcomes and statistical analyses in Sec.  11.48(a)(3)(ii). 
Therefore, consistent with section 402(j)(3)(C)(i) of the PHS Act and 
pursuant to our authority under section 402(j)(3)(D)(iii)(IV) of the 
PHS Act, final Sec.  11.48(a)(1) requires the submission of the 
following participant flow information: (1) Participant Flow Arm 
Information, (2) Pre-assignment Information, and (3) Participant Data.
    Although we did not receive any comments in response to our request 
for comment on the topic of describing study periods, milestones, and 
reasons for non-completion on ClinicalTrials.gov, we intend to continue 
to provide responsible parties with a means of submitting, on an 
optional basis, additional details about the participant flow in a 
manner consistent with CONSORT guidelines [Ref. 93]. This information 
consists of details about the flow of participants through different 
periods or milestones defined for the clinical trial and the reason(s) 
why participants did not complete the clinical trial or reach a 
particular milestone. Clinical trials often proceed through multiple 
periods (e.g., wash-out, consecutive cycles of the intervention), and 
having information about the participant flow in each period and the 
reasons why participants did not complete the clinical trial or reach a 
particular milestone, if applicable, improves users' understanding of 
the clinical trial results data. Clinical trials vary considerably in 
their design, and some may not include specific periods or milestones. 
However, when a study does include such aspects, we will continue to 
encourage responsible parties to provide clinical trial results 
information in a manner that most clearly describes the study design 
and what happened to participants as they progressed through the study. 
We intend to provide additional guidance, including case examples, to 
help responsible parties understand how to optimally present various 
study designs.
Sec.  11.48(a)(2)--Demographic and Baseline Characteristics
Overview of Proposal
    Proposed Sec.  11.48(a)(2) addressed the statutory requirement for 
the submission of demographic and baseline characteristics as part of 
clinical trial results information. Section 402(j)(3)(C)(i) of the PHS 
Act specifies that a responsible party must submit ``[a] table of the 
demographic and baseline data collected overall and for each arm of the 
clinical trial to describe the patients who participated in the 
clinical trial . . .'' (79 FR 69639). Consistent with this section of 
the PHS Act, the Agency proposed in Sec.  11.48(a)(2) to require 
``[i]nformation for completing a table of demographic and baseline 
measures and data collected by arm or comparison group and for the 
entire population of human subjects who participated in the clinical 
trial.'' The information must include the following: (i) Baseline 
Characteristics Arm/Group Information; (ii) Overall Number of Baseline 
Participants; (iii) Baseline Measure Information, to include the Name 
and Description of the measure, Measure Type, Measure of Dispersion, 
and Unit of measure; and (iv) Baseline Measure Data. We further 
proposed that Baseline Measure Information must include ``[a] 
description of each baseline or demographic characteristic measured in 
the clinical trial, including age, gender, and any other measure(s) 
that were assessed at baseline and used in the analysis of outcome 
measures in accordance with Sec.  11.48(a)(3).'' We invited public 
comment on the sufficiency of this proposed approach for submitting 
baseline characteristics as well as whether we should require the 
submission of additional demographic or baseline characteristics 
collected during the clinical trial that are common across many trials, 
such as country-of-origin or country-of-residence. We also invited 
comment on whether the list of proposed choices for measures of central 
tendency and of dispersion was adequate to provide an accurate 
description of the measures used in any clinical trial (79 FR 69640).
Comments and Response
    Commenters addressed specific aspects of the proposed requirements 
for demographic and baseline characteristics in Sec.  11.48(a)(2). One 
commenter provided general support for the proposed baseline 
characteristics requirements. Some commenters supported adding a 
requirement for reporting race and ethnicity information, with several 
commenters citing similar FDA and NIH requirements. One commenter 
stated that having race and ethnicity information was important for 
different groups ``seeking to understand how representative minority 
populations are in [applicable clinical trials] . . .'' Some of these 
commenters also recommended including an option to specify that race 
and ethnicity information was not collected. While we did not propose 
to require race and ethnicity information because of a concerns that 
this information may not be routinely collected during all clinical 
trials, we agree that providing the responsible party with a mechanism 
to indicate that race and/or ethnicity information was not collected 
would address this concern. Therefore, the final rule adds a 
requirement for the reporting of race and ethnicity information, or an 
indication that such information was not collected during the trial, as 
a component of Baseline Measure Information. The final rule follows the 
same approach to indicating that information was not collected during 
the trial as for other baseline measures required by ClinicalTrials.gov 
(e.g., age, sex/gender). One commenter indicated that country of origin 
information ``could be an important data point'' to require but did not 
provide further elaboration on why it is important. Although it may be 
important for some clinical trials, in considering other commenters 
concerns about additional requirements (noted below) as well as the 
addition of a requirement to submit race and ethnicity informatoin, we 
are not persuaded that the benefits of requiring country-of-origin 
information would outweigh the burdens. However, we will, continue to 
make available ``region of enrollment'' as part of the limited list of 
options for Baseline

[[Page 65082]]

Measure Information to facilitate the optional reporting of such 
information if it was assessed at baseline. One commenter recommended 
that the term ``gender'' be replaced by ``sex.'' We partially addressed 
this issue in Sec.  11.10, and to address the same issue in the context 
of clinical trial results information, we are revising the term 
``gender'' to ``sex/gender'' to indicate that the submission of 
Baseline Measure Information on sex and/or gender would meet the 
requirement. Other commenters opposed any additional requirements for 
demographic information, citing concerns that expanded reporting 
requirements would lead to future requirements to collect such data 
during a trial. As explained in proposed Sec.  11.48(a)(2)(iii), only 
summary data for measures assessed at baseline are required to be 
reported, and the final rule does not impose requirements on the design 
or conduct of clinical trials or on the data that must be collected 
during clinical trials.
    After consideration of the comments, we believe it is appropriate 
in the final rule to limit the requirement to report any measure(s) 
assessed at baseline and used in the analysis of outcome measure(s) in 
Sec.  11.48(a)(2)(iii) to those baseline measure(s) used in the 
analysis of primary outcome measure(s). One commenter suggested that 
baseline measures related to outcome measures be reported as part of 
outcome measure information in proposed Sec.  11.48(a)(3). We 
acknowledge that, in limited circumstances, the arms or groups used for 
demographics and baseline characteristics may differ from those used in 
the primary outcome measure and agree with the commenter that providing 
such Baseline Measure Information as part of Outcome Measure 
Information would be appropriate in such circumstances. When relevant, 
the final rule also permits the reporting of baseline measure 
information as a component of both demographic and baseline 
characteristics in Sec.  11.48(a)(2) as well as outcomes and 
statistical analyses in Sec.  11.48(a)(3). In addition, we will 
continue to evaluate methods for displaying results information on 
ClinicalTrials.gov to improve linking these two relevant sections when 
the baseline and outcome measures are related.
    Based on our experience with submitted results information and 
routine queries from users, we note that some clinical trials include 
baseline measures and outcome measures that are based on units of 
analysis other than participants. While the NPRM did not address how 
such information could be specified in proposed Sec.  11.48(a)(2), 
Demographic and baseline characteristics, it did include a proposal for 
reporting such information as an outcome measure in Sec.  
11.48(a)(3)(ii) Analysis Population Information. To address this 
inadvertent omission and facilitate the accurate submission of Baseline 
Measure Information and Baseline Measure Data in a manner that is 
consistent with the design, conduct and analysis of the clinical trial, 
the final rule adds similar data elements to Sec.  11.48(a)(2) for the 
limited cases in which units of analysis are other than participants 
(e.g., lesions, eyes, implants). We also note that if such a 
requirement were not added, it would not be possible for a responsible 
party to submit baseline measure(s) that were assessed at baseline and 
used in the analysis of the primary outcome measures(s), when the unit 
of analysis for the primary outcome measure(s) is other than 
participants. We also add an element to describe the analysis 
population when the Overall Number of Baseline Participants (or units) 
differs from the number of human subjects (or units) assigned to an arm 
or comparison group, similar to Analysis Population Description in 
Sec.  11.48(a)(3)(ii)(C). Analysis Population Description was added to 
Demographic and baseline characteristics as an optional data element in 
January 2013 in response to queries routinely received from responsible 
parties as well as our experience with submitted results information. 
Based on a review of clinical trials with results posted on 
ClinicalTrials.gov, the number of participants analyzed in Demographic 
and baseline characteristics differed from the number assigned to an 
arm in 15 percent of clinical trials. The addition of this data element 
is therefore necessary to enable users of ClinicalTrials.gov to 
understand why some participants (or units) were excluded from the 
analysis of Demographic and baseline characteristics. These data 
elements in final Sec.  11.48(a)(2) are consistent with section 
402(j)(3)(C)(i) of the PHS Act and are promulgated pursuant to our 
authority under section 402(j)(3)(D)(iii)(IV) of the PHS Act.
    We invited comments on whether the lists of proposed choices for 
Measure Type and Measure of Dispersion were adequate, but we did not 
receive any specific comments on this topic. However, based on our 
experience with submitted results information and routine queries from 
users of ClinicalTrial.gov, we have identified two issues with the 
following limited list of options for Measure Type proposed in the NPRM 
preamble: ``Number,'' ``mean,'' ``median,'' ``least squares mean,'' 
``geometric mean,'' and ``log mean.'' First, because the ``log mean'' 
option is not needed, we have excluded it from the limited list of 
options for Measure Type. Of the more than 22,000 records with posted 
results on ClinicalTrials.gov as of July 2016, only 3 indicated ``log 
mean'' in Baseline Measure Information, and in each case the data were 
the mean of log transformed data (rather than a logarithmic mean) and 
should have been specified as a Measure Type of ``mean'' instead. 
Second, as discussed in this preamble for Outcome measures and 
statistical analyses, we also add ``geometric least squares mean'' to 
the list of options for Measure Type. Third, the ``number'' option is 
not sufficiently granular to allow for discrimination among different 
methods of aggregation that use ``number'' for Measure Type (such as 
count of participants or percentage of participants). To address this, 
we are adding two additional options to Measure Type to specify whether 
the number is a ``count of participants'' or a ``count of units.'' 
These choices will improve the clarity of results data by making such 
counts unambiguous, thereby ensuring that these data are properly 
interpreted by human users as well as (semi-) automated systems.
Final Rule
    Taking into consideration the comments, our experience with the 
ClinicalTrials.gov data bank, and the statutory requirements for 
clinical trial results information, we are modifying the NPRM approach 
for Baseline Measure Information to specify that Demographic and 
baseline characteristics includes a new requirement to provide race and 
ethnicity information, if collected, or indicate that it was not 
collected, and modifies the requirement to provide other measures 
assessed at baseline to those used in the analysis of a primary outcome 
measure. In addition, based on our operational experience and routine 
queries from users, we add provisions in final Sec.  11.48(a)(2)(ii), 
Baseline Analysis Population Information to address how the responsible 
party provides demographic and baseline characteristics when the unit 
of analysis is not human subjects and how to describe the analysis 
population, if needed. Final Sec.  11.48(a)(2)(v) also explains how to 
specify the number of baseline participants (and units) analyzed, if 
different from the Overall Number of Baseline Participants or Units 
Analyzed. Additional elaboration

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is provided on the information required to be submitted as a brief 
description of each arm/group (a similar omission was described for 
Sec.  11.48(a)(1)), the use of ``categories'' used to submit Baseline 
Measure Data, and options for specifying Measure Type. We have made 
minor revisions to clarify the Name and description of the measure in 
final Sec.  11.48(a)(2)(iii)(A) to indicate that the information must 
include ``any categories that are used to submit Baseline Measure 
Data'' (revised from the proposed broader phrasing of ``any categories 
that are used in submitting results''). We also have revised the 
description of the population for whom Baseline Measure Data is 
provided in Sec.  11.48(a)(2)(iv) (proposed ``human subjects who 
participated in the clinical trial'') to be consistent with a similar 
description for Overall Number of Baseline Participants in Sec.  
11.48(a)(2)(ii)(A) (``human subjects for whom baseline characteristics 
were measured''). Final Sec.  11.48(a)(2) requires the submission of 
the following demographic and baseline characteristic information: (i) 
Baseline Characteristics Arm/Group Information; (ii) Baseline Analysis 
Population Information; (iii) Baseline Measure Information; (iv) 
Baseline Measure Data; and (v) Number of baseline participants (and 
units), if different from Overall Number of Baseline Participants or 
Units Analyzed.
    ClinicalTrials.gov will use the Arm Information, Intervention Name, 
and Intervention Description data elements (submitted as clinical trial 
registration information) as well as Participant Flow Arm Information 
to provide the responsible party with options for pre-populating table 
column names and descriptions for Baseline Characteristics Arm/Group 
Information (described in final Sec.  11.48(a)(2)(i)). The responsible 
party will review and edit the information as needed to ensure that it 
appropriately and accurately reflects the baseline arms/groups for the 
clinical trial, or the responsible party may instead define new groups 
to reflect how baseline information was analyzed. As described in the 
discussion of the term ``comparison group'' in Sec.  11.10(a) of the 
preamble, the reference to comparison groups recognizes that when data 
collected during clinical trials are analyzed, the data are often 
aggregated into groupings of human subjects (i.e., comparison groups) 
other than the arms to which the subjects were assigned for the study. 
It is expected that Baseline Characteristics Arm/Group Information will 
be the same as Participant Flow Arm Information, unless human subjects 
were analyzed in groups that are different from those to which they 
were assigned. In this situation, there must be sufficient detail to 
understand how the arm(s) or comparison groups used for submitting 
Baseline Characteristics Arm/Group Information were derived from 
Participant Flow Arm Information. In general, Baseline Characteristics 
Arm/Group Information must include all participants assessed at 
baseline, with each participant belonging to only one arm or comparison 
group, as specified in the pre-specified protocol and/or SAP. Baseline 
Characteristics Arm/Group Information must also include sufficient 
detail to understand the intervention strategy being described in that 
arm/group, similar to what is described in this preamble for 
Participant Flow Arm Information in Sec.  11.48(a)(1).
    Baseline Analysis Population Information, as described in final 
Sec.  11.48(a)(2)(ii), consists of (A) Overall Number of Baseline 
Participants, (B) Overall Number of Units Analyzed, and (C) Analysis 
Population Description. Baseline Analysis Population Information is 
similar to that described for Analysis Population Information for 
outcome measures in Sec.  11.48(a)(3)(ii). The Overall Number of 
Baseline Participants is defined as the ``[t]he total number of human 
subjects for whom baseline characteristics were measured, by arm or 
comparison group, and overall.'' Overall Number of Baseline 
Participants is necessary to indicate whether some subjects enrolled in 
the clinical trial were not measured at baseline (e.g., because they 
dropped out of the clinical trial before that point in time) and to 
help ensure that results information is submitted for all subjects who 
were measured at baseline. If any of the demographic or baseline 
characteristics are based on a unit other than human subjects (e.g., 
lesions, eyes, implants), the responsible party is also required to 
provide the Overall Number of Units Analyzed, which is defined as ``. . 
. a description of the unit of analysis and the number of units for 
which baseline measures were measured and analyzed, by arm or 
comparison group and overall.'' In addition, the Analysis Population 
Description in baseline must be used ``[i]f the Overall Number of 
Baseline Participants (or units) differs from the number of human 
subjects (or units) assigned to the arm or comparison group and 
overall, [with] a brief description of the reason(s) for the 
difference.''
    Baseline Measure Information, as described in Sec.  
11.48(a)(2)(iii), consists of ``[a] description of each baseline or 
demographic characteristic measured in the clinical trial, including 
age, sex/gender, race, ethnicity (if collected under the protocol), and 
any other measure(s) that were assessed at baseline and are used in the 
analysis of the primary outcome measure(s) in accordance with Sec.  
11.48(a)(3).'' If any Baseline Measure Information (described in Sec.  
11.48(a)(2)(iii)) is not measured in the clinical trial (e.g., age, 
sex/gender, race and ethnicity), ClinicalTrials.gov will provide a 
mechanism for the responsible party to indicate that such information 
was not collected. A responsible party must submit demographic and 
baseline characteristics using the following limited list of options 
for Baseline Measure Information: ``Age,'' ``sex/gender,'' ``race and 
ethnicity,'' ``region of enrollment'' (if assessed at baseline), and 
``study-specific measure(s),'' by arm or comparison group and overall 
for the clinical trial. Age information must be submitted as ``age, 
continuous'' (e.g., for Measure Types of ``mean'' or ``median''), 
``age, categorical'' (pre-defined categories of <18 years, 18 to 65 
years, and >65 years), or ``age, customized'' (age categories defined 
by responsible party). For sex/gender data, the responsible party must 
submit using ``sex, male, female'' (pre-formatted categories of male 
and female) and/or ``gender, customized'' (gender categories defined by 
the responsible party). The responsible party may use the description 
of the measure to provide additional, free-text information about the 
collection and/or reporting methods used for sex and/or gender 
information. Race and ethnicity data must be submitted as ``race (NIH/
OMB),'' ``ethnicity (NIH/OMB),'' or ``race/ethnicity, customized.'' The 
options that reference NIH/OMB reflect the classification system of the 
Office of Management and Budget (OMB) (see 62 FR 58782, Oct. 30, 1997), 
which has been adopted by Federal agencies, including NIH. 
Alternatively, the responsible party may select ``race/ethnicity, 
customized'' in order to customize race and ethnicity categories for 
consistency with how information was collected in the protocol for the 
clinical trial, if different from the NIH/OMB classification. If region 
of enrollment information is provided, the measure information will be 
pre-filled with the countries described for Facility Information in 
Sec.  11.28(a)(2)(iii)(C), but this information can be edited as 
needed. Responsible parties must select from this limited list of 
options for Baseline Measure Information to ensure that the required 
information is

[[Page 65084]]

provided and to allow for the identification of such information in a 
search by users of the public site. In addition, ClinicalTrials.gov 
accommodates the submission of information to describe an unlimited 
number of customized demographic and baseline characteristics (using 
the ``study-specific measure'' option). In general, we cannot specify 
in advance which other demographic and baseline characteristics would 
be provided for a particular clinical trial. Only those conducting the 
clinical trial will know which characteristics are important for their 
clinical trial and which were actually collected. Important demographic 
and baseline characteristics are those that a responsible party 
determines are useful for comparing participants across comparison 
groups and for describing the population enrolled in the clinical 
trial. Although we cannot specify these characteristics in advance, we 
do believe it is important that baseline measures include any 
characteristic used in assessing primary outcome measure(s). For 
example, if an outcome measure compares a subject's blood pressure 
after 6 weeks of receiving a particular intervention, the baseline 
measure of blood pressure must be submitted. Similarly, if a clinical 
trial includes a statistical analysis of a primary outcome measure that 
uses baseline data from participants enrolled in the clinical trial as 
part of the calculation (e.g., a regression analysis), it is necessary 
to submit the relevant baseline data. The use of these baseline data in 
analyzing the primary outcome measure indicates that these data would 
have been collected during the clinical trial and would be important to 
the interpretation of results. In the limited circumstance in which 
Baseline Characteristics Arm/Group Information is different from the 
Arms/Groups used in the analysis of the primary outcome measure(s), it 
is acceptable to provide the relevant Baseline Measure Information only 
as part of Outcome Measure Information.
    For each measure, Baseline Measure Information in Sec.  
11.48(a)(2)(iii) must include the following elements: ``(A) Name and 
description of the measure, including any categories that are used to 
submit Baseline Measure Data; (B) Measure Type and Measure of 
Dispersion [for] each baseline measure submitted, an indication of the 
type of data to be submitted and the associated measure of dispersion; 
[and] (C) Unit of Measure.'' Providing Baseline Measure Information in 
this structured manner is intended to ensure that the information is 
meaningful to users, ensure that submitted information is complete, and 
improve the comparability of information across clinical trials. With 
respect to the categories that are used to submit Baseline Measure 
Data, in our experience operating ClinicalTrials.gov, we have observed 
that responsible parties use categories for two general types of 
information: Either a list of mutually exclusive and exhaustive 
categories to which each participant belongs to one and only one (e.g., 
participants with history of smoking, no history of smoking, unknown) 
or a list of items that are not mutually exclusive and exhaustive for 
which a single participant may be represented in more than one row (or 
not all) (exposure to ``A,'' ``B,'' and/or ``C''). To distinguish these 
two different types of information and to allow for improved options 
for validation (e.g., the system can ensure that the sum of 
participants in mutually exclusive and exhaustive categories is the 
same as the overall number of baseline participants), responsible 
parties may indicate which information type is being reported. When 
specifying the Measure Type, the responsible party is required to 
select one option from the following limited list of options: ``Count 
of participants,'' ``count of units,'' ``number,'' ``mean,'' 
``median,'' ``least squares mean,'' ``geometric mean,'' and ``geometric 
least squares mean.'' When specifying the associated Measure of 
Dispersion, the responsible party is required to select one option from 
the following limited list of options: ``Standard deviation,'' ``inter-
quartile range,'' ``full range,'' and ``not applicable'' (which would 
be permitted only if the specified measure type is ``count of 
participants,'' ``count of units,'' or ``number''). No ``other'' option 
is available for either Measure Type or Measure of Dispersion, but 
responsible parties have the option of voluntarily providing additional 
information about the baseline measures as part of a free-text 
description of the baseline measure. Unit of Measure describes what is 
being quantified by the data (e.g., blood pressure in ``millimeters of 
mercury'' or ``participants''). Each baseline measure can have only one 
Unit of Measure.
    Final Sec.  11.48(a)(2)(iv) specifies that Baseline Measure Data 
consists of ``[t]he value(s) for each submitted baseline measure, by 
arm or comparison group and for the entire population of human subjects 
. . .'' Section 11.48(a)(2)(v) indicates that, for each submitted 
baseline measure, the number of baseline participants (and units) must 
be specified if different from the Overall Number of Baseline 
Participants or Overall Number of Units Analyzed (e.g., a participant 
was unable to complete one of the baseline assessments). The ``[n]umber 
of baseline participants (and units)'' is provided ``by arm or 
comparison group and overall'' as part of Baseline Measure Data.
Sec.  11.48(a)(3)--Outcomes and Statistical Analyses
Overview of Proposal
    Proposed Sec.  11.48(a)(3) addressed the statutory requirement for 
the submission of outcomes and statistical analyses as part of clinical 
trial results information. Section 402(j)(3)(C)(ii) of the PHS Act 
specifies that a responsible party must submit ``[t]he primary and 
secondary outcome measures as submitted under paragraph 
(2)(A)(ii)(I)(ll), and a table of values for each of the primary and 
secondary outcome measures for each arm of the clinical trial, 
including the results of scientifically appropriate tests of the 
statistical significance of such outcome measures'' (79 FR 69640). 
Consistent with this section of the PHS Act, the Agency proposed in 
Sec.  11.48(a)(3) to require ``[i]nformation for completing a table of 
data for each primary and secondary outcome measure by arm or 
comparison group, including the result(s) of scientifically appropriate 
statistical analyses that were performed on the outcome measure data, 
if any.'' The NPRM noted that the information must include the 
following: (i) Outcome Measure Arm/Group Information; (ii) Analysis 
Population Information; (iii) Outcome Measure Information, to include 
the Name of the specific measure, Description of the metric, Time 
point(s) at which the measurement was assessed, Outcome Measure Type, 
Outcome Measure Reporting Status, Measure Type, to include type of data 
and related measure of dispersion or precision, and Unit of measure; 
(iv) Outcome Measure Data; and (v) Statistical Analyses information for 
results of scientifically appropriate statistical analyses. The NPRM 
included options that could be selected to describe the type of data 
and related measure of dispersion or precision and invited public 
comment on whether the proposed options were sufficient for collecting 
data from the full range of clinical trials that would be subject to 
the proposed rule. Statistical Analyses were proposed to be defined as 
``[r]esult(s) of scientifically appropriate statistical analyses, if 
any . . .'' The criteria for what would be considered scientifically 
appropriate were proposed in Sec.  11.48(a)(3)(v) as ``including any 
statistical analysis that is: (A) Pre-

[[Page 65085]]

specified in the protocol and/or statistical analysis plan [SAP] that 
was performed on the outcome measure data, (B) Made public by the 
sponsor or responsible party prior to the date on which results 
information is submitted for all primary and secondary outcome measures 
studied in the clinical trial, or (C) Conducted in response to a 
request made by the U.S. Food and Drug Administration prior to the date 
on which complete clinical trial results information is submitted for 
all of the primary outcome measures studied in the clinical trial.'' We 
invited public comment on these and other criteria that the Agency 
should consider when determining what constitutes a scientifically 
appropriate statistical analysis. Finally, the NPRM described 
approaches for reporting information for outcome measures and 
statistical analyses in the following situations: (1) When a trial is 
terminated before data are collected for one or more of the pre-
specified outcome measures and (2) when outcome measure data are 
collected, but the actual enrollment falls well below the target 
enrollment. We invited public comments on other way to highlight the 
limitations of the submitted data when either situation occurs (79 FR 
69643).
Comments and Response
    Commenters addressed specific aspects of the proposed requirements 
for Outcomes and statistical analyses in Sec.  11.48(a)(3). Most of the 
commenters addressed the proposed criteria for determining when a 
statistical analysis would be considered scientifically appropriate. 
Many of these commenters expressed concern that the proposal may 
require statistical analyses for exploratory outcome measures described 
in the protocol and/or SAP to be reported. Other commenters indicated 
that some statistical analyses associated with a primary or secondary 
outcome measure are considered exploratory, post-hoc, or of sub-groups, 
rather than primary, and they requested clarification on which of these 
would be required to be reported. We clarify that the proposal was 
intended to require the submission of statistical analyses for only 
primary and secondary outcome measures and, therefore, would not have 
the effect of requiring statistical analyses for other pre-specified or 
post-hoc outcome measures (including for sub-groups) not considered 
primary or secondary outcome measures in the protocol and/or SAP. 
Similarly, we interpret Sec.  11.48(a)(3)(v) to exclude statistical 
analyses considered exploratory, even if they are pre-specified in the 
protocol and/or SAP for primary and secondary outcome measures. In 
addition, the requirement to submit statistical analyses is limited to 
those that inform the interpretation of the primary and secondary 
Outcome Measure Information and Outcome Measure Data that are 
submitted. Alternatively stated, if the statistical analysis does not 
rely on data that are specified as primary or secondary outcome measure 
information in Sec.  11.48(a)(3)(i)-(iv), that analysis does not need 
to be submitted. For example, if a statistical analysis is requested by 
FDA for a primary outcome measure based on a different analysis 
population or is limited to certain sub-groups not summarized in the 
primary or secondary Outcome Measure Information or Outcome Measure 
Data, that analysis would generally not meet this requirement. To help 
the public understand when a reported statistical analysis is pre-
specified or post-hoc, the responsible party may voluntarily provide 
additional information in the accompanying free-text fields as needed 
to support an understanding of the nature of the analysis.
    One commenter suggested that the statistical analysis requirements 
be applied only to the primary outcome measure(s). Section 
402(j)(3)(C)(ii) of the PHS Act requires the submission of ``the 
results of all scientifically appropriate tests of statistical 
significance of [primary and secondary] outcome measures.'' However, 
based on our interpretation of which statistical tests are 
scientifically appropriate, we are limiting some statistical analysis 
reporting requirements to primary outcome measures, as described below. 
Other commenters suggested that scientifically appropriate analyses 
done in response to an FDA request be limited to the primary outcome 
measure(s), with one noting that not all FDA-requested analyses are 
determined to be relevant; another commenter expressed concern that 
reporting statistical analyses without proper context could be 
confusing to the public, particularly if analyses requested by FDA were 
not originally specified in the protocol or analysis plan. This 
commenter also indicated that clinical trial results presented on 
ClinicalTrials.gov should always be based on the CSR submitted to FDA 
or other health authorities. For the purposes of results information 
reporting under the final rule, the results of all scientifically 
appropriate statistical analyses (as defined in Sec.  11.48(a)(3)(v)) 
for all pre-specified primary and secondary outcome measures must be 
reported to ClinicalTrials.gov. When these analyses are the same as 
analyses reported to other regulatory authorities in CSRs, it would be 
reasonable to use the CSR as the source document for reporting. We 
further clarify that the requirement for reporting statistical analyses 
made public by the sponsor or responsible party is limited to analyses 
of primary outcome measure(s) conducted prior to the date on which 
clinical trial information about that primary outcome measure is 
submitted to ClinicalTrials.gov. We clarify that the requirement for 
reporting statistical analyses conducted in response to a request by 
FDA, which is already limited to analyses of the primary outcome 
measures, is further limited to those analyses of primary outcome 
measures for which results information has not yet been submitted to 
ClinicalTrials.gov. That is, primary outcome measures are not required 
to be updated under Sec.  11.64(a) with statistical analyses conducted 
in response to a request made by FDA, if such analyses are conducted 
after clinical trial results information is submitted for the primary 
outcome measure(s) to which the statistical analysis applies.
    In addition, as previously stated, the requirement is limited to 
statistical analyses that rely on the outcome measure data submitted. 
We also note that ClinicalTrials.gov includes optional free-text fields 
to allow responsible parties the option to provide additional 
descriptive information about any submitted statistical analysis, 
including information regarding why the analysis was done, why it is 
being reported (e.g., in the case of an FDA-requested analysis), and 
any limitations of the analysis. This descriptive information should 
generally not include interpretations of results or conclusions about 
the analyses because of concerns regarding the introduction of bias 
discussed in greater detail elsewhere in the preamble. One commenter 
indicated that statistical analyses requested by FDA may contain 
confidential commercial information and suggested that the results of 
statistical analyses should be required to be submitted only when pre-
specified in the protocol or SAP. As such, the final rule retains the 
proposed criteria, with the clarification that statistical analyses 
conducted in response to a request from FDA are limited to those 
performed on primary outcome measures. We believe that these criteria 
identify those statistical analyses that either the responsible party 
or FDA considers scientifically appropriate. We believe that excluding 
from the requirement analyses that were

[[Page 65086]]

prespecified as ``exploratory'' or that were requested by FDA on 
outcomes other than the primary outcome measure(s) appropriately 
balances the reporting burden with the informational benefit.
    Several commenters suggested that the proposed structure of, and 
drop-down choices for, the Statistical Analysis Overview, Statistical 
Test of Hypothesis, and Method of Estimation elements are too rigid for 
non-drug/device studies and smaller studies. We note that the scope of 
this rule is limited to studies of drug products (including biological 
products) and device products. To help ensure that all required 
statistical analyses can be fully accommodated, we will provide a 
general ``other'' option that can be used to describe and report the 
results of statistical analyses that cannot be submitted using the 
options available for Statistical Test of Hypothesis and Method of 
Estimation. In addition, the list of options for describing the 
procedure for Statistical Test of Hypothesis and the estimation 
parameter for Method of Estimation both include an ``other'' option, 
and free-text fields are provided for additional explanation, as 
needed. Commenters suggested that the proposed options for type of 
statistical test conducted (as part of Statistical Analysis Overview) 
be expanded from ``superiority,'' ``non-inferiority,'' ``equivalence,'' 
and ``not applicable'' to include ``estimation'' (e.g., rate of events 
in a given arm) and ``descriptive'' (e.g., safety analyses). We note 
that EMA's EudraCT results data bank has a similar data element named 
``Analysis type'' and uses the following list of options: 
``equivalence,'' ``non-inferiority,'' ``superiority,'' and ``other'' 
[Ref. 98a]. To accommodate these comments and align with EudraCT more 
closely, we are modifying the list of options for the type of 
statistical test conducted by replacing ``not applicable'' with 
``other'' and requiring a description of the type of analysis if the 
``other'' option is selected. One commenter suggested that, based on 
deficiencies in reporting found in their analysis [Ref. 14], the final 
rule should require the specification of the non-inferiority or 
equivalence margin. We note that although this recommendation is 
consistent with the proposal in section IV.C.4 of the NPRM, the 
proposed codified provision inadvertently omitted mention of the 
equivalence analysis. This has been corrected in the final rule. One 
commenter provided general support for the proposed requirement for 
Analysis Population Description as part of Analysis Population 
Information.
    We invited comments on whether the list of proposed choices for 
Measure Type and Measure of Dispersion or Precision was adequate. One 
commenter requested that ``geometric least squares mean'' be added to 
the list of choices. We know from a similar request from a 
ClinicalTrials.gov user that this measure is useful when summarizing 
data evaluating pharmacokinetics. Based on this comment and our 
experience, we are adding ``geometric least squares mean'' to the list 
of choices for Measure Type in both Demographic and baseline 
characteristics and Outcomes and statistical analyses. In addition, 
based on operational experience and routine queries from users, we have 
identified two other issues with the proposed list of options for 
Measure Type (i.e., ``number,'' ``mean,'' ``median,'' ``least squares 
mean,'' ``geometric mean,'' and ``log mean.'' As described in the 
Comments and Response section for Sec.  11.48(a)(2), we have excluded 
the ``log mean'' option from the list of options in the final rule 
because it is not needed. Second, as also described in this preamble 
for Sec.  11.48(a)(2), the ``number'' option is not sufficiently 
granular to allow for discrimination among different methods of 
aggregation that use ``number'' as the Measure Type (such as count of 
participants or percentage of participants). To address this, we are 
adding two options to Measure Type to allow responsible parties to 
specify whether the number is a ``count of participants'' or a ``count 
of units''. We note that this modification more closely aligns the data 
fields with the EMA's EudraCT results data bank [Ref. 98a], which 
distinguishes between ``countable'' and ``measurable'' types of data. 
The final rule also updates ``Measure Type'' to ``Measure Type and 
Measure of Dispersion or Precision'' for consistency with the similar 
data element ``Measure Type and Measure of Dispersion'' in Sec.  
11.48(a)(2)(iii)(B).
    We also requested comments on the proposed approach for reporting 
outcome measure information when (1) a trial is terminated before data 
are collected for one or more of the pre-specified outcome measures and 
(2) when outcome measure data are collected but the actual enrollment 
falls well below the target enrollment. For the first situation, we 
proposed that the responsible party may specify zero (``0'') for the 
Number of Participants Analyzed and that Outcome Measure Data would not 
need to be submitted. The responsible party would still be expected to 
provide the clinical trial results information in proposed Sec.  
11.48(a)(1),(2), and (4) (79 FR 69642). For the second situation, we 
proposed that collected results information for the primary or 
secondary outcome measure must be submitted but statistical analysis 
information would not be expected to be submitted because it would not 
be considered scientifically valid (79 FR 69643). We received comments 
supporting full reporting of results information for terminated or 
withdrawn studies. A study with an Overall Recruitment Status of 
``withdrawn'' does not include any enrolled participants and would not 
require results information submission. We received one comment on the 
second situation, in which outcome measure data are required to be 
submitted for a clinical trial in which actual enrollment falls well 
below the target enrollment. The commenter was concerned about the 
misinterpretation of such results and suggested that the final rule 
require the responsible party to provide additional information about 
the limitations of the data. We note that, in this particular 
situation, the posted study record would clearly reflect that the trial 
was terminated (i.e., the responsible party submitted the Overall 
Recruitment Status as ``terminated''), and we intend to include 
information on the posted study record so that the public can easily 
see when actual enrollment was below the target enrollment goals (using 
information from the Enrollment data element and submitted estimated 
and actual values). We believe that this information will make it 
easier for the public to consistently identify across studies the 
specific limitations raised by the commenter, thereby reducing the need 
to make this a requirement. However, we agree that providing additional 
information about the limitations of the clinical trial and/or the 
collected data may be helpful in this and other situations, and we 
strongly encourage responsible parties to use the related free-text 
fields and/or the optional Limitations and Caveats data element to 
provide such information, when appropriate. Additional relevant 
comments were received in the context of waivers and are addressed in 
Sec.  11.54, accordingly.
Final Rule
    Taking into consideration the comments, our experience operating 
the ClinicalTrials.gov data bank, and the statutory requirements for 
clinical trial results information, the final rule modifies the 
proposed approach for Outcome measures and statistical analyses. We 
clarify in Sec.  11.48(a)(3)(v) that one type of scientifically

[[Page 65087]]

appropriate statistical analysis is an analysis that is conducted on a 
primary outcome measure, in response to an FDA request. In the same 
section, we correct an error that suggested that the submission of 
statistical analysis information applied only to the information in 
proposed Sec.  11.48(a)(3)(v)(C). Additional elaboration is also 
provided on the information required to be submitted as a brief 
description of each arm/group (a similar omission was described for 
Sec.  11.48(a)(1) and (a)(2)). We remove the requirement to submit 
Outcome Measure Reporting Status (see proposed Sec.  
11.48(a)(3)(iii)(E)) because a more streamlined approach makes this 
item obsolete (i.e., the submission of Measure Type and Measure of 
Dispersion or Precision, Unit of Measure, and Outcome Measure Data are 
sufficient for determining that Outcome Measure Information and Outcome 
Measure Data are intended to be posted). We explain how to specify, as 
part of Outcome Measure Data, whether the number of participants (or 
units) analyzed in a category differs from the overall Number of 
Participants Analyzed and Number of Units Analyzed in Sec.  
11.48(a)(3)(ii). We have also updated the options available for 
specifying the type of statistical test in the Statistical Analysis 
Overview as well as the Measure Type and Measure of Dispersion or 
Precision (includes additional options for counts of participants or 
units and for specifying a confidence interval). Finally, minor changes 
have been made for consistency with similar data items in Demographic 
and baseline characteristics in Sec.  11.48(a)(2). Final Sec.  
11.48(a)(3) otherwise retains the following outcomes and statistical 
analyses information as proposed: (i) Outcome Measure Arm/Group 
Information, (ii) Analysis Population Information, (iii) Outcome 
Measure Information, (iv) Outcome Measure Data, and (v) Statistical 
Analyses.
    As discussed in Section IV.B.4 of this preamble, primary and 
secondary outcome measures are submitted as part of the registration 
process. ClinicalTrials.gov was designed to display the results of each 
outcome measure in separate tables organized by arm or comparison 
group. The responsible party determines the rows and columns for each 
outcome measure table; columns represent arms or comparison groups, and 
rows represent data categories (e.g., for categorical data types). The 
responsible party populates the table cells with data from the clinical 
trial. Attributes such as measure type (e.g., mean), measure of 
dispersion or precision (e.g., standard deviation), and unit of measure 
(e.g., milliseconds) provide context for interpreting the numerical 
data. In this way, the system can accommodate either continuous or 
categorical data, as desired by the responsible party based on the 
design and analysis of the clinical trial as specified in the protocol 
and SAP. For example, time-to-event data could be provided as either a 
continuous measure (e.g., median time to response) or as categorical 
data (e.g., number of participants with response by year 5).
    In order to enhance the ability of users to understand and 
interpret the submitted clinical trial results information and help 
ensure that submitted information is complete, Sec.  11.48(a)(3)(i)-(v) 
requires the responsible party to submit information for completing a 
table of data for each primary and secondary outcome measure, by arm or 
comparison group, including the results of scientifically appropriate 
tests of the statistical significance. This is done by submitting the 
following information, which is used to create and populate the outcome 
data tables:
    (1) Outcome Measure Arm/Group Information, which is described in 
Sec.  11.48(a)(3)(i) as ``[a] brief description of each arm or 
comparison group used for submitting an outcome measure for the 
clinical trial, including a descriptive title to identify each arm or 
comparison group.'' As discussed in Section IV.C.4 of this preamble on 
Demographic and baseline characteristics, this information describes 
the grouping of human subjects for the purposes of analysis, whether by 
arm of the clinical trial or another comparison group. 
ClinicalTrials.gov will use the Arm Information, Intervention Name, and 
Intervention Description data elements (submitted as clinical trial 
registration information), as well as Participant Flow Arm Information 
and Baseline Characteristics Arm/Group Information, to provide the 
responsible party with options for pre-populating table column names 
and descriptions for Outcome Measure Arm/Group Information. The 
responsible party must review and edit the information as needed to 
ensure that it appropriately and accurately reflects the outcome 
measure arms/groups for the clinical trial, or the responsible party 
may instead define new groups to reflect how outcome measure 
information was analyzed. As described in the discussion of the term 
``comparison group'' in Sec.  11.10(a) of the preamble, the reference 
to comparison groups recognizes that when data collected during 
clinical trials are analyzed, the data are often aggregated into 
groupings of human subjects (i.e., comparison groups) other than the 
arms to which the subjects were assigned for the study. It is expected 
that Outcome Measure Arm/Group Information will be the same as 
Participant Flow Arm Information, unless human subjects were analyzed 
in groups different from those to which they were assigned. In this 
situation, there must be sufficient details for users to understand how 
the arm(s) or comparison groups used for submitting outcome measures 
were derived from Participant Flow Arm Information. In general, the 
Outcome Measure Arm/Group Information must be inclusive of all arms or 
comparison groups, based on the pre-specified protocol and/or SAP. The 
Outcome Measure Arm/Group Information must also include sufficient 
details for users to understand the intervention strategy being 
described in that arm/group, similar to what is described in this 
preamble for Participant Flow Arm Information in Sec.  11.48(a)(1).
    (2) Analysis Population Information, as described in Sec.  
11.48(a)(3)(ii), consists of the following: (A) Number of Participants 
Analyzed, (B) Number of Units Analyzed, and (C) Analysis Population 
Description. Number of Participants Analyzed means ``[t]he number of 
human subjects for whom an outcome was measured and analyzed, by arm or 
comparison group.'' If the analysis is based on a unit other than 
participants (e.g., lesions, eyes, implants), the responsible party is 
also required to provide the Number of Units Analyzed, which is defined 
as ``. . . a description of the unit of analysis and the number of 
units for which an outcome was measured and analyzed, by arm or 
comparison group.'' In addition, if the Number of Participants Analyzed 
or Number of Units Analyzed in an arm or comparison group differs from 
the number of human subjects or units assigned to the arm or comparison 
group, the responsible party is also required to provide an Analysis 
Population Description, which is explained as ``a brief description of 
the reason(s) for the difference.'' For example, if some participants 
assigned to arms drop out before one of the outcome measures is 
assessed or if some participants are otherwise ineligible for analysis, 
the responsible party would include an explanation in the Analysis 
Population Description. Similarly, if a clinical trial enrolled 
participants but was terminated before outcome measure data were 
collected, the entry would explain why the Number of Participants 
Analyzed is zero even though

[[Page 65088]]

participants had been assigned to the relevant arm or comparison group.
    (3) Outcome Measure Information, as described in Sec.  
11.48(a)(3)(iii), includes the following components: (A) Name of the 
specific outcome measure, including the titles of any categories into 
which Outcome Measure Data in Sec.  11.48(a)(3)(iv) are aggregated; (B) 
Description of the metric used to characterize the specific outcome 
measure; (C) Time point(s) at which the measurement was assessed for 
the specific metric; (D) Outcome Measure Type, which indicates whether 
the outcome measure is one of the following types of outcome measures: 
primary, secondary, other pre-specified, or post-hoc; (E) Measure Type 
and Measure of Dispersion or Precision, which indicates the type of 
data submitted and the measure of dispersion or precision; and (F) Unit 
of Measure (e.g., blood pressure in ``millimeters of mercury'' or 
``participants''). As described Section IV.B.4 of this preamble for 
Sec.  11.28(a)(2)(i)(W) and (X), when an attribute such as blood 
pressure is summarized using more than one metric or method of 
aggregation (e.g., mean and median) and/or summarized at more than one 
time point (e.g., 3 months, 6 months, 9 months), each of these is 
considered a different outcome measure. In addition, the description of 
the time point(s) of assessment must be specific to the submitted 
outcome measure and is generally the specific duration of time over 
which each human subject is assessed (not the overall duration of the 
trial). As described in this section of this preamble for Baseline 
Measure Information, when responsible parties submit information using 
categories, they may indicate which information type is being reported 
(participants in mutually exclusive and exhaustive categories or a list 
of items for which participants may be represented in more than one 
row) to allow for improved options for data validation (e.g., the 
system can ensure that the sum of participants in mutually exclusive 
and exhaustive categories is the same as Number of Participants 
Analyzed).
    In specifying the type of data to be submitted as part of Measure 
Type and Measure of Dispersion or Precision, the responsible party is 
required to select one option from the following limited list of 
options for Measure Type: ``count of participants,'' ``count of 
units,'' ``number,'' ``mean,'' ``median,'' ``least squares mean,'' 
``geometric mean,'' and ``geometric least squares mean.'' In specifying 
the Measure of Dispersion or Precision, the responsible party is 
required to select one option from the following limited list of 
options: ``standard deviation,'' ``standard error,'' ``inter-quartile 
range,'' ``full range,'' ``geometric coefficient of variation'' (which 
is permitted only if the specified Measure Type is ``geometric mean'' 
or ``geometric least squares mean''), ``not applicable'' (which is 
permitted only if the specified Measure Type is ``count of 
participants,'' ``count of units,'' ``number''), ``80% confidence 
interval,'' ``90% confidence interval,'' ``95% confidence interval,'' 
``97.5% confidence interval,'' ``99% confidence interval,'' and ``other 
confidence interval level'' (which must also include a specification of 
the numerical value of the confidence interval level). There is no 
general ``other'' option for either the Measure Type or Measure of 
Dispersion or Precision entries, but responsible parties may optionally 
provide additional descriptive information as part of the free-text 
Outcome Measure Description. Collecting Measure Type and Measure of 
Dispersion or Precision in this format improves the ability of users' 
to compare submitted information across clinical trials and also 
ensures complete data submission. For example, if the responsible party 
indicates that the measure of dispersion is inter-quartile range, 
ClinicalTrials.gov can prompt the submission of the two values 
corresponding to the upper and lower bounds of the inter-quartile 
range, instead of only the single value needed to submit a standard 
deviation. Unit of Measure describes what is quantified by the data 
(e.g., blood pressure in ``millimeters of mercury'' or 
``participants''). Each outcome measure can only have one unit of 
measure.
    In most cases, Name of the specific outcome measure, Description of 
the metric, Time point(s), and Outcome Measure Type (Sec.  
11.48(a)(3)(iii)(A), (B), (C), and (D)) for the primary and secondary 
outcome measures would have been submitted at the time of clinical 
trial registration, as specified in Sec.  11.28(a)(2)(i)(W) and (X), 
and updated during the course of the clinical trial, as specified in 
Sec.  11.64. Final Sec.  11.64(a) specifically requires responsible 
parties to update information submitted during registration at the time 
they submit results. To ensure consistent data entry and reduce the 
data entry burden on responsible parties, ClinicalTrials.gov will 
automatically pre-populate the results data tables with the previously 
submitted (and updated) registration information and will allow the 
responsible party to make further updates as necessary or desired 
(e.g., to provide clarification that would enable users to better 
interpret the submitted results values). If data were not collected for 
an outcome measure in a clinical trial (i.e., Number of Participants 
Analyzed in all arms or comparison groups is zero for that outcome 
measure), the responsible party is not required to submit Measure Type 
and Measure of Dispersion or Precision and Unit of Measure (Sec.  
11.48(a)(3)(iii)(E) and (F)) for that outcome measure, as no Outcome 
Measure Data in Sec.  11.48(a)(3)(iv) would be submitted. This 
situation may occur, for example, if a clinical trial is terminated 
before data are collected for a pre-specified primary or secondary 
outcome measure.
    (4) Outcome Measure Data, which is described in Sec.  
11.48(a)(3)(iv), consists of ``[t]he measurement value(s) for each 
outcome measure for which data are collected, by arm or comparison 
group and by category (if specified).'' The information provided for 
Outcome Measure Data must use the Unit of Measure and correspond to the 
Measure Type and Measure of Dispersion or Precision submitted as 
described in Sec.  11.48(a)(3)(iii)(E) and (F). In addition, the 
responsible party may specify the number of participants (and units, if 
applicable), by arm or comparison group, if different in any category 
from the Number of Participants Analyzed or Number of Units Analyzed in 
Sec.  11.48(a)(3)(ii)(A) or (B).
    (5) Statistical Analyses are specified in Sec.  11.48(a)(v) as the 
``[r]esults of scientifically appropriate tests of the statistical 
significance of the primary and secondary outcome measures, if any.'' 
In implementing this requirement, we clarify the meaning of 
``scientifically appropriate'' as it relates to Statistical Analyses 
for the purposes of this regulation only. In this final rule, we 
specify in Sec.  11.48(a)(3)(v)(A) that a statistical analysis is 
required to be submitted if it meets any one of the following three 
criteria in the context of a particular applicable clinical trial:
     A statistical analysis that is pre-specified in the 
protocol and/or SAP and was performed on primary or secondary outcome 
measure data. Statistical analyses that are pre-specified in the 
protocol for a primary or secondary outcome measure, but are considered 
exploratory, are excluded from these requirements.
     A statistical analysis for a primary or secondary outcome 
measure that is made public by the sponsor or responsible party, where 
``made public'' is considered to be when the statistical analysis is 
available in written form (e.g., journal publication, scientific 
abstract, press release). We believe that the decision by the sponsor 
or responsible party to publicly disseminate a statistical analysis for 
a

[[Page 65089]]

primary or secondary outcome measure implicitly indicates that an 
assessment of the scientific appropriateness of the analysis has been 
made. The fact that the Agency is adopting this approach in the 
regulation does not reflect the Agency's agreement that such 
statistical analyses are necessarily scientifically valid. Recognizing 
that the time at which an analysis is made public and the submission 
requirements under this rule may not overlap, this criterion is limited 
to analyses made public before clinical trial results information is 
submitted for the primary outcome measure(s) studied in the clinical 
trial.
     A statistical analysis conducted on a primary outcome 
measure in response to a request made by FDA. We limit the requirement 
regarding FDA-requested statistical analyses to those analyses 
requested by FDA for a primary outcome measure prior to the submission 
of clinical trial results information for all primary outcome measures. 
This avoids requiring a responsible party to submit FDA-requested 
analyses if such analyses would be based on results information that 
was submitted to ClinicalTrials.gov prior to FDA's request.
    Statistical analyses that meet any of these criteria must be 
submitted to ClinicalTrials.gov at the time of results or partial 
results information submission. In addition, we clarify that these 
criteria apply only to statistical analyses that rely on information 
and data that are specified as primary or secondary outcome measure 
information in Sec.  11.48(a)(3)(i)-(iv). This limitation is necessary 
because statistical analyses are only interpretable in the context of 
the summary outcome measure information that forms the basis for the 
analysis. These criteria, therefore, do not have the effect of 
requiring a responsible party to submit primary or secondary outcome 
measure information in Sec.  11.48(a)(3)(i)-(iv) that is not otherwise 
required to be submitted.
    We specify in Sec.  11.48(a)(3)(v)(B) that the information that a 
responsible party must submit for statistical analyses of primary and 
secondary outcome measures is as follows:
    (1) Statistical Analysis Overview, which identifies the arms or 
comparison groups compared in the statistical analysis (by selecting 
the arms or comparison groups already defined for the outcome measures) 
and specifies the type of analysis conducted. The type of analysis 
conducted would be selected from the following limited set of options: 
``superiority,'' ``non-inferiority,'' ``equivalence,'' or ``other'' 
(which must also include a description of the analysis type). The 
``other'' option would be appropriate for a single group analysis or 
other descriptive statistics, for example. If the type of analysis 
selected is ``non-inferiority'' or ``equivalence,'' the responsible 
party is also required to provide a free-text description of key 
parameters of the statistical analysis to include, at minimum, 
information about the power calculation and the non-inferiority or 
equivalence margin. An additional comment field is offered to provide 
the responsible party with the opportunity to submit optional 
additional information about the statistical analysis.
    (2) The Responsible Party must provide either the Statistical Test 
of Hypothesis or the Method of Estimation, as applicable. If the 
statistical analysis performed cannot be submitted using the 
Statistical Test of Hypothesis or Method of Estimation options, a 
general ``other'' option is available for submitting any other 
scientifically appropriate tests of statistical significance. 
Statistical Test of Hypothesis consists of the p-value and the 
procedure used for statistical analysis of the outcome data. For 
convenience in specifying the procedure used for the statistical 
analysis, ClinicalTrials.gov includes the following list of commonly 
used statistical tests for calculating p-values from which responsible 
parties may select: ``ANCOVA;'' ``ANOVA;'' ``Chi-squared;'' ``Chi-
squared, Corrected;'' ``Cochran-Mantel-Haenszel;'' ``Fisher Exact;'' 
``Kruskal-Wallis;'' ``Log Rank;'' ``Mantel Haenszel;'' ``McNemar;'' 
``Mixed Models Analysis;'' ``Regression, Cox;'' ``Regression, Linear;'' 
``Regression, Logistic;'' ``Sign Test;'' ``t-Test, 1-sided;'' ``t-Test, 
2-sided;'' and ``Wilcoxon (Mann-Whitney).'' Responsible parties may 
also select the ``other'' option and provide the name of another 
method. Additional comment fields are available to provide the 
responsible party with an opportunity to submit optional additional 
information about the statistical test of hypothesis, such as a 
description of the null hypothesis, adjustments for multiple 
comparisons, a priori thresholds for statistical significance, and 
degrees of freedom. Method of Estimation consists of the estimation 
parameter, estimated value, and confidence interval (if calculated). 
For convenience in describing Method of Estimation, ClinicalTrials.gov 
includes the following list of more than a dozen commonly used 
estimation parameters from which responsible parties may select: ``Cox 
Proportional Hazard;'' ``Hazard Ratio (HR);'' ``Hazard Ratio, log;'' 
``Mean Difference (Final Values);'' ``Mean Difference (Net);'' ``Median 
Difference (Final Values);'' ``Median Difference (Net);'' ``Odds Ratio 
(OR);'' ``Odds Ratio, log;'' ``Risk Difference (RD);'' ``Risk Ratio 
(RR);'' ``Risk Ratio, log;'' and ``Slope.'' Responsible parties may 
also select the ``other'' and provide the name of another estimation 
parameter. If a confidence interval was calculated, the responsible 
party will submit the confidence level, indicate whether the confidence 
interval is one-sided or two-sided, and provide the upper and/or lower 
limits of the confidence interval. A responsible party could specify 
that the confidence interval is one-sided and provide only the upper or 
lower limit. If one of the limits of a two-sided confidence interval 
cannot be calculated, the responsible party is required to specify that 
limit as ``Not Available'' and provide a brief narrative explanation 
(e.g., because an insufficient number of clinical trial participants 
reached the event at the final time point for assessment). A 
responsible party may also submit, on an optional basis, a dispersion 
value. If a dispersion value is submitted, the responsible party is 
required to specify the parameter of dispersion by selecting one of the 
following options: ``standard deviation'' or ``standard error of the 
mean.'' No ``other'' option for the parameter of dispersion is 
available. An additional comment field is available to provide the 
responsible party with an opportunity to submit optional additional 
information about the method of estimation, such as the direction of 
the comparison (e.g., for a relative risk). The requirements for 
submitting statistical analysis information attempt to balance the 
benefits of structured data with minimal narrative text with the need 
to describe what was evaluated in the statistical analysis. For the 
reasons discussed in section III.C., in addition to the information 
specified above, responsible parties also have the option of 
voluntarily submitting additional, free-text information in order to 
provide a more complete description of the statistical analyses. This 
free-text information should not include an interpretation of results 
or conclusions, just a description of the statistical test(s) 
conducted. Submitted statistical analyses are linked to each submitted 
outcome measure. Although a responsible party is not limited in the 
number of statistical analyses that can be submitted for each outcome 
measure, only statistical analyses that rely on submitted outcome 
measure information

[[Page 65090]]

and data can be described. Specifically, the requirement is limited to 
statistical analyses that rely on the summary outcome information and 
data submitted, including Outcome Measure Arm/Group Information, 
Analysis Population Information, Outcome Measure Information, and 
Outcome Measure Data. Statistical analyses that use data external to 
the clinical trial or different analysis populations or are limited to 
certain sub-groups would generally not meet this requirement unless, 
for example, the summary sub-group data were submitted as part of the 
primary or secondary outcome measure (e.g., using categories or 
comparison groups).
    In specifying requirements for outcome measures and statistical 
analyses under Sec.  11.48(a)(3), two situations merit further 
clarification. The first involves a clinical trial terminated before 
data are collected for one or more of the pre-specified outcome 
measures. Certain information is still required to be submitted for 
outcome measures for which data were not collected. Under Sec.  
11.48(a)(3)(ii) the responsible party would be required to submit the 
Number of Participants Analyzed, which would be zero (``0'') for an 
outcome measure for which no data were collected. The responsible party 
is not required to submit the Measure Type and Measure of Dispersion or 
Precision, and Unit of Measure data elements specified in Sec.  
11.48(a)(3)(iii)(E) and (F), for any outcome measure for which data 
were not collected but would be required to provide the other elements 
of Outcome Measure Information specified in Sec.  11.48(a)(3)(iii)(A), 
(B), (C), and (D). As specified in Sec.  11.48(a)(3)(iv), the 
responsible party is not required to submit Outcome Measure Data for 
the outcome measure(s) for which no data were collected but is required 
to submit Outcome Measure Data for any other primary and secondary 
outcomes for which data were collected. For terminated trials, the 
responsible party must still meet the requirements specified in Sec.  
11.48(a)(1), (2), and (4) for the submission of results information for 
the Participant Flow, Demographic and baseline characteristics, and 
Adverse event information modules. If a clinical trial enrolls no 
participants, the information to be updated for the Enrollment data 
element under Sec.  11.64(a) would be zero (``0'') and no results 
information would be required to be submitted for that clinical trial.
    The second situation involves a clinical trial for which outcome 
measures are collected but the actual enrollment falls well below the 
target enrollment. This could occur, for example, if a clinical trial 
is terminated due to poor enrollment after only some participants are 
enrolled but outcomes are measured. Even in such situations, collected 
results information must be submitted to ClinicalTrials.gov as 
specified in this rule (taking into account the privacy considerations 
discussed in section III.C.16 of the NPRM preamble (79 FR 69591) if 
actual enrollment is very small). The submission and posting of results 
information for such a clinical trial would be consistent with section 
402(j) of the PHS Act and provide a way of tracking the progress of the 
clinical trial and demonstrating what happened to the human subjects 
who were enrolled. If the clinical trial was terminated because of 
safety concerns or efficacy, the results information would be of 
considerable interest to users interested in human health and safety 
information. In order to reduce the chances that users of 
ClinicalTrials.gov might misinterpret submitted results information, we 
encourage the responsible party to submit additional optional 
information about the clinical trial in the Analysis Population 
Description data element and/or in the Limitations and Caveats module 
of ClinicalTrials.gov. This additional information could highlight that 
enrollment in the clinical trial did not reach the target number of 
subjects needed to achieve target power and was insufficient to produce 
statistically reliable results. If the trial was terminated, the posted 
study record will clearly reflect that the trial was terminated (i.e., 
the responsible party indicates Overall Recruitment Status as 
``terminated''), and we intend to include information on the posted 
study record to allow the public to easily see when actual enrollment 
was below the target enrollment goals (using information from the 
Enrollment data element and submitted expected and actual values). We 
believe that this information will make it easier for the public to 
consistently identify across studies when a trial was terminated and/or 
actual enrollment was below the target enrollment goals. We expect 
that, in most of these situations, no statistical analysis information 
would be submitted for the affected outcome measure(s) because no 
statistical analyses would have been performed or would be considered 
scientifically appropriate.
Sec.  11.48(a)(4)--Adverse Event Information
Overview of Proposal
    The proposal for submitting adverse event information in Sec.  
11.48(a)(4) was based on the information required to complete the two 
tables specified as additional results information in sections 
402(j)(3)(I)(iii)(I) and (II) of the PHS Act, with modifications to 
further assist users in understanding and interpreting submitted 
adverse event information. Specifically, section 402(j)(3)(I)(i) of the 
PHS Act requires the Secretary, by regulation, to ``determine the best 
method for including in the registry and results data bank appropriate 
results information on serious adverse and frequent adverse events for 
applicable clinical trials . . . in a manner and form that is useful 
and not misleading to patients, physicians, and scientists.'' Section 
402(j)(3)(I)(ii) of the PHS Act specifies that if regulations are not 
issued by the date that is 24 months after the date of the enactment of 
FDAAA (i.e., by September 27, 2009), the requirement to submit results 
information necessary to complete the two tables specified in sections 
402(j)(3)(I)(iii)(I) and (II) of the PHS Act would take effect as 
stated in section 402(j)(3)(I)(ii). The statutorily mandated adverse 
event reporting provisions require the submission of two tables of 
information, as follows: (1) ``[a] table of anticipated and 
unanticipated serious adverse events grouped by organ system, with 
number and frequency of such event in each arm of the clinical trial'' 
(section 402(j)(3)(I)(iii)(I) of the PHS Act), referred to hereinafter 
as the ``serious adverse events table'' and (2) ``[a] table of 
anticipated and unanticipated adverse events that are not included in 
the [serious adverse events table] . . . that exceed a frequency of 5 
percent within any arm of the clinical trial, grouped by organ system, 
with number and frequency of such event in each arm of the clinical 
trial'' (section 402(j)(3)(I)(iii)(II) of the PHS Act). In the NPRM and 
in the ClinicalTrials.gov data bank, we refer to adverse events that do 
not fit the definition of a serious adverse event as ``other adverse 
events,'' and we refer to the adverse events table in item (2) above as 
the ``other adverse events table'' (79 FR 69588).
    Consistent with this section of the PHS Act, the Agency proposed in 
Sec.  11.48(a)(4)(i) to require ``[i]nformation for completing two 
tables summarizing adverse events collected during an applicable 
clinical trial: (A) Table of all serious adverse events, grouped by 
organ system, with the number and

[[Page 65091]]

frequency of each event by arm or comparison group; (B) Table of all 
adverse events, other than serious adverse events, that exceed a 
frequency of 5 percent within any arm of the clinical trial, grouped by 
organ system, with the number and frequency of each event by arm or 
comparison group.'' Proposed Sec.  11.48(a)(4)(ii) further specified 
that information for each table must include the following: (A) Adverse 
Event Arm/Comparison Group Information; (B) Total Number Affected by 
Arm or Comparison Group; (C) Total Number at Risk by Arm or Comparison 
Group; (D) Total Number Affected by Organ System; (E) Total Number at 
Risk by Organ System; (F) Adverse Event Information, to include a 
descriptive term for the adverse event and organ system associated with 
the adverse event; (G) Adverse Event Data, to include for each adverse 
event the number of human subjects affected and at risk; and (H) 
Additional Adverse Event Description. The NPRM also indicated in 
proposed Sec.  11.48(a)(4)(iii) that information provided by organ 
system must be grouped using the organ system classification 
established on ClinicalTrials.gov. These data elements (with the 
exception of the new Total Number Affected by Organ System and Total 
Number at Risk by Organ System data elements) were first made available 
in September 2008 as optional data elements; they became required as of 
September 27, 2009. The Additional Adverse Event Description data 
element has been available as an optional data element since September 
2008 (named Adverse Event Reporting Additional Description) with the 
following other optional data elements: Time Frame for Adverse Event 
Reporting, Assessment Type (i.e., collection approach), Source 
Vocabulary Name (for specifying a standard vocabulary), and Number of 
Events (for number of occurrences of an adverse event). The NPRM 
proposal and request for comment on additional data elements was also 
based on our operational experience with adverse event information 
since 2008.
    In section III.C.15 of the NPRM, we requested comments on all 
aspects of the proposed requirements for submission of adverse event 
information. This included considerations of the following: (1) Benefit 
and burden of the proposed modifications to the statutorily mandated 
adverse event reporting provisions (i.e., number of participants 
affected and at risk for adverse events at the organ system level); (2) 
benefit and burden of additional information considered but not 
included in the proposal, including the time frame for collecting 
adverse events, the collection approach (systematic or non-systematic), 
all-cause mortality information, a standard vocabulary for submitted 
adverse event terms, number of occurrences of an adverse event and 
attribution of an adverse event to the intervention(s) under study; (3) 
ways to reduce the data submission burden without reducing the value of 
the data; and (4) approaches to increasing standardization in the 
vocabularies used for adverse event information (79 FR 69591). The 
Agency also specifically requested comments on whether the organ system 
classification is sufficient and whether additional categories or an 
``other'' option are necessary (79 FR 69644).
Comments and Response
    Most of the commenters who addressed the requirements for adverse 
event information were generally supportive of the requirements that 
were consistent with current practice and the statutorily mandated 
adverse event reporting provisions. Some commenters expressed support 
for the proposal for adverse event information, including the 
submission of additional information and the data elements on adverse 
events on which we sought comment. One commenter expressed overall 
support for the proposal but generally indicated that it is a change 
from current practice in academic medical centers and expressed concern 
about the burden of the requirements. Many commenters addressed issues 
related to specific data elements and opposed the proposal to require 
the submission of adverse event information aggregated by the total 
number of participants affected and at risk for adverse events for each 
organ system. Commenters expressed opposition to these requirements 
because they considered the requirements to be beyond the statutorily 
mandated adverse event reporting provisions and they questioned the 
Agency's legal authority to require information not specified in those 
provisions.
    We first address the general issue of the Agency's legal authority 
to require adverse event information not specified in the statutorily 
mandated adverse event reporting provisions. The adverse event 
information proposed to be required in Sec.  11.48(a)(4) is based on 
the provisions in sections 402(j)(3)(I)(iii)(I) and (II) of the PHS 
Act, with some modifications. We interpret the provision as providing 
the Secretary with authority to modify the required information, by 
regulation, under section 402(j)(3)(D)(v)(VI) of the PHS Act, which 
specifies that the regulations shall establish ``additions or 
modifications to the manner of reporting of the data elements 
established under [section 402(j)(3)(C) of the PHS Act].'' Section 
402(j)(3)(I)(v) of the PHS Act deems adverse event information to be 
``clinical trial information included in [the] data bank pursuant to . 
. . [section 402(j)(3)(C) of the PHS Act].'' We also interpret that 
this clinical trial information is therefore included in the ``data 
elements established under . . . [section 402(j)(3)(C) of the PHS 
Act]'' referred to in section 402(j)(3)(D)(v)(VI) of the PHS Act. 
Therefore, we conclude that the Secretary has the authority, under 
section 402(j)(3)(D)(v)(VI) of the PHS Act, to modify the statutorily 
mandated adverse event reporting provisions for the submission of 
adverse event information via regulation, because such modifications 
represent ``additions or modifications to the manner of reporting 
[adverse event information] . . .''
    The modifications to the statutorily mandated adverse event 
reporting provisions in this final rule represent modifications to the 
``manner of reporting'' required adverse event information. As 
described above, section 402(j)(3)(D)(v)(VI) of the PHS Act authorizes 
the Secretary to make ``additions or modifications to the manner of 
reporting of the data elements established under [section 402(j)(3)(C) 
of the PHS Act]'' by regulation. We interpret the ``manner of reporting 
of the data elements'' to include specific content requirements for 
reporting information in the categories of information under section 
402(j)(3)(C) of the PHS Act. For example, section 402(j)(3)(C) of the 
PHS Act identifies certain content requirements for data elements, such 
as ``Primary and Secondary Outcomes.'' If the ``manner of reporting of 
the data elements established under [section 402(j)(3)(C) of the PHS 
Act]'' does not include the content requirements for these categories, 
then ``additions or modifications'' would be strangely limited to 
changing only how the information must be submitted (e.g., on paper or 
electronically), not what information must be submitted. This 
interpretation would leave us in the untenable situation, which we 
believe was not Congress' intent, of having to limit ``additions or 
modifications'' to changes only in how information must be submitted, 
not to what information must be submitted. Section 402(j)(3)(I)(i) of 
the PHS Act also informs this question by directing the Secretary 
within 18 months to determine by

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regulation ``the best method for including in the registry and results 
data bank appropriate results information on serious adverse and 
frequent adverse events . . . in a manner and form that is useful and 
not misleading to patients, physicians, and scientists.'' Because the 
``manner'' and ``form'' must be ``useful and not misleading,'' it would 
not be reasonable to conclude that such regulations could only specify 
the means of submitting and displaying the adverse event information, 
but not the information content. Finally, we believe Congress intended 
the Agency to have broad rulemaking authority to add to the information 
requirements of the data bank, as demonstrated in section 
402(j)(3)(D)(i) of the PHS Act, which directs that the data bank be 
expanded by rulemaking ``[t]o provide more complete results information 
and to enhance patient access to and understanding of the results of 
clinical trials.'' In this section, we explain the modifications made 
to the statutorily mandated adverse event reporting provisions and 
clarify how these modifications represent ``additions or modifications 
to the manner of reporting'' adverse event information.
    Commenters were concerned about the burden of providing adverse 
event information aggregated by the total number of participants 
affected and at risk for adverse events for each organ system, 
particularly for studies at academic medical centers and, in general, 
because this information is not routinely summarized for adverse events 
occurring during a trial. Some were concerned about adverse event data 
being reported differently on ClinicalTrials.gov as compared to EMA, 
FDA labeling, and other summary reports available on the FDA Web site 
(e.g., 510(k) summary). One commenter was supportive of the proposal 
only if it meant that all participants affected by an adverse event 
(whether serious or not) would be summarized by system organ class. 
Having considered the comments, the Agency is not including a 
requirement in this final rule to submit the total number of 
participants affected and at risk for adverse events by organ system. 
This data element was proposed as a new requirement; it was not part of 
other adverse event data elements that were implemented in 2009 as 
optional or required information. The comments helped us understand the 
extent to which such information is not routinely aggregated in this 
manner and the potential burdens associated with the requirement. We 
note that, in general, there will be differences between the 
information reported on ClinicalTrials.gov and in other reports, such 
as those submitted to FDA, because of differences in the underlying 
statutory framework and the requirements of the related regulations and 
elaborations provided in guidance.
    There were comments on the proposal to provide adverse event 
information by system organ class, based on the use of an organ system 
classification established in ClinicalTrials.gov. Most of these 
comments were in the context of the proposed requirement to summarize 
the total number of participants affected and at risk for adverse 
events for each organ system, which is not included in the final rule. 
The NPRM preamble described this organ system classification as based 
on the Medical Dictionary for Regulatory Affairs (MedDRA) [Ref. 99] (79 
FR 69589) As a standardized medical terminology, MedDRA is used 
internationally for the reporting of drug and biologic regulatory 
information and was adopted by ICH [Ref. 100]. Commenters indicated 
that at academic institutions there are not institution-wide systems 
established for the collection of adverse event information in a 
standard manner that would include MedDRA's organ system classification 
and that investigator-sponsors may not have access to MedDRA. In 
addition, commenters indicated that the requirements should be kept 
simple and ``consistent with current practice.'' One commenter 
requested an extended transition period for ongoing studies to allow 
for the incorporation of MedDRA into their processes. Some commenters 
also requested implementation of a new PRS feature to assist 
investigators who are responsible parties in classifying adverse events 
using MedDRA system organ classes. Although the final rule no longer 
includes the proposal to require the total number of participants 
affected and at risk by organ system, there is still a requirement to 
provide, for each adverse event, the ``[o]rgan system associated with 
the adverse event.''
    The proposal to require this organ system information is derived 
from the statutorily mandated adverse event reporting provisions that 
specified that adverse events need to be ``grouped by organ system.'' 
The organ system classification used to describe a specific adverse 
event submitted to ClinicalTrials.gov has been based on MedDRA organ 
system classes since the adverse events module was made available in 
September 2008 (and was required in September 2009). Thus, the final 
rule is consistent with current practice. Our experience indicates that 
responsible parties are able to use these classes effectively and that 
a single set of organ system classes provides a consistent way to 
display information about adverse events among the tables for a single 
trial and across trials. We also note that there are publicly available 
resources for mapping to MedDRA system organ classes, such as the NCI's 
thesaurus [Ref. 101], ``a widely recognized standard for biomedical 
coding and reference, used by a broad variety of public and private 
partners both nationally and internationally including the Clinical 
Data Interchange Standards Consortium Terminology (CDISC), the U.S. 
Food and Drug Administration (FDA), the Federal Medication 
Terminologies (FMT), and the National Council for Prescription Drug 
Programs (NCPDP).'' In the final rule, to clarify the circumstances in 
which the organ system is relevant, we have removed the general 
provision from the codified that stated that the information ``must be 
grouped according to the organ system classification established in 
ClinicalTrials.gov.'' Instead, when submitting the organ system 
associated with the adverse event, as specified in final Sec.  
11.48(a)(4)(iii)(D)(2), the responsible party is required to select one 
option describing the organ system from a list of options established 
on ClinicalTrials.gov. This approach improves consistency with other 
data elements in which the format (also described in Section IV.A.4) is 
to select from menu options. The use of this particular list for organ 
system class is based on our experience with voluntary and mandatory 
adverse events submission since September 2008, which indicates that 
responsible parties are able to use these classes effectively and that 
a single set of organ system classes provides a consistent way to 
display information about adverse events among the tables for a single 
trial and across trials.
    Two commenters indicated that, for certain trials of devices, the 
protocol specifies adverse event reporting only for organ systems that 
may be affected by the device. We note that we do not intend for these 
regulations to result in requiring an investigator to collect adverse 
event information of any type or in any way that is not specified in 
the protocol. Therefore, if adverse events were collected for only some 
organ systems, as pre-specified in the protocol, the responsible party 
would need to submit only those adverse events to ClinicalTrials.gov. 
The Additional Adverse Events Description data element (renamed 
``Adverse Event

[[Page 65093]]

Reporting Description'' in the final rule) could be used to describe 
the methods for adverse event collection, including any organ system 
classes that were not evaluated. We also note that since the 
publication of the NPRM, MedDRA version 19.0 was released, which 
includes a new system organ class called ``product issues.'' We will 
add this to the classification on ClinicalTrials.gov, bringing the 
total number of organ system classes to 27. Although we requested 
comments on whether an ``other'' option is necessary for the organ 
system class, no specific comments were received.
    Commenters requested that instead of the proposed requirement to 
report other adverse events that exceed a frequency of 5 percent within 
any arm of the clinical trial, the final rule require all other adverse 
events to be reported (i.e., other adverse events that exceed a 
frequency of 0 percent). These commenters were concerned that the 5 
percent threshold for reporting other adverse events did not have a 
clear scientific basis and potentially would allow some findings to go 
unreported. Similarly, one commenter requested that ``all adverse 
events occurring in five percent or more of patients across arms 
receiving the investigational product'' be required to be reported, 
based on a concern that if there are multiple arms with the 
investigational product, the overall frequency of adverse events among 
participants receiving the investigational product may be higher than 5 
percent. Another commenter suggested that the 5 percent threshold could 
be used for differentiating expected and unexpected adverse events. Our 
proposal for reporting anticipated and unanticipated other adverse 
events that exceed a frequency of 5 percent within any arm of the trial 
is based on section 402(j)(3)(I)(iii)(II) of the PHS Act. As stated in 
the NPRM (79 FR 69588), we will allow the submission of other adverse 
events with a frequency of 5 percent or less on an optional basis, as 
many responsible parties are currently doing. This allows responsible 
parties to determine whether a threshold of 5 percent or less is 
scientifically appropriate for their study. We believe that this 
approach strikes an appropriate balance between the potential burden of 
reporting all adverse events for all applicable clinical trials and the 
scientific value of allowing responsible parties to report adverse 
events occurring below the 5 percent threshold for a particular 
clinical trial. If a responsible party chooses to report adverse events 
that occur at a lower frequency (i.e., 5 percent or less), the specific 
threshold must be identified (e.g., 3 percent) and used for reporting 
all adverse events in each arm of the trial. This approach helps avoid 
the type of reporting bias that occurs when the reporting threshold 
varies by adverse event or by arm. Similarly, not permitting the 
threshold to be higher than 5 percent, which is consistent with section 
402(j)(3)(I)(iii)(II) of the PHS Act, avoids another type of reporting 
bias that could occur if the threshold was allowed to be set at any 
value (i.e., higher thresholds in some trials but not others could 
exclude the submission of important adverse event information). 
Therefore, we maintain the approach described in the NPRM to require 
the reporting of all other adverse events, other than serious adverse 
events, that exceed a frequency of 5 percent within any arm of the 
clinical trial.
    We invited comments on the benefits and burdens of requiring 
additional adverse event information, including time frame, collection 
approach, all-cause mortality information, and a standard vocabulary 
for adverse event terms (79 FR 69590). Some commenters were in favor of 
adding a requirement to submit the adverse event reporting time frame; 
one reason given was that the provision of this information would help 
avoid inappropriate comparisons across clinical trials that used 
different time frames. We agree that the time frame is important for 
comparing information across trials, and we note that it is also 
important for interpreting clinical trial results information within 
the context of a single trial, since the time frames for data 
collection for primary outcome measures, secondary outcome measures, 
and adverse events may all be different. Similarly, we note that Sec.  
11.44(d) describes partial results information submission deadlines 
based on when final data collection occurs for primary outcome 
measures, secondary outcome measures, and additional adverse event 
information. In this context, it is particularly important to have a 
description of the adverse event reporting time frame so that it is 
clear what time frame for assessment applies to adverse event 
information submitted as partial results. In the NPRM, we noted that 
responsible parties provided time frame information for more than half 
of the results information submitted in 2012 for probable applicable 
clinical trials (79 FR 69590). (See the explanation of probable 
applicable clinical trial in section IV.B.2). In 2015, nearly 60 
percent of results submitted for probable applicable clinical trials 
included information for the time frame data element. Based on the 
current use of this data element and the implications for interpreting 
adverse event information in the context of a single clinical trial and 
across trials, we are adding adverse event reporting time frame as a 
requirement in the final rule. As explained in detail earlier in this 
section, we consider this required information to represent a 
modification to the ``manner of reporting'' in section 
402(j)(3)(D)(v)(VI) of the PHS Act; the information helps elucidate the 
adverse event information in the statutorily mandated reporting 
provisions.
    Commenters who addressed the issue of collection approach for 
adverse event information were generally in favor of adding a 
requirement to submit this information, suggesting that such contextual 
information is important for interpreting the benefits and harms of an 
intervention evaluated in a trial and for comparing adverse event 
information across trials. Collection approach information includes an 
indication of the type of approach taken to collect adverse event 
information, either a systematic assessment or a non-systematic 
assessment. In the NPRM, we explained that a ``systematic assessment'' 
involves the use of a specific method of ascertaining the presence of 
an adverse event (e.g., the use of checklists, questionnaires,specific 
laboratory tests at regular intervals), and a ``non-systematic 
assessment'' relies on the spontaneous reporting of adverse events, 
such as unprompted self-reporting by participants (79 FR 69590). [Ref. 
102] One commenter suggested that the information be provided in a 
free-text field (instead of as a binary indication) to allow the 
responsible party to describe how adverse events were collected and 
adjudicated. We acknowledge that this can be a complex issue; however, 
we believe that the binary, structured indication of either a 
systematic or non-systematic assessment provides users of 
ClinicalTrials.gov with a consistent way of understanding what was done 
in the clinical trial. We also note that the free-text field for 
Adverse Event Reporting Description can be used by the responsible 
party to describe the methods for adverse event collection and provide 
any further details about adjudication. The submission of the protocol, 
as described in Sec.  11.48(a)(5), also would typically provide 
additional supporting information that is important for interpreting 
the collection approach and the submitted adverse event information. 
Another commenter requested clarification ``on the classification of 
routine investigator assessment of adverse events (when an

[[Page 65094]]

investigator asks if the subject has had an adverse event) as a 
Systematic Assessment.'' We interpret this routine investigator 
assessment to mean that the investigator asks a general question about 
whether a participant had any adverse events at prespecified intervals, 
rather than more targeted questions about specific categories or types 
of adverse events. We clarify that such a routine, general assessment 
would be considered a ``non-systematic assessment.'' However, if more 
specific questions were asked about adverse events at regular 
intervals, this approach could be considered a ``systematic 
assessment.'' We agree with the commenters that knowledge of the 
collection approach affects comparability of information across 
clinical trials and we believe that such information is similarly 
important for interpreting adverse event information for a single 
clinical trial. As we noted in the NPRM, clinical trials using non-
systematic assessment approaches typically record fewer adverse events 
than those using a systematic assessment approach [Ref. 102]. We also 
noted in the NPRM that, of the results for probable applicable clinical 
trials submitted to ClinicalTrials.gov in 2012, 76 percent voluntarily 
included information about the approach to collecting adverse events 
(79 FR 69590). In 2015, reporting was about the same, with 74 percent 
of results submitted for probable applicable clinical trials including 
information on the collection approach for adverse events. Based on the 
current use of this data element and the importance of this information 
for interpreting adverse event information, we require this information 
in the final rule. As explained in detail earlier in this section, this 
required information constitutes a modification to the ``manner of 
reporting'' in section 402(j)(3)(D)(v)(VI) of the PHS Act; this 
information helps elucidate the adverse event information in the 
statutorily mandated adverse event reporting provisions.
    Commenters who addressed the topic of including all-cause mortality 
information supported requiring the submission of such information, 
with the exception of one commenter. Commenters who supported the 
requirement stated that accurate information about the number of deaths 
in each arm of the clinical trial was critical for interpreting the 
trial's results. One of these commenters suggested that it would be 
misleading to have a statement specific to all-cause mortality 
information that explains that deaths may not be related to the 
intervention evaluated because this is actually what randomized trials 
are designed to understand. In addition, if there were such a 
statement, it would apply equally to other results, including outcomes. 
Some commenters (including some who supported the requirement) 
expressed concern about the interpretation of all-cause mortality 
information, particularly in the absence of information about 
attribution (i.e., whether the deaths were considered related to the 
intervention). The commenter opposed to the requirement expressed 
concern that the reporting of all-cause mortality information would 
increase the risk of re-identification of participants in the clinical 
trial, leading to requests for waivers of the clinical trial results 
information submission requirements, but the commenter did not provide 
further explanation of how the risk of re-identification would 
increase.
    We have considered these comments and require in the final rule the 
submission of all-cause mortality information in addition to the 
serious adverse events and other adverse events tables. This required 
information constitutes a modification to the ``manner of reporting'' 
in section 402(j)(3)(D)(v)(VI) of the PHS Act; this information helps 
elucidate the adverse event information in the statutorily mandated 
adverse event reporting provisions. Specifically, although other 
clinical trial results information may include information about 
deaths, the total number of deaths that occurred during the clinical 
trial might not be readily apparent (e.g., submitted serious adverse 
event information indicates the number of subjects who experienced a 
myocardial infarction, but it would not necessarily indicate how many 
of the subjects died from the event).
    As noted in the NPRM, submission of all-cause mortality information 
would be consistent with other clinical trial reporting guidelines (79 
FR 69590) [Ref. 56, 103]. The all-cause mortality information is 
described in Sec.  11.48(a)(4)(ii) of the final rule as being provided 
by the responsible party in a separate table. This approach allows the 
responsible party to use the Adverse Event Arm/Group Information as the 
table columns and, for each arm/group (i.e., separate column), to 
specify the overall number of human subjects affected by death due to 
any cause and the overall number of human subjects included in the 
assessment as a table row. The information will then be displayed as a 
row in the serious adverse events table in the posted study record. As 
with serious and other adverse event information, we will make 
available an optional data element for providing descriptive 
information that the responsible party deems appropriate.
    We acknowledge the concerns expressed by some of the commenters 
about potential misinterpretation of adverse event information. To 
address those concerns, we intend to provide standard explanatory 
information on each posted record that will help the public understand 
the definition of ``all-cause mortality'' and that will further explain 
that all-cause mortality information, serious adverse events, and other 
adverse events appearing on ClinicalTrials.gov are generally reported 
regardless of attribution. Similarly, in the context of all results 
information, a standard statement on the posted record will indicate 
that results of a single clinical trial may not be representative of 
the overall efficacy and safety profile of the product and that the 
FDA-approved product labeling should be consulted for information for 
approved drug products (including biological products) and device 
products. In response to the comment about waivers, we note that the 
NPRM indicated that a high risk of re-identification would be an 
appropriate reason for requesting that the requirement for submitting 
all-cause mortality information be waived, using the process described 
in proposed Sec.  11.54. However, because adverse event information is 
summary data provided in aggregate, we expect that waivers would be 
requested and granted in a very limited number of situations.
    Comments were mixed on the issue of whether attribution of an 
adverse event to a specific intervention evaluated in a study should be 
provided. Some commenters were opposed to providing information about 
attribution because of a lack of consensus about the optimal 
methodology for making such determinations, leading to concerns about 
the potential for tremendous variability and subjectivity across 
clinical trials regarding how decisions about attribution were made. 
Commenters indicated that attribution can only be assessed after a 
trial is completed (e.g., by comparing rates of events across arms of 
the clinical trial), and even then, decisions about attribution based 
on a single clinical trial may be incorrect. Similarly, one of these 
commenters cited FDA guidance to reviewers that instructs them to 
``discount'' attribution information [Ref. 104]. One commenter 
suggested that because of the challenges in correctly assigning 
attribution, such information should be prohibited. One commenter 
suggested that a disclaimer be added to adverse event information to 
explain

[[Page 65095]]

that the data do not necessarily reflect a conclusion by the sponsor or 
FDA that the event was caused or contributed to by the intervention. 
Some commenters were in favor of the submission of attribution 
information because they thought it was necessary to prevent 
misunderstandings about the safety of study interventions, including 
devices, and the risks of trial participation. One commenter indicated 
that the requirements for adverse event submission should be limited to 
only those serious adverse events and adverse events considered related 
to the intervention. In addition to the concerns raised by the 
commenters, we note that providing information on attribution would add 
an additional burden on responsible parties. Given the challenges 
described by commenters in accurately assigning attribution within the 
context of a single clinical trial, as well as similar concerns that we 
raised in the NPRM (79 FR 69589), we are not including attribution 
information in the final rule. We recognize that the monitoring of 
adverse events during a clinical trial has an important role in 
identifying the risks and benefits for human subjects participating in 
the clinical trial. [Ref. 105]. Attempts to determine attribution of an 
intervention to each individual adverse event, however, may be 
subjective (and potentially misleading), particularly after study 
completion when aggregate adverse event information is available to 
make objective quantitative assessments of the potential attribution of 
the intervention to the adverse event. [Ref. 106, 107, 108]. As noted 
in the discussion for all-cause mortality, we intend to include a 
standard statement on ClinicalTrials.gov to help the public understand 
that all-cause mortality information, serious adverse events, and other 
adverse events are generally reported regardless of attribution. We 
received one comment in support of requiring the submission of the 
number of occurrences of an adverse event (in addition to the number of 
participants affected by the adverse event). This optional data element 
has been available to responsible parties since the adverse events 
module was released in September 2008, and we will continue to make it 
available as an optional data element.
    A few commenters addressed the topic of whether we should require 
the submission of adverse event terms using a standard vocabulary. One 
of the commenters was opposed, citing in particular the burden that 
would be imposed if that particular vocabulary had not been used in a 
trial from the outset. Another commenter recommended that a standard 
vocabulary for adverse events be used, noting that emerging 
technologies could potentially take advantage of standard 
terminologies. We also interpret many of the comments received on using 
the MedDRA classification system for summarizing the total number of 
participants affected and at risk for adverse events by organ system as 
opposition to requiring a specific vocabulary. We did not receive any 
other suggested approaches for standardizing the vocabularies used for 
adverse event information. Taking into consideration the burden and the 
potential for this requirement to cause a responsible party to report 
or collect adverse event information in any way that is not specified 
in the protocol, we do not include in the final rule a requirement to 
submit adverse event terms using a standard vocabulary. We will, 
however, continue to provide optional data elements to allow 
responsible parties to describe the standard vocabulary that was used, 
if applicable.
    We also received some comments in response to our request for 
additional input on ways to reduce the data submission burden without 
reducing the value of the data. Commenters requested tools (in addition 
to XML) for uploading datasets for the adverse event tables. In the 
preamble of this final rule describing the format required for 
submitting clinical trial information in Sec.  11.8, we note that the 
PRS has allowed the submission of adverse event information in a 
spreadsheet format (e.g., Microsoft Excel) since 2013. We will continue 
to support uploading of adverse event information that uses this format 
and meets the technical specifications.
    Some commenters suggested that the regulations explicitly state 
that only adverse event information collected ``per protocol'' is 
required to be submitted. The requirements in the final rule are not 
intended to cause an investigator to collect information of a type or 
in a way not specified in the protocol. However, situations may arise 
during the conduct of a trial in which the responsible party collects 
and reports certain relevant adverse events that were not anticipated 
in the protocol and/or that occur in participants thus not following 
the protocol. Therefore, we maintain the proposed language in the final 
rule (i.e., ``collected during'') to cover all relevant situations. But 
we reiterate that the requirements in the final rule do not impose data 
collection requirements for an applicable clinical trial. One commenter 
suggested that adverse event information requirements should be less 
rigorous for products not being conducted under an IND/IDE because the 
safety and efficacy has already been established. We do not agree that 
the reporting of adverse event information for clinical trials not 
being conducted under an IND/IDE should be less rigorous. We believe 
that the purpose of the ClinicalTrials.gov database to make information 
available to the public is best achieved by requiring the same adverse 
event reporting requirements for all applicable clinical trials.
Final Rule
    Final Sec.  11.48(a)(4) generally maintains the NPRM approach, but 
we are making the following changes in the final rule: First, we remove 
the proposed requirement that the overall number of participants 
affected and at risk, by arm or comparison group, be reported by organ 
system class. Second, we add a requirement to submit all-cause 
mortality information by arm or comparison group. Third, we add a 
requirement to provide the time frame for adverse event data 
collection. Fourth, we add a requirement to provide the collection 
approach (systematic or non-systematic) for adverse events. In 
addition, in developing the final rule we have identified a few issues 
that would benefit from further clarification, based on our operational 
experience and routine queries from users. Specifically, we are 
clarifying the additional information required to be provided including 
a brief description of each arm/group (a similar omission was described 
for Sec.  11.48(a)(1), (2), and (3)). We have renamed the proposed 
Additional Adverse Event Description data element to ``Adverse Event 
Reporting Description'' and included it as Sec.  11.48(4)(i)(B) with 
the other requirements added in the final rule (i.e., Time Frame and 
Collection Approach) that also pertain to information about methods for 
adverse event collection. In addition, this name change is intended to 
reduce the potential for misinterpreting the data element as relating 
to a specific adverse event, rather than to definitions related to 
adverse event reporting overall. The change also better aligns the name 
of this data element with the optional data element in place on 
ClinicalTrials.gov prior to the final rule.[Ref. 97]. In addition, 
minor changes have been made for consistency with terms used in the 
statute and with similar data items in Demographic and baseline 
characteristics specified in Sec.  11.48(a)(2) and Outcomes and 
statistical analyses in Sec.  11.48(a)(3).

[[Page 65096]]

    Final Sec.  11.48(a)(4) requires the submission of summary 
information on anticipated and unanticipated adverse events that 
occurred during an applicable clinical trial. This includes a table of 
all serious adverse events; a table of adverse events other than 
serious adverse events that exceed a frequency of 5 percent within any 
arm of the clinical trial; and a table of all-cause mortality 
information, which will be displayed as a row in the serious adverse 
event table. Such information is considered part of results 
information. The requirements derive from the statutorily mandated 
adverse event reporting provisions in sections 402(j)(3)(I)(ii)-(iii) 
of the PHS Act and include the following additional requirements 
intended to assist users in understanding and interpreting the 
submitted adverse event information: Arm/group description, adverse 
event reporting description, time frame, collection approach, and all-
cause mortality information.
    We interpret modifications to the ``manner of reporting'' in 
section 402(j)(3)(d)(v)(VI) of the PHS Act to include, among other 
things, information that helps elucidate the adverse event information 
required by the statutorily mandated adverse event reporting 
provisions. The definitions of ``adverse event'' and ``serious adverse 
event'' are provided in Sec.  11.10(a).
    Final Sec.  11.48(a)(4)(i) requires the responsible party to submit 
information that describes the methods for collecting adverse event 
information. The Time Frame data element, as specified in Sec.  
11.48(a)(i)(A), describes the time period over which the submitted 
adverse event information was collected as well the overall period of 
time for which additional adverse event information was, is being, or 
will be collected (e.g., primary outcome measure data and adverse 
events collected over the same time period as the primary outcome are 
submitted, but secondary outcome measure and additional adverse event 
data collection is ongoing). Similar to the information provided for 
outcome measures on the time points of assessment (Sec.  
11.48(a)(3)(iii)(C)), the time frame for adverse event reporting is 
generally the specific duration of time over which each human subject 
is assessed for adverse events. Time frame information is a ``manner of 
reporting'' adverse event information and helps elucidate the adverse 
event information required by the statutorily mandated adverse event 
reporting provisions.
    In cases in which the protocol specifies the collection of only a 
limited set of adverse events (e.g., unanticipated adverse reactions), 
the responsible party is still required to submit three tables of 
information that summarize the information collected during the 
clinical trial with respect to serious adverse events, other adverse 
events (other than serious adverse events) that exceed a frequency of 5 
percent within any arm of the trial, and all-cause mortality. The all-
cause mortality information will be displayed as a row in the serious 
adverse event table. As specified in Sec.  11.48(a)(4)(i)(B), if the 
adverse event information collected in the trial is collected based on 
a definition of ``adverse event'' and/or ``serious adverse event'' that 
is diffrerent from the definitions in Sec.  11.10(a), the responsible 
party must use the Adverse Event Reporting Description data element to 
explain the differences. Similarly, the responsible party must use the 
Adverse Event Reporting Description data element to explain whether 
these definitional differences include adverse event collection methods 
that exclude certain types of adverse events required to be reported in 
Sec.  11.48(a)(4) (e.g., protocol specified that other adverse events 
are not to be collected, only serious adverse events are collected). 
This explanation facilitates the understanding of required adverse 
event information in situations where different definitions or methods 
of collection are used. Adverse Event Reporting Description constitutes 
a ``manner of reporting'' adverse event information that facilitates 
understanding the nature of the events being reported. Responsible 
parties may also use the Adverse Event Reporting Description data 
element, on an optional basis, to provide general information that they 
deem important for explaining methods of adverse event collection and 
reporting, including additional details about the collection approach.
    Collection Approach, specified in Sec.  11.48(a)(i)(C), allows the 
responsible party to identify whether a ``systematic assessment'' or 
``non-systematic assessment'' approach was taken to collect adverse 
event information during the trial. Responsible parties must specify 
the assessment type for adverse event information as a whole or for 
each adverse event in each table. Systematic assessment involves the 
use of a specific method of ascertaining the presence of an adverse 
event (e.g., the use of checklists, questionnaires, or specific 
laboratory tests at regular intervals). Non-systematic assessment 
relies on spontaneous reporting of adverse events, such as unprompted 
self-reporting by participants. This information explains how the 
statutorily mandated adverse event information was obtained and 
constitutes a ``manner of reporting'' this information authorized to be 
required by section 402(j)(3)(D)(v)(VI) of the PHS Act. We note that 
the requirements are not intended to cause an investigator to collect 
adverse event information of any type or in any way not specified in 
the protocol.
    Final Sec.  11.48(a)(4)(ii) specifies that responsible parties must 
submit three tables summarizing information on all serious adverse 
events, other adverse events with a frequency higher than 5 percent in 
any arm or comparison group of the clinical trial, and all-cause 
mortality. Final Sec.  11.48(a)(4)(iii) specifies that there must be a 
description of each arm or comparison group for which adverse event 
information was collected and the overall number of human subjects 
affected by and at risk must be described for each of the following 
tables: (1) Serious adverse events, (2) adverse events other than 
serious adverse events that exceed a frequency threshold of 5 percent 
within any arm, and (3) deaths due to any cause. We note that the death 
of a human subject could be reflected in information included in the 
serious adverse event table and in the all-cause mortality table. For 
example, a death separately identified in the serious adverse event 
table with a descriptive term for the adverse event such as 
``myocardial infarction'' (as specified Sec.  11.48(a)(4)(iii)(D)(1)) 
would also be included in the overall number of human subjects affected 
in the all-cause mortality table. The all-cause mortality information 
required by this rule is simply another meaningful way to aggregate and 
report one important type of serious adverse event (i.e., those that 
led to death). The all-cause mortality information is a ``manner of 
reporting'' the adverse event information authorized to be required by 
section 402(j)(3)(D)(v)(VI) of the PHS Act.
    The arm and comparison group information is provided once by the 
responsible party and is used for all three tables. As similarly 
discussed in this section under Demographic and baseline 
characteristics and Outcomes and statistical analyses, the Adverse 
Event Arm/Group Information data element describes the grouping of 
human subjects for the purposes of summarizing adverse event 
information. These descriptions are necessary to understand the 
statutorily mandated adverse event reporting information. Adverse Event 
Arm/Group Information is another ``manner of reporting'' the

[[Page 65097]]

adverse event information authorized to be required by section 
402(j)(3)(D)(v)(IV) of the PHS Act. ClinicalTrials.gov will use the Arm 
Information, Intervention Name, and Intervention Description data 
elements (submitted as clinical trial registration information), as 
well as Participant Flow Arm Information, Baseline Characteristics Arm/
Group Information, and Outcome Measure Arm/Group Information, to 
provide the responsible party with options for pre-populating table 
column names and descriptions for Adverse Event Arm/Group Information. 
The responsible party must review and edit the information as needed to 
ensure that it appropriately and accurately reflects the adverse event 
arms/groups for the clinical trial, or the responsible party may 
instead define new groups to reflect how adverse event information was 
analyzed. As described in the discussion of the term ``comparison 
group'' in Sec.  11.10(a) of the preamble, the reference to comparison 
group recognizes that when data collected during clinical trials are 
analyzed, the data are often aggregated into groupings of human 
subjects (i.e., comparison groups) other than the arms to which the 
subjects were assigned for the study. It is expected that Adverse Event 
Arm/Group Information will be the same as Participant Flow Arm 
Information, unless human subjects were analyzed in groups that are 
different from those to which they were assigned. In this situation, 
there must be sufficient detail to understand how the arm(s) or 
comparison groups used for submitting adverse events were derived from 
Participant Flow Arm Information. In general, Adverse Event Arm/Group 
Information must be inclusive of all arms or comparison groups, based 
on the pre-specified protocol and/or SAP. Adverse Event Arm/Group 
Information must also include sufficient details to understand the 
intervention strategy being described for that arm/group, similar to 
that which is described in Sec.  11.48(a)(1) for Participant Flow Arm 
Information.
    For each of the serious and other adverse events tables described 
in Sec.  11.48(a)(4)(ii)(A) and (B), respectively, the responsible 
party must provide a descriptive term for each serious adverse event 
and other adverse event with a frequency higher than 5 percent in any 
arm of the clinical trial (Sec.  11.48(a)(4)(iii)(D)(1)), along with 
the organ system that is associated with the adverse event (Sec.  
11.48(a)(4)(iii)(D)(2)), number of participants experiencing the 
adverse event (Sec.  11.48(a)(4)(iii)(E)(1)), and number of 
participants at risk for the adverse event (Sec.  
11.48(a)(4)(iii)(E)(2)). In most cases, the number of participants at 
risk for the adverse event will equal the number of participants who 
started that arm of the clinical trial. However, the number of 
participants at risk could differ if, for example, participants were 
assigned to an arm but did not receive the intervention (e.g., because 
they dropped out of the clinical trial) or because a comparison group 
combines participants from multiple arms of the trial. The number of 
participants at risk for each adverse event will generally be the same 
as the overall number of participants at risk in the arm or comparison 
group. To minimize the burden of data entry, the overall number of 
participants at risk will be pre-populated for each adverse event term. 
However, if these numbers are not the same (e.g., certain adverse 
events were only systematically evaluated in a sub-group of human 
subjects enrolled in the clinical trial), the responsible party can 
modify the number of participants at risk for each adverse event, as 
needed. Using the data submitted for the number of participants that 
experienced the adverse event and the number of participants at risk, 
ClinicalTrials.gov will automatically calculate the frequency 
(percentage of participants who experienced the event). This approach 
helps reduce calculation errors and helps users interpret the frequency 
information in those cases in which the full study population may not 
have been at risk for a specific adverse event or when the number of 
participants at risk is different across comparison groups.
    Adverse events described in Sec.  11.48(a)(4)(iii)(D)(1) must be 
submitted with an indication of the organ system associated with the 
adverse event (as described in Sec.  11.48(a)(4)(iii)(D)(2)) using the 
classification scheme specified on ClinicalTrials.gov, which includes 
the following 27 items adapted from the MedDRA version 19.0: Blood and 
lymphatic system disorders; Cardiac disorders; Congenital, familial and 
genetic disorders; Ear and labyrinth disorders; Endocrine disorders; 
Eye disorders; Gastrointestinal disorders; General disorders; 
Hepatobiliary disorders; Immune system disorders; Infections and 
infestations; Injury, poisoning and procedural complications; 
Investigations; Metabolism and nutrition disorders; Musculoskeletal and 
connective tissue disorders; Neoplasms benign, malignant and 
unspecified (including cysts and polyps); Nervous system disorders; 
Pregnancy, puerperium and perinatal conditions; Product issues; 
Psychiatric disorders; Renal and urinary disorders; Reproductive system 
and breast disorders; Respiratory, thoracic and mediastinal disorders; 
Skin and subcutaneous tissue disorders; Social circumstances; Surgical 
and medical procedures; and Vascular disorders organ classes [Ref. 99]. 
No ``other'' option is included. ``Product issues'' is not an organ 
class (like most of the other categories), but this term is used in 
MedDRA for issues with ``product quality, devices, product 
manufacturing and quality systems, supply and distribution, and 
counterfeit products'' [Ref. 109]. ``Social circumstances'' is also not 
an organ class but is used in MedDRA to accommodate the classification 
of some types of adverse events that are not specific to an organ 
system, such as an automobile accident, a homicide, or a fall. Adverse 
events that affect multiple systems must be reported only once (to 
avoid over-counting), preferably under the organ system class that is 
considered primary. If there is no primary organ system class, the 
event should be listed under ``General disorders,'' and additional 
information may be provided in the optional free-text field, Adverse 
Event Term Additional Description.
    Finally, we note that the Agency interprets section 402(j)(3)(I)(v) 
of the PHS Act to deem the adverse event information required under 
section 402(j)(3)(I) of the PHS Act as clinical trial results 
information not only for all applicable clinical trials but also for 
all voluntarily-submitted clinical trials under section 402(j)(4)(A) of 
the PHS Act. Therefore, responsible parties who submit clinical trial 
information subject to section 402(j)(4)(A) of the PHS Act must submit 
adverse event information in accordance with Sec.  11.48(a)(4). 
Additional information on the clinical trial information requirements 
for voluntarily-submitted clinical trials under section 402(j)(4)(A) of 
the PHS Act, is described in Section IV.D.1.
Sec.  11.48(a)(5)--Protocol and Statistical Analysis Plan
    Section 11.48(a)(5) adds a requirement to submit the protocol and 
statistical analysis plan as part of clinical trial results 
information. The proposal, comments and response, and final rule 
requirements are discussed in detail in Section III.D.
Sec.  11.48(a)(6)--Administrative Information
Overview of Proposal
    Proposed Sec.  11.48(a)(5)(i) implemented section 402(j)(3)(C)(iii) 
of the PHS Act,

[[Page 65098]]

which requires that ``a point of contact for scientific information 
about the clinical trial results'' be submitted as part of clinical 
trial results information, and specified the submission of the 
following information to allow users of ClinicalTrials.gov to inquire 
about the results of a clinical trial: (1) Name or official title of 
the point of contact, (2) name of affiliated organization, and (3) 
telephone number and email address of the point of contact (79 FR 
69644). This proposal reflects the Results Point of Contact data 
element used on ClinicalTrials.gov since the results database was first 
launched in September 2008 [Ref. 97].
    Proposed Sec.  11.48(a)(5)(ii) implemented section 402(j)(3)(C)(iv) 
of the PHS Act, which requires responsible parties to indicate 
``whether there exists an agreement . . . between the sponsor or its 
agent and the principal investigator . . . that restricts in any manner 
the ability of the principal investigator, after the primary completion 
date of the trial, to discuss the results of the trial at a scientific 
meeting or any other public or private forum, or to publish in a 
scientific or academic journal information concerning the results of 
the trial.'' The statutory provision also provides that this 
requirement does not apply to an agreement between a sponsor or its 
agent and the principal investigator solely to comply with applicable 
provisions of law protecting the privacy of participants in the 
clinical trial. We explained in the proposed rule preamble that in 
accordance with proposed Sec.  11.48(a)(5)(ii), we required responsible 
parties to indicate (yes/no) whether the principal investigator is an 
employee of the sponsor. If the principal investigator is an employee 
of the sponsor (yes), no further information must be provided, although 
it may be provided voluntarily. If the principal investigator is not 
(no), the responsible party would be required to indicate (yes/no) 
whether an agreement (other than one solely to comply with applicable 
provisions of law protecting the privacy of human subjects 
participating in the clinical trial) exists between the sponsor or its 
agent and the principal investigator that restricts in any manner the 
ability of the principal investigator, after the primary completion 
date of the clinical trial, to discuss the results of the clinical 
trial at a scientific meeting or any other public or private forum or 
to publish in a scientific or academic journal information concerning 
the results of the clinical trial. We also proposed to permit 
responsible parties to provide additional optional information about 
existing agreements. The proposal reflected the Certain Agreements data 
element used on ClinicalTrials.gov since the results component of the 
database was first launched in September 2008 [Ref. 97]. We invited 
public comment on the proposed approach, on any experience to date with 
the current approach, and on other information that might be collected 
on a voluntary basis (e.g., types of principal investigator disclosure 
restrictions) (79 FR 69644).
Comments and Response
    Regarding the results point of contact in proposed Sec.  
11.48(a)(5)(i), a few commenters suggested that the final rule not 
require the submission and posting of information that would identify 
an individual employee. One commenter proposed to instead require a 
general facility email address or contact form. We generally agree with 
these comments and note that the proposed approach, which is retained 
in the final rule, did not require the disclosure of an individual's 
name or specific contact information, but permitted the use of an 
official title and a general organizational phone number or email 
address. While the name of a specific individual and contact 
information for that individual are not required, a responsible party 
must provide sufficient information to allow users to reach a contact 
able to provide additional scientific information about the clinical 
trial results found on a posted record.
    Some commenters addressed the certain agreements provision in 
proposed Sec.  11.48(a)(5)(ii). One commenter suggested the addition of 
another category to the existing three optional choices currently 
available on ClinicalTrials.gov, to help viewers understand 
restrictions related to multi-site trials. For example, a sponsor may 
limit or prohibit individual-site principal investigators from 
disclosing single-site results before the overall results aggregated 
from all sites of a multi-center trial are disclosed. Another commenter 
proposed that such agreements be nullified in the event that clinical 
trial information submitted by a sponsor without the consent or 
knowledge of the principal investigator is found to be misrepresented 
or in the event of any legal proceedings arising from false or 
misleading data. In response to the first commenter, the Agency will 
consider the suggestion when deciding in the future whether to modify 
or restructure the optional principal investigator Disclosure 
Restriction Type component of the Certain Agreements data element. In 
response to the second commenter, the legal status of agreements 
between a sponsor or its agent and the principal investigator is 
outside the scope of this rulemaking. Final Sec.  11.48(a)(6)(ii) 
provides the mechanism for mandatory reporting of the existence of such 
agreements for applicable clinical trials under this part.
Final Rule
    Taking into consideration the commenters' suggestions and the 
statutory requirements for the submission of additional components of 
clinical trial results information, the final rule maintains the 
approach proposed in Sec.  11.48(a)(5). Final Sec.  11.48(a)(6)(i) 
requires the submission of the following information for a point of 
contact for scientific information about the results information for a 
clinical trial: Name or official title, name of the affiliated 
organization, and the telephone number and email address. We note that 
point of contact information is required to be submitted even if it is 
the same as the information for the responsible party, because we do 
not plan to make public the responsible party's contact information.
    Final Sec.  11.48(a)(6)(ii) requires the submission of information 
about certain agreements between the principal investigator and the 
sponsor. The responsible party must indicate whether the principal 
investigator is an employee of the sponsor. If the principal 
investigator is not an employee, the responsible party must indicate 
whether any agreement exists that restricts the principal investigator 
from disclosing the results of the clinical trial after the primary 
completion date. Consistent with the definition of ``principal 
investigator'' in Sec.  11.10, we interpret this provision as applying 
to a principal investigator who has oversight of the entire applicable 
clinical trial, not to site-specific investigators or other 
investigators (such as those on grant-funded studies) who may be 
referred to as principal investigators in other contexts but who do not 
meet the definition of ``principal investigator'' under this part. We 
clarify that when the responsible party for a clinical trial is a 
sponsor-investigator, for the purposes of submitting information about 
certain agreements in Sec.  11.48(a)(6)(ii), we interpret that the 
sponsor-investigator is both the sponsor and the principal investigator 
and is therefore considered an employee of the sponsor for the purposes 
of this section. We also clarify that the information about certain 
agreements that is required to be submitted under this regulation must 
accurately represent the status at the time of initial results

[[Page 65099]]

information submission, and if that information has changed since the 
previous submission of partial clinical trial results information, the 
responsible party must submit information to reflect the new status of 
certain agreements between the principal investigator and the sponsor 
at the time of the subsequent submission of partial results 
information, in accordance with Sec.  11.44(d)(3)(ii). For example, if 
the principal investigator had been an employee of the sponsor prior to 
results information submission but is no longer employed by the sponsor 
at the time of initial results information submission, the principal 
investigator would not be considered an employee of the sponsor for the 
purposes of submitting partial results information about certain 
agreements. However, if the principal investigator's employment status 
subsequently changes and he or she becomes an employee of the sponsor 
prior to the submission of final results information, the certain 
agreements information would need to be included when submitting 
partial results information as specified in Sec.  11.44(d)(3)(ii). Note 
that the Certain Agreements results data element specified in Sec.  
11.48(a)(6)(ii) is excluded from the update requirements specified in 
Sec.  11.64(a)(2).
    Additionally, in our interactions with responsible parties and 
consultations with stakeholders, we have learned that certain 
agreements of the nature described in section 402(j)(3)(C)(iv) of the 
PHS Act are routine in the clinical trials community, although they may 
vary in their terms and the duration of their limitations on the 
principal investigator. Such agreements, as we understand them, 
typically permit the sponsor or its delegate to review results 
communications prior to public release and impose a short-term embargo 
of 60 days or less, from the date that the communication is submitted 
to the sponsor for review, although other agreements may impose 
restrictions that are much longer in duration or broader in scope [Ref. 
110]. In order to allow responsible parties to provide additional 
information about the agreements in place between the sponsor or its 
delegate and the principal investigator, we permit the submission of 
optional, structured information about the agreement. These optional 
data elements, which are separate and distinct from the two data 
elements required as part of clinical trial results information, as 
previously discussed, are: (1) Whether the principal investigator is an 
employee of the sponsor and, if not, (2) whether any agreement exists 
that restricts the principal investigator from discussing or publishing 
the results of the clinical trial after the primary completion date. 
Thus, currently on ClinicalTrials.gov, a responsible party who wishes 
to provide this additional information may choose from among the 
following:
    (1) The only disclosure restriction on the principal investigator 
is that the sponsor can review results communications prior to public 
release and can embargo communications regarding clinical trial results 
for a period that is less than or equal to 60 days from the date that 
the communication is submitted to the sponsor for review. The sponsor 
cannot require changes to the communication and cannot unilaterally 
extend the embargo.
    (2) The only disclosure restriction on the principal investigator 
is that the sponsor can review results communications prior to public 
release and can embargo communications regarding clinical trial results 
for a period that is more than 60 days but less than or equal to 180 
days from the date that the communication is submitted to the sponsor 
for review. The sponsor cannot require changes to the communication and 
cannot unilaterally extend the embargo.
    (3) Other disclosure agreement that restricts the right of the 
principal investigator to disclose, discuss or publish clinical trial 
results after the trial is completed. The responsible party may provide 
an additional description of the disclosure agreement.
    Based on our experience operating ClinicalTrials.gov, the usage of 
these optional responses suggests that they provide an acceptable way 
to describe these agreements in a consistent format. These categories 
of optional information may be modified over time to reflect 
information that we learn about changes in clinical trials practice or 
to provide other information of interest to users. As permitted by law, 
we may make these changes without notice and comment rulemaking. 
However, we will provide prior notice and seek public comment on any 
proposed changes of a substantive nature to the format of required 
results information submission information (see Sec.  11.8 and the 
discussion in Section IV.A.4 of this preamble).
Sec.  11.48(a)(7)--Additional Clinical Trial Results Information for 
Applicable Device Clinical Trials of Unapproved or Uncleared Device 
Products
Overview of Proposal
    Proposed Sec.  11.48(a)(6)(i) enumerated additional descriptive 
information that responsible parties would need to submit as part of 
the clinical trial results information for applicable device clinical 
trials of unapproved or uncleared devices for display on the posted 
record. For applicable device clinical trials of unapproved or 
uncleared devices subject to delayed posting of registration 
information in proposed Sec.  11.35(b)(2)(i), the results information 
specified in proposed Sec.  11.48(a)(1) through (5) can be submitted as 
specified in proposed Sec.  11.44(c) and publicly posted as required by 
proposed Sec.  11.52 prior to the date on which clinical trial 
registration information is publicly posted (79 FR 69645).
    In proposing Sec.  11.48(a)(6)(i), we exercised the authority 
granted under sections 402(j)(3)(D)(ii)(II) and 402(j)(3)(D)(iii) of 
the PHS Act to require responsible parties of applicable device 
clinical trials of unapproved or uncleared devices to submit, as part 
of results information, certain additional descriptive information that 
is similar to the type of information submitted at the time of 
registration. In particular, section 402(j)(3)(D)(ii)(II) of the PHS 
Act authorizes the Secretary to determine through rulemaking whether 
responsible parties for applicable clinical trials of unapproved 
products would be subject to the results information submission 
requirements under proposed subpart C. Additionally, section 
402(j)(3)(D)(iii)(IV) of the PHS Act grants the Secretary wide 
discretion in determining what information can be required through 
rulemaking to be submitted as part of results information, stating that 
the regulations ``shall require, in addition to the elements described 
in [section 402(j)(3)(C)] . . . [s]uch other categories as the 
Secretary determines appropriate.'' Therefore, the Secretary can 
require, through rulemaking, submission of not only the results 
information required under section 402(j)(3)(C) of the PHS Act, but 
also ``such other categories'' of information as the Secretary 
determines appropriate. We noted in the NPRM that we interpret ``such 
other categories'' of results information for applicable device 
clinical trials of unapproved or uncleared device products to include, 
among other things, certain descriptive information that is similar to 
the type of information required to be submitted

[[Page 65100]]

under section 402(j)(2)(A)(ii) of the PHS Act. We pointed out that if 
clinical trial registration information is not available until after 
the posting of results information, users of ClinicalTrials.gov would 
lack access to certain descriptive information necessary to enhance 
access to and understanding of, the submitted results information and 
to determine whether the required results information has been 
submitted (e.g., for all arms of the study). Therefore, this 
descriptive information, as a component of clinical trial results 
information for unapproved or uncleared devices, would be posted based 
on the timeline specified in Sec.  11.52 (79 FR 69645).
    To make submission of the necessary descriptive information easier 
and to reduce the risk of inconsistency or error, Sec.  11.48(a)(6)(ii) 
proposed to require responsible parties to affirm the accuracy of the 
descriptive information that is similar to the type of information 
submitted when the trial is registered by verifying and updating it as 
necessary and then affirming that this descriptive information is ready 
to be posted with the results information. Once affirmed, the proposed 
rule explained, ClinicalTrials.gov would automatically populate the 
clinical trial results descriptive information data elements using the 
previously submitted clinical trial registration elements that are 
similar to the type of information to be submitted when the trial is 
registered. The proposed approach would decrease the burden on 
responsible parties, reduce inconsistencies between information 
previously submitted at registration and information submitted with 
results, and increase administrative efficiency by reducing the need 
for the Agency to conduct a wholly-new quality control review of the 
submitted information (79 FR 69645).
Comments and Response
    We did not receive any specific comments about the proposal to 
require additional descriptive results information for applicable 
device clinical trials of unapproved or uncleared devices in proposed 
Sec.  11.48(a)(6). We did receive comments concerning the submission of 
any results information for unapproved or uncleared devices, and these 
comments are addressed in Section III.B. of this preamble.
Final Rule
    Final Sec.  11.48(a)(7)(i) specifies the additional results 
information necessary to enhance access to and understanding of the 
results of applicable clinical trials of unapproved or uncleared device 
products consistent with the proposed rule. However, this section 
clarifies that this requirement is limited to applicable clinical 
trials of unapproved or uncleared device products for which clinical 
trial registration information has not been posted publicly by the 
Director on ClinicalTrials.gov in accordance with Sec.  11.35(b)(2)(i). 
This section also includes minor modifications to the names of data 
elements for consistency with modifications to the data elements in 
Sec.  11.10(b). Additionally, final Sec.  11.48(a)(7) clarifies that 
``device'' means ``device product.''
    Final Sec.  11.48(a)(7)(ii) states that responsible parties must 
submit all the results information specified in Sec.  11.48(a)(7)(i). 
We clarify that this applies to all applicable device clinical trials 
of unapproved or uncleared device products that are subject to Sec.  
11.48(a)(7)(i), regardless of when the trial was initiated. We also 
clarify that if a responsible party indicates to the Director that it 
is authorizing the Director, in accordance with Sec.  11.35(b)(2)(ii), 
to publicly post its clinical trial registration information on 
ClinicalTrials.gov prior to the date of FDA approval or clearance of 
the device product, the applicable device clinical trial of its 
unapproved or uncleared device product is not subject to Sec.  
11.48(a)(7)(i).
    Section 11.48(a)(7)(ii) additionally requires responsible parties 
to submit an affirmation that any information previously submitted to 
ClinicalTrials.gov for the data elements listed in paragraph Sec.  
11.48(a)(7)(i) of this section have been updated in accordance with 
Sec.  11.64(a) and are to be included as clinical trial results 
information. As described above, to make submission of the necessary 
descriptive information under Sec.  11.48(a)(7)(i) easier and to reduce 
the risk of inconsistency or error, ClinicalTrials.gov will 
automatically populate the clinical trial results descriptive 
information data elements using the previously submitted clinical trial 
registration elements that are similar to the type of information 
submitted when the trial is registered. This automatic population 
approach is intended to decrease the burden on responsible parties, 
reduce inconsistencies between information previously submitted and 
information submitted with results, and increase administrative 
efficiency. The affirmation in Sec.  11.48(a)(7)(ii) therefore applies 
to the previously submitted information that will be used to populate 
the data elements listed in Sec.  11.48(a)(7)(i). The responsible party 
must enter any additional descriptive information that has not been 
automatically populated, as Sec.  11.48(a)(7)(ii) requires the 
submission of all results information specified in Sec.  
11.48(a)(7)(i).
Sec.  11.48(b)--Results Information for a Pediatric Postmarket 
Surveillance of a Device Product That Is Not a Clinical Trial
Overview of Proposal
    Proposed Sec.  11.48(b) specified the results information that must 
be submitted to ClinicalTrials.gov for a pediatric postmarket 
surveillance of a device that is not a clinical trial. We proposed that 
the final report submitted to FDA according to 21 CFR 822.38 (or any 
successor regulation) must be submitted to ClinicalTrials.gov in a 
common electronic document format and must include redactions of 
personally identifiable information and commercial confidential 
information. We invited public comment on the proposed approach (79 FR 
69646).
Comments and Response
    Commenters addressed the proposal for a pediatric postmarket 
surveillance of a device that is not a clinical trial in proposed Sec.  
11.48(b). Commenters recommended that the final rule alternatively 
allow for the submission of a study summary in place of a redacted 
final report, suggesting that the redacted final report ``might be 
confusing and virtually unreadable.'' One commenter indicated that a 
pediatric postmarket surveillance of a device that is not a clinical 
trial should be required to provide the same clinical trial results 
information (as for a clinical trial) identified in proposed Sec.  
11.48(a). As noted in the NPRM, ``pediatric postmarket surveillances 
under section 522 of the FD&C Act can take various forms [other than a 
clinical trial], including a detailed review of the complaint history 
and the scientific literature, non-clinical testing, observational 
studies . . .'' (79 FR 69576). As such, it may not always be possible 
or appropriate for the responsible party for a pediatric postmarket 
surveillance of a device that is not a clinical trial to provide all of 
the specified results data elements or data tables required for 
clinical trials in proposed Sec.  11.48(a). Regarding the suggested 
submission of a study summary, it is not clear, based on the comments, 
which specific items would be included in such a summary and how the 
components could be described in the context of this final rule. 
Because of the broad spectrum of types of studies that may be 
considered pediatric

[[Page 65101]]

postmarket surveillances of a device, it is not possible to fully 
elucidate the items that should be present in such a summary that would 
apply to all types of studies. On the other hand, the final report 
submitted to FDA would include the results information that was deemed 
important by FDA. Therefore, we maintain the approach in the final rule 
that the responsible party is required to provide a copy of the final 
report submitted to FDA. This approach ensures that the information and 
requirements are consistent for all types of pediatric postmarket 
surveillances of a device product that are not clinical trials. We 
have, however, modified the requirement as described in the NPRM, in 
that we are not requiring that the final report be redacted. Upon 
further consideration, we believe that it is appropriate to leave 
decisions about information to be redacted to the discretion of the 
responsible party.
Final Rule
    Taking into consideration the commenters' suggestions and the 
statutory requirements for the submission of clinical trial results 
information for a pediatric postmarket surveillance of a device that is 
not a clinical trial, we maintain in the final rule the approach 
proposed in Sec.  11.48(b), but we remove the requirement to redact 
information from the final report submitted to FDA and clarify that 
``device'' means ``device product.''
    Final Sec.  11.48(b) specifies the results information that must be 
submitted to ClinicalTrials.gov for a pediatric postmarket surveillance 
of a device product that is not a clinical trial. We recognize that a 
pediatric postmarket surveillance of a device product may take any of 
several forms, including prospective surveillance studies and 
historical reviews of the health records of those who have received a 
device as an intervention, and may not meet the definition of a 
``clinical trial'' under this part. For this reason, it is not possible 
to specify particular data elements or tables of data for all types of 
pediatric postmarket surveillances of a device product that are not 
clinical trials. For each pediatric postmarket surveillance of a device 
product that is not a clinical trial, the final report submitted to FDA 
according to 21 CFR 822.38 (or any successor regulation) is required to 
be submitted to ClinicalTrials.gov. The responsible party may redact 
names, addresses, and other personally identifiable information, as 
well as any proprietary information (i.e., trade secrets and/or 
confidential commercial information) contained in the report, but the 
redacted information should not include any of the information required 
to be submitted under Sec. Sec.  11.28(a) or 11.48(a) of this part. The 
final report is required to be submitted in a common electronic 
document format specified on ClinicalTrials.gov at https://prsinfo.clinicaltrials.gov (or successor site).
5. Sec.  11.52--By when will the NIH Director post submitted clinical 
trial results information?
Overview of Statutory Provisions and Proposal
    According to section 402(j)(3)(G) of the PHS Act, for applicable 
clinical trials, the Director of NIH is required to post results 
information ``publicly in the registry and results database not later 
than 30 days after such submission.'' Proposed Sec.  11.52 implemented 
this provision, stating that NIH will post publicly ``clinical trial 
results information submitted under this subpart at ClinicalTrials.gov 
not later than 30 calendar days after the date of submission'' (79 FR 
69646).
Comments and Response
    The comments received on the provisions specified in Sec.  11.52 
for posting of clinical trial results information pertained to the 
proposed quality control procedures (described in section III.C.12 of 
the NPRM and proposed Sec.  11.66) and the timing of posting in 
relationship to those procedures. These comments are addressed in full 
in Section IV.D.3 of this preamble which addresses the requirements for 
corrections in Sec.  11.64(b)(1) (which now includes the provisions 
proposed in Sec.  11.66). We describe here the comments specific to the 
timeline for posting. Some commenters supported the proposal for 
posting, however, a number of commenters favored the quality control 
review of information and suggested that information on both 
registration and results should be posted only after quality control 
review process has concluded. Commenters expressed concern about the 
potential to misinform those using the public record and suggested only 
posting sections that have fulfilled quality control criteria. Some 
commenters suggested that the harm of posting information before the 
quality control review process has concluded is greater than the 
benefit of posting the information in a timely manner. While we 
understand these concerns, we interpret the statutory posting deadline 
to be a clearly delineated timeline between submission and posting. In 
addition, in the event that a study record is posted in accordance with 
the statutory posting deadline and the quality control review process 
has not concluded, the clinical trial record will contain information 
that will be visible to those viewing the record on ClinicalTrials.gov 
to make it clear that the quality control review process has not 
concluded for the posted clinical trial information.
Final Rule
    Taking into consideration the commenters' concerns and the 
statutory requirements for posting clinical trial results information, 
we maintain the NPRM proposal in the final rule. For clarity, we have 
modified the title of Sec.  11.52 such that it is now ``By when will 
the NIH Director post submitted clinical trial results information?'' 
As discussed further in the preamble for Sec.  11.10, we clarified that 
clinical trial results information means the data elements the 
responsible party is required to submit to ClinicalTrials.gov as 
specified in the PHS Act or as specified in these regulations, as 
applicable. Thus, we have clarified Sec.  11.52 by removing the phrase 
``submitted under this subpart.'' We have also clarified that the 
requirement does not apply to information submitted under section 
402(j)(4)(A) of the PHS Act and Sec.  11.60.
    Section 11.52 applies only to clinical trial results information 
required to be submitted to ClinicalTrials.gov. Reflecting section 
402(j)(2)(C) of the PHS Act, as codified in Sec.  11.42, clinical trial 
results information is required to be submitted for certain applicable 
clinical trials ``for which clinical trial registration information is 
required to be submitted'' (see Sec.  11.42(a) and (b)). Section 11.22 
specifies which applicable clinical trials must be registered. For such 
trials that voluntarily register with ClinicalTrials.gov, regardless of 
whether they are subject to the requirements for voluntary submission 
under Sec.  11.60 or are subject to the requirements in Sec.  
11.60(a)(2)(ii), we intend to post results information as soon as 
practicable after clinical trial results information has been submitted 
and after the issues identified during quality control are corrected or 
adequately addressed.
6. Sec.  11.54--What are the procedures for requesting and obtaining a 
waiver of the requirements for clinical trial results information 
submission?
Overview of Proposal
    Section 402(j)(3)(H) of the PHS Act provides that ``[t]he Secretary 
may

[[Page 65102]]

waive any applicable requirements of this paragraph [(3) of the PHS 
Act] for an applicable clinical trial, upon written request from the 
responsible party, if the Secretary determines that extraordinary 
circumstances justify the waiver and that providing the waiver is 
consistent with the protection of public health or in the interest of 
national security . . .'' The statute also stipulates that if such a 
waiver is granted, the Secretary will notify the appropriate 
congressional committees that the waiver has been granted and explain 
why it has been granted, not later than 30 calendar days after the 
waiver has been granted. Proposed Sec.  11.54 implemented this 
provision by outlining procedures by which a responsible party may 
submit a written request for a waiver from the requirements of subpart 
C for an applicable clinical trial. Proposed Sec.  11.54(a) specified 
the details for the submission and content of the waiver request, 
including that the request identify the specific requirement(s) for 
which the waiver is requested. Proposed Sec.  11.54(b) specified the 
procedures and deadlines for appealing a denied waiver request, and 
Sec.  11.54(c) provided that the Director would include a notation in 
the clinical trial record for the waived results submission requirement 
and that the Secretary would notify the appropriate congressional 
committees of the waiver and why it was granted (79 FR 69646).
    The proposed rule noted that we expected that waivers would be 
requested and granted in only a very limited number of situations, and 
we described an example of a situation in which a waiver might be 
granted, namely if results information could be submitted only in a 
manner that would likely enable the re-identification of clinical trial 
participants. We invited public comments on other situations in which a 
waiver might be granted and would be consistent with the protection of 
public health or in the interest of national security. With regard to 
the notation on the clinical trial record, we explained that it was 
intended to inform users of ClinicalTrials.gov that the absence of 
certain results information does not constitute a failure to comply 
with the statute and implementing regulation. We also explained that 
because the waiver would be based on extraordinary circumstances that 
could include considerations of public health and/or national security, 
we proposed that we would not publicly post information describing the 
reason for the waiver. We invited public comment on this proposal as 
well (79 FR 69646).
Comments and Response
    Several commenters addressed the Agency's proposed procedures for 
handling waiver requests. Commenters suggested additional examples of 
situations that they thought would warrant a waiver of the results 
information submission requirements. Several commenters suggested that 
a waiver was warranted when the principal investigator could no longer 
serve as the responsible party such as when the investigator relocates 
or in the event of their death or disability. Commenters suggested that 
a waiver would relieve the institution of the burden of having to 
fulfill the responsible party's obligations to submit results 
information. We do not consider a principal investigator's inability to 
fulfill their responsibilities as an extraordinary circumstance that 
would satisfy the statutory standard. Section 11.4(c)(3) provides for 
the reassignment of the responsible party function when the principal 
investigator no longer meets or is no longer able to meet all of the 
requirements for designation as the responsible party or in the event 
of the principal investigator's death or incapacity. Other comments 
emphasized the importance of maintaining flexibility in the process of 
considering requests for waivers for results information reporting and 
asserted that without flexibility in the system, waiver requests may be 
unnecessarily denied. We believe that the proposed rule provides the 
necessary mechanisms and the flexibility for considering waivers while 
also protecting public health and national security.
    Comments were also received suggesting that the proposed rule's 15 
calendar day deadline for data submission following waiver denial or 
appeal denial should be extended, including a proposal to allow the 
waiver request to be submitted 60 calendar days before the results 
information submission deadline, allowing the Secretary 30 calendar 
days to transmit a decision and an additional 60 calendar days for an 
appeal resolution. We agree with the comments that longer timeframes 
are appropriate and have included 30-calendar day deadlines in the 
final rule.
    Commenters also supported the use of justified waiver requests as 
well as a publicly posted notation on the clinical trial record if 
results information submission is waived. Other commenters suggested 
making the waiver request and appeal public and allowing the public to 
appeal a reason given in a waiver request by a responsible party. Since 
the waiver would be based on extraordinary circumstances that could 
include considerations of public health and/or national security, the 
Agency will retain the proposed approach of not posting information 
describing the reason for the waiver.
Final Rule
    Taking into consideration the public comments and the statutory 
requirements set forth in section 402(j)(3)(H) of the PHS Act, the 
final rule retains the proposed rule with the exception of the 
timeframes for submitting results information after a waiver denial, 
for appealing a waiver denial, and for submitting results information 
after a denial of the waiver on appeal. These timeframes have been 
extended from 15 calendar days to 30 calendar days. The final rule also 
clarifies in Sec.  11.54(d) that for an applicable clinical trial with 
a primary completion date before the effective date of the rule, the 
responsible party may submit a waiver request as specified in section 
402(j)(3)(H) of the PHS Act. This is consistent with the differing 
requirements that apply to applicable clinical trials, depending on the 
primary completion date of the applicable clinical trial, as discussed 
further in Section IV.F of this preamble. Section 11.54 of the rule 
outlines procedures by which a responsible party may submit a request 
for a waiver from any or all requirements of results information 
submission. We expect that waivers will be requested and granted only 
for extraordinary circumstances that could include the need to protect 
the public health and/or the interests of national security. The Agency 
will issue guidance on how to submit such waiver requests.
    Section 11.54(a) of the rule specifies that waiver requests must be 
submitted by the responsible party to the Secretary or a delegated 
official in the format specified at https://prsinfo.clinicaltrials.gov/ 
(or successor site) and indicate the NCT number, Brief Title, and Name 
of the Sponsor of the applicable clinical trial. This information is 
necessary to ensure accurate identification of the specific trial for 
which the waiver is requested (i.e., the combination of NCT number and 
Brief Title will assist in identifying mistyped NCT numbers) and the 
key parties involved (i.e., sponsor and responsible party). Since the 
statute grants the Secretary the authority to waive ``any applicable 
requirements'' for the submission of results information if justified 
by ``extraordinary circumstances,'' the rule

[[Page 65103]]

requires the responsible party to identify the specific provisions(s) 
for which a waiver is requested and provide a description of the 
extraordinary circumstances that are believed to justify the waiver. 
The responsible party will not be required to comply with the results 
information submission provisions in subpart C for which the waiver is 
granted. Such provisions could include all or just some of the 
provisions for which the waiver is requested. The responsible party 
will continue to be required to comply with any remaining provisions of 
subpart C for which the waiver is not requested or not granted. It is 
important to note, however, that a responsible party may still need to 
provide certain information in the PRS to indicate that the results 
information submission requirement was waived for that information. 
After a waiver is granted, the Agency will work with the responsible 
party to address the specific requirements that are waived. In some 
cases, for example, the responsible party may need to enter ``0 
participants'' with an explanation that a waiver was provided for such 
information. While a waiver request is pending, the responsible party 
will not be required to submit other required clinical trial results 
information. The deadline for submitting results information to 
ClinicalTrials.gov is the later of the original submission deadline or 
30 calendar days after a notification denying the waiver is sent to the 
responsible party.
    Section 11.54(b) details the process by which a responsible party 
may appeal a denied waiver request to the Secretary or delegated 
official and indicates that additional information about the format of 
the appeal will be specified at https://prsinfo.clinicaltrials.gov/ (or 
successor site). If this responsibility is delegated to a Department or 
Agency official, the delegated official will, as a matter of practice, 
differ from the delegated official for reviewing the initial waiver 
request. As with the original request, the responsible party is not 
required to comply with specific provisions of subpart C for which the 
waiver is granted upon appeal. For the provisions for which a waiver is 
not granted upon appeal, the responsible party is required to submit 
results information by the later of the original results information 
submission deadline or 30 calendar days after the notification denying 
the appeal is sent to the responsible party. Of note, we have replaced 
the word ``transmitted,'' used in the proposed rule, with the phrase 
``sent to the responsible party'' in final Sec.  11.54(b)(1) and added 
the phrase ``to the responsible party'' in final Sec.  11.54(b)(3). 
Although these changes do not alter the meaning of these provisions, we 
believe they further clarify that the responsible party has 30 calendar 
days from the date the notification is sent from the Agency as 
evidenced by the date stamp on the notification.
    Section 11.54(c)(1) requires the Director to include a notation in 
the clinical trial record that specified elements of the results 
information submission requirements have been waived. This notation is 
intended to inform users of ClinicalTrials.gov that the absence of 
certain results information does not necessarily constitute a failure 
to comply with the statute and implementing regulation. Section 
11.54(c)(2) implements section 402(j)(3)(H) of the PHS Act by requiring 
the Secretary, if a waiver is granted, to notify the appropriate 
congressional committees that the waiver has been granted and explain 
why it has been granted, not later than 30 calendar days after any part 
of the waiver is granted. Since the waiver would be based on 
extraordinary circumstances that could include considerations of public 
health and/or national security, the Agency will not post publicly 
information describing the reason for the waiver.
    Section 11.54(d), as described above, states that a responsible 
party for an applicable clinical trial with a primary completion date 
before the effective date of the rule may request a waiver from any of 
the applicable requirement(s) for clinical trial results information 
submission in accordance with the procedures specified in section 
402(j)(3)(H) of the PHS Act.

D. Subpart D--Additional Submissions of Clinical Trial Information

1. Sec.  11.60--What requirements apply to the voluntary submission of 
clinical trial information for clinical trials of FDA-regulated drug 
products (including biological products) and device products?
Overview of Proposal
    Proposed Sec.  11.60 described requirements that would apply to 
voluntary submissions of information for certain clinical trials not 
otherwise subject to the registration and results information 
submission requirements of section 402(j) of the PHS Act. Section 
402(j)(4)(A) of the PHS Act specified that ``[a] responsible party for 
a clinical trial that is not an applicable clinical trial, or that is 
an applicable clinical trial that is not subject to paragraph (2)(C), 
may submit complete clinical trial information described in paragraph 
(2) or paragraph (3) [of the PHS Act] provided the responsible party 
submits clinical trial information for each applicable clinical trial 
that is required to be submitted under section 351 [of the PHS Act] or 
under section 505, 510(k), 515, or 520(m) of the Federal Food, Drug, 
and Cosmetic Act in an application or report for licensure, approval, 
or clearance of the drug or device for the use studied in the clinical 
trial.'' Based on this provision, the proposed rule described two types 
of clinical trials of FDA-regulated drugs or devices for which 
submission of information is not otherwise required: (1) Clinical 
trials that do not meet the definition of an applicable clinical trial; 
and, (2) clinical trials that are applicable clinical trials but are 
not required to register under proposed section Sec.  11.22(a) (i.e., 
clinical trials that are applicable clinical trials that were initiated 
on or before September 27, 2007, and that reached their completion 
dates before December 26, 2007) (79 FR 69647).
    Under proposed Sec.  11.60, if a responsible party voluntarily 
submitted clinical trial information for either type of clinical trial 
for which submission of information is not otherwise required, the 
responsible party would be required to submit registration information 
as specified in proposed Sec.  11.60(a)(2)(i)(A) or results information 
as specified in proposed Sec.  11.60(a)(2)(i)(B) for the voluntarily 
submitted clinical trial. In addition, proposed Sec.  11.60(a)(2)(ii) 
and Sec.  11.60(a)(2)(iii) described additional applicable clinical 
trials (i.e., ``triggered'' trials) for which clinical trial 
information would be required to be submitted if a responsible party 
voluntarily submitted clinical trial information for a clinical trial 
not otherwise required to be registered. In this context, ``triggered'' 
trials referred to ``each applicable clinical trial that is required to 
be submitted under section 351 [of the PHS Act] or under section 505, 
510(k), 515, or 520(m) of the [FD&C] Act in an application or report 
for licensure, approval, or clearance of the drug or device for the use 
studied in the clinical trial'' as specified in section 402(j)(4)(A) of 
the PHS Act. Requiring the submission of information for ``triggered'' 
trials helps prevent selective voluntary submissions of results 
information from clinical trials that only show positive results for a 
particular product, but not from those applicable clinical trials that 
show negative or uncertain results for the same product (79 FR 69648). 
Additionally, proposed Sec.  11.60(a)(2)(iv) provided deadlines 
applying to voluntary submissions and proposed Sec.  11.60(a)(2)(v) 
specified that

[[Page 65104]]

all voluntary submissions would be subject to the update and 
corrections requirements proposed in Sec. Sec.  11.64 and 11.66, 
respectively. Finally, proposed Sec.  11.60(b) provided a statement to 
accompany applicable clinical trial information that was submitted 
voluntarily as specified in section 402(j)(3)(D)(v)(V) of the PHS Act 
(79 FR 69649).
Comments and Response
    Several commenters addressed proposed Sec.  11.60. Some commenters 
supported the proposed requirements, while one suggested that the scope 
of the mandatory submission requirements should be modified to 
encompass all trials covered by the proposed voluntary submissions 
requirements, including those of currently marketed drugs and devices 
completed before the enactment of FDAAA. The Agency appreciates these 
comments and the underlying sentiment for broad trial registration and 
results information reporting policies. We note that responsible 
parties have always been able to submit voluntarily the registration 
and/or results information for clinical trials of currently marketed 
drugs and devices that were completed before the enactment of FDAAA. We 
also note that Sec.  11.60 of the final rule provides that, as of 
September 27, 2007, responsible parties who make such voluntary 
submissions and are manufacturers of the studied product must also 
submit clinical trial information for all ``triggered'' applicable 
clinical trials required to be provided to FDA in a marketing 
application or premarket notification, in order to avoid selective 
disclosure of information about a product on ClinicalTrials.gov.
    Other commenters suggested that the Agency consider including fewer 
requirements in the final rule to encourage more voluntary submissions, 
while another requested the removal of proposed requirements for 
updating and correcting voluntarily submitted trial information because 
of concerns that such a burden may have the unintended consequence of 
discouraging voluntary submissions. In response, the Agency has 
reviewed proposed Sec.  11.60(a) and determined that each requirement 
is necessary to ensure that voluntary submissions would be provided in 
accordance with the statute. Further, we have added the Study 
Completion Date data element, as defined in Sec.  11.10 of the final 
rule and discussed in Section IV.A.5 of this preamble, to the list of 
required additional results data elements that must be provided when 
the responsible party voluntarily submits clinical trial results 
information for a clinical trial for which the clinical trial 
registration information specified in Sec.  11.60(b)(2)(i)(B), and 
11.60(c)(2)(i)(B) have not been submitted. The Study Completion Date is 
needed to identify that the requirements for voluntary partial results 
information submission in Sec.  11.60(a)(2)(iv)(A), 11.60(b)(2)(iv)(A), 
and 11.60(c)(2)(iv)(A), and obligations for updates and corrections in 
Sec. Sec.  11.60(c)(2)(v) and 11.64 have been fulfilled. That is, even 
though a responsible party for a trial may need to submit partial 
results information several times voluntarily in order to meet 
different deadlines (i.e., because of different dates for final data 
collection for primary and/or secondary outcome measures or for the 
pre-specified time frame for collecting adverse events), that 
responsible party's obligation for voluntary results information 
submission is only completely fulfilled after all required results 
information is submitted not later than 1 year following the Study 
Completion Date. With regard to the updating and correction 
requirements in proposed Sec.  11.60, section 402(j)(4)(A) of the PHS 
Act provides that voluntary submissions of information must consist of 
``complete'' clinical trial registration and/or results information. 
The updating requirements help ensure that any subsequent changes in 
clinical trial information for a voluntarily submitted trial (e.g., 
overall recruitment status) are reflected in the data bank. 
Additionally, the error correction requirements provide for the timely 
revision of submitted clinical trial information. As with mandatory 
submissions, these requirements are intended to help assure that all 
voluntary submissions are complete and accurate.
    A commenter expressed concerns over a statement to accompany 
applicable clinical trials submitted voluntarily in proposed Sec.  
11.60(b). The commenter suggested that submitted statements may be 
written in language too technical for the public to understand and 
recommended several approaches to clarifying the meaning, such as 
providing a hyperlink to a page containing an explanation written in 
non-technical language or amending the statement directly with non-
technical language. The Agency agrees that the proposed language was 
too technical and has modified the statement in the final rule by 
adding a non-technical first sentence and placing the original 
technical statement in parenthesis for clarity: ``This clinical trial 
information was submitted voluntarily under the applicable law and, 
therefore, certain submission deadlines may not apply. (That is, 
clinical trial information for this applicable clinical trial was 
submitted under section 402(j)(4)(A) of the Public Health Service Act 
and 42 CFR 11.60 and is not subject to the deadlines established by 
sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 
11.24 and 11.44.)''
    In addition, a few commenters requested clarification on additional 
issues. In particular, one commenter requested clarification of the 
word ``triggered'' as used in the preamble section of the proposed 
rule. In the preamble of the proposed rule and this final rule, we use 
the term ``triggered'' to refer to the statutory requirement that a 
responsible party who has voluntarily submitted clinical trial 
information for a clinical trial that is not an applicable clinical 
trial or that is an applicable clinical trial that is not subject to 
the registration requirements, and who is the manufacturer of the FDA-
regulated drug product (including a biological product) or device 
product being studied, must also submit clinical trial information for 
each applicable clinical trial required to be submitted to FDA in a 
marketing application or premarket notification for approval, 
licensure, or clearance of the drug product (including a biological 
product) or device product for the use studied in the voluntarily 
submitted trial. However, the term ``triggered'' is not used in the 
regulatory text of the final rule in Sec.  11.60.
    Another commenter expressed concern that proposed Sec.  11.60 could 
be used for the voluntary submission of clinical trial information for 
studies of unproven stem cell and cell based therapy interventions to 
ClinicalTrials.gov as ``phase 1'' trials for promoting medical tourism 
and other activities. The comment further suggested that the Agency 
consider additional requirements for voluntary submissions in the final 
rule, such as review of the approval status for each submitted 
intervention by the relevant competent authorities. The Agency 
appreciates these comments and the underlying sentiment for trial 
registration and results reporting information. Nevertheless, allowing 
voluntary submissions for clinical trials not otherwise subject to 
submission requirements under section 402(j) of the PHS Act or this 
final rule increases public access to information about clinical trials 
regardless of the apparent nature, quality, or other characteristics of 
a clinical trial. Making the clinical research enterprise more 
transparent allows the public to track ongoing trials and informs 
decision makers involved

[[Page 65105]]

with clinical trial policies and practices (Section I of this preamble 
discusses public health benefits of registration and results 
reporting).
    One commenter suggested that the Agency develop results templates 
for observational studies, which some sponsors may want to report at 
ClinicalTrials.gov. Observational studies that are not pediatric 
postmarket surveillances of a device are not subject to section 402(j) 
of the PHS Act. In the future, we may consider developing tools to 
assist sponsors who provide optional results information for 
observational studies (other than certain pediatric postmarket 
surveillances of a device product that are not a clinical trial), which 
are outside the scope of this rule. The Agency does provide online 
access to results templates for interventional studies to assist and 
guide responsible parties in submitting results information under 
section 402(j) of the PHS Act [Ref. 111].
    Another commenter sought clarification about whether linking study 
results that have been published or posted on another Web site would be 
permitted for clinical trials that were voluntarily submitted with 
registration information only. ClinicalTrials.gov currently provides a 
number of optional data elements such as Citations and Links, which can 
be used to link a record to relevant trial results cited in 
publications or are available at a another Web site, respectively. 
These optional data elements will continue to be available on 
ClinicalTrials.gov. Note that, as discussed in greater detail in 
Section III.B of this preamble, such links to other studies and Web 
sites from ClinicalTrials.gov do not constitute a government 
affirmation or verification that the information within or referenced 
in the database, or communications that rely on that information, are 
truthful and non-misleading.
Final Rule
    Taking into consideration the commenters' suggestions and the 
statutory requirements for voluntary submissions, the final rule 
retains the requirements as proposed in Sec.  11.60(a), but modifies 
the statement from proposed Sec.  11.60(b) to accompany voluntarily 
submitted applicable clinical trials and clarifies that ``drug'' means 
``drug product'' and ``device'' means ``device product.'' In addition, 
consistent with the discussion in Section IV.F of this preamble, we 
have made revisions to address the differing requirements that apply to 
applicable clinical trials (and, if voluntarily submitted, other 
clinical trials).
    Section 11.60(a) applies to clinical trials initiated before the 
effective date of the final rule and that have a primary completion 
date before the effective date of the final rule. Consistent with the 
discussion in Section IV.F, below, those clinical trials would be 
subject to the registration requirements specified in section 
402(j)(2)(A)(ii) of the PHS Act and subject to results information 
submission requirements specified in sections 402(j)(3)(C) and 
402(j)(3)(I) of the PHS Act. Section 11.60(b) applies to clinical 
trials initiated before the effective date of the final rule and that 
have a primary completion date on or after the effective date of the 
final rule. Consistent with the discussion in Section IV.F, below, 
those clinical trials would be subject to the registration requirements 
specified in section 402(j)(2)(A)(ii) of the PHS Act and subject to 
results information submission requirements specified in 42 CFR part 
11. Section 11.60(c) applies to clinical trials initiated on or after 
the effective date of the final rule and that have a primary completion 
date on or after the effective date of the final rule. Consistent with 
the discussion in Section IV.F, below, those clinical trials would be 
subject to the registration and results information submission 
requirements specified in 42 CFR part 11.
    Section 11.60(a)(1), (b)(1), and (c)(1) specify that the 
requirements for voluntary submission of clinical trial information 
apply to two types of clinical trials for which submission of 
information is not otherwise required, as follows: (1) Clinical trials 
of FDA-regulated drug products (including biological products) or 
device products that do not meet the definition of an applicable 
clinical trial (e.g., a phase 1 drug trial or small feasibility device 
study); and, (2) clinical trials that are applicable clinical trials 
that were initiated on or before September 27, 2007, and that reached 
their completion dates before December 26, 2007 (i.e., applicable 
clinical trials not required to be registered under section 
402(j)(2)(C) of the PHS Act or Sec.  11.22(a), as applicable). We 
interpret section 402(j)(4)(A) of the PHS Act in a way that is 
consistent with the scope of FDA's regulatory authorities and the scope 
of this regulation. Thus, Sec.  11.60 applies only to clinical trials 
of FDA-regulated drug products (including biological products) and 
device products. For example, this section applies to a phase 1 trial 
of an FDA-regulated drug product (including a biological product) or a 
small clinical trial that evaluates the feasibility of an FDA-regulated 
device product, but does not apply to a clinical trial that studies 
only behavioral interventions that are not drug products (including 
biological products) or device products.
    In addition, as explained in the proposed rule, we interpret the 
phrase ``applicable clinical trial that is not subject to [the 
mandatory registration requirement of] paragraph (2)(C),'' in section 
402(j)(4)(A) of the PHS Act, to mean a clinical trial that meets the 
definition of an applicable clinical trial, as specified in section 
402(j)(1)(A) of the PHS Act and this part, but that was initiated on or 
before September 27, 2007, and that reached its completion date prior 
to December 26, 2007 (79 FR 69647).
    In considering the information that must be submitted to 
ClinicalTrials.gov for a voluntarily submitted clinical trial, we 
interpret section 402(j)(4)(A) of the PHS Act as permitting a 
responsible party to voluntarily submit registration information for a 
clinical trial, results information, or both. Thus, Sec.  
11.60(a)(2)(i), (b)(2)(i), and (c)(2)(i) expressly permit the voluntary 
submission of registration information, results information, or both. 
When a responsible party voluntarily submits only registration 
information for a clinical trial, Sec.  11.60(a)(2)(i)(A), 
(b)(2)(i)(A), and (c)(2)(i)(A) establish that registration information 
specified in section 402(j)(2)(A)(ii) of the PHS Act or specified in 
Sec.  11.28(a) (as applicable) must also be submitted.
    For clinical trials with a primary completion date on or after the 
effective date, Sec.  11.60(b)(2)(i)(B) and (c)(2)(i)(B) specify that 
when a responsible party voluntarily submits results information for a 
clinical trial for which registration information is specified in 
section 402(j)(2)(A)(ii) of the PHS Act or specified in Sec.  11.28(a) 
(as applicable) has not been submitted, results information as 
specified in Sec.  11.48(a), as well as additional descriptive 
information set forth in Sec.  11.60(b)(2)(i)(B) and (c)(2)(i)(B) and 
defined in Sec.  11.10(b), must be submitted. We believe that such 
additional descriptive information is necessary to enhance access to 
and understanding of the results of a clinical trial of a drug product 
(including a biological product) or device product (e.g., Study Phase 
is necessary to enable a user to understand the relative stage of 
development of an experimental drug product (including a biological 
product) studied in a clinical trial). Further, we believe that several 
other data elements must be submitted with voluntarily submitted 
results information in order for the Agency to confirm that a clinical

[[Page 65106]]

trial for which information is voluntarily submitted is not an 
applicable clinical trial subject to mandatory registration or results 
information submission under this part (e.g., Product Manufactured in 
and Exported from the U.S., and U.S. Food and Drug Administration IND 
or IDE Number). For situations in which a responsible party submits 
voluntarily only clinical trial results information under section 
402(j)(4)(A) of the PHS Act, the Agency is using its authority under 
section 402(j)(3)(D)(iii)(IV) of the PHS Act to interpret results 
information to include the data elements under Sec.  11.60(a)(2)(i)(B) 
and (c)(2)(i)(B) in addition to the data elements set forth in Sec.  
11.48(a). We have added Sec.  11.60(a)(2)(i)(C), (b)(2)(i)(C), and 
(c)(2)(i)(C) to clarify that a responsible party who voluntarily 
submits registration information and voluntarily submits results 
information for a clinical trial must submit registration information 
as specified in section 402(j)(2)(A)(ii) of the PHS Act or specified in 
Sec.  11.28(a) (as applicable) and results information specified in 
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or specified in 
Sec.  11.48(a) (as applicable).
    Sections 11.60(a)(2)(ii), (b)(2)(ii), and (c)(2)(ii) require that a 
responsible party who submits clinical trial information voluntarily 
for a clinical trial must additionally submit clinical trial 
information for any applicable clinical trial (including those 
initiated on or before September 27, 2007, and reached their completion 
date prior to December 26, 2007) that is required to be submitted in a 
marketing application or premarket notification to FDA for approval, 
licensure, or clearance of the drug product (including a biological 
product) or device product for the use studied in the voluntarily 
submitted clinical trial. The final rule maintains the approach in the 
proposed rule by clarifying that this statutory requirement applies to 
(1) applications or premarket notifications submitted to the FDA by a 
manufacturer on or after September 27, 2007; and (2) when the 
responsible party for the voluntarily submitted clinical trial is also 
the manufacturer submitting the marketing application or premarket 
notification, thereby avoiding the situation in which a responsible 
party would be required to submit information for triggered applicable 
clinical trials for which they are not the responsible party and do not 
have access to the relevant data. While the Agency encourages 
submissions of registration information and results information for all 
types of clinical trials, regardless of whether they are subject to 
section 402(j) of the PHS Act, responsible parties should consider the 
above requirements before deciding whether to register a clinical trial 
or submit results information voluntarily.
    In the final rule, Sec.  11.60(a)(2)(iii), (b)(2)(iii), and 
(c)(2)(iii) specify that the clinical trial information required to be 
submitted for a triggered applicable clinical trial is, at minimum, the 
same as that for the voluntarily submitted clinical trial. That is, if 
a responsible party voluntarily submits registration information for a 
clinical trial pursuant to Sec.  11.60(a), the responsible party must 
submit registration information specified in section 402(j)(2)(A)(ii) 
of the PHS Act for any triggered applicable clinical trial(s). 
Similarly, if a responsible party voluntarily submits clinical trial 
results information for a clinical trial pursuant to Sec.  11.60(a), 
then the responsible party must submit results information specified in 
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act for any triggered 
applicable clinical trial(s). Since the submission of clinical trial 
information for a triggered applicable clinical trial is a condition of 
voluntary submission, the Agency does not propose to treat the 
submission of such information as a voluntary submission under Sec.  
11.60(a)(2)(ii), (b)(2)(ii), and (c)(2)(ii) that itself could trigger 
the submission of clinical trial information for other applicable 
clinical trials. In other words, the submission of information for an 
applicable clinical trial that is triggered under section 402(j)(4)(A) 
of the PHS Act and subject to Sec.  11.60 would not, in turn, itself 
trigger the requirement to submit information for additional applicable 
clinical trials under that section. For example, voluntary submission 
of information for trial X may trigger the submission of information 
for applicable clinical trials Y and Z that were required to be 
included in FDA marketing application 001, as required under Sec.  
11.60(a)(2)(ii), (b)(2)(ii), and (c)(2)(ii). However, submission of 
information for applicable clinical trials Y and Z would not further 
trigger the requirement to submit information for additional applicable 
clinical trials (e.g., even if applicable clinical trial Y were used to 
support marketing application 002, the applicable clinical trials 
required to be included in 002 would not be triggered).
    In general, an initial voluntary submission is not subject to any 
regulatory deadlines in Sec. Sec.  11.24 and 11.44 and so may be 
submitted at any time in relation to the conduct of the trial (e.g., 
before, during, or after the study start date or primary completion 
date). However, when a voluntary submission is made, Sec.  
11.60(a)(2)(iv), (b)(2)(iv), and (c)(2)(iv) establish two deadlines 
that apply to voluntary submissions of results information. Sections 
11.60(a)(2)(iv)(A), (b)(2)(iv)(A), and (c)(2)(iv)(A) specify that if 
data collection for the secondary outcome measure(s) or the pre-
specified timeframe for collecting adverse event information for such 
clinical trials is not completed by the primary completion date of the 
voluntarily submitted clinical trial, then results information for the 
secondary outcome measure(s) and/or adverse event information must be 
submitted by the later of either the date that the results information 
is voluntarily submitted for the primary outcome measure(s) or 1 year 
after the date on which (1) the final subject was examined or received 
an intervention for the purposes of final collection of data for the 
secondary outcome measure(s) or (2) after the final subject was 
observed for adverse events, whether the clinical trial was concluded 
according to the pre-specified protocol or was terminated. We clarify 
that while initial voluntary submission of partial results information 
is permitted (pending completion of data collection for secondary 
outcomes and/or the pre-specified time frame for collecting adverse 
events information according to the reporting deadlines specified in 
Sec.  11.60(a)(2)(iv)(A), (b)(2)(iv)(A), and (c)(2)(iv)(A)), the 
responsible party is required to submit the clinical trial results 
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) or 
specified in Sec.  11.48(a) (as applicable) that is otherwise available 
when submitting partial results information. This means that, with 
respect to adverse event information, a responsible party would be 
required to submit information summarizing serious and frequent adverse 
events recorded to-date each time results information for a secondary 
outcome is submitted, until all the adverse event information required 
by this part has been submitted. This clarification is now included in 
the final rule in Sec.  11.60(a)(2)(iv)(A)(2), (b)(2)(iv)(A)(2), and 
(c)(2)(iv)(A)(2). We emphasize, however, this provision does not impose 
requirements on the design or conduct of the clinical trial or on the 
data that must be collected during the clinical trial.
    Sections 11.60(a)(2)(iv)(B), (b)(2)(iv)(B), and (c)(2)(iv)(B) 
specify that clinical trial information for triggered applicable 
clinical trials must be submitted not later than the date on which the 
application or premarket notification is submitted to FDA or the

[[Page 65107]]

date on which clinical trial information is submitted for the 
voluntarily submitted clinical trial to ClinicalTrials.gov, whichever 
is later. This approach prevents a responsible party from having to 
submit information for a clinical trial that is not subsequently 
included in the marketing application or premarket notification. 
Section 11.60(c)(2)(v) specifies that responsible parties who 
voluntarily submit clinical trial information to ClinicalTrials.gov 
would be required to update and correct submitted information, 
including information submitted for triggered trials, in accordance 
with Sec.  11.64 (as applicable).
    Section 11.60(d) specifies the text of the statement to accompany 
voluntarily submitted applicable clinical trials to clarify that the 
voluntary submission was not subject to the deadlines imposed by 
section 402(j) of the PHS Act for mandatory submission of registration 
and results information. The required statement would apply to any 
applicable clinical trial, including any triggered applicable clinical 
trial, submitted under section 402(j)(4)(A) of the PHS Act and Sec.  
11.60(a), (b), and (c). Accordingly, the statement will be as follows: 
``This clinical trial information was submitted voluntarily under the 
applicable law and, therefore, certain submission deadlines may not 
apply. (That is, clinical trial information for this applicable 
clinical trial was submitted under section 402(j)(4)(A) of the Public 
Health Service Act and 42 CFR 11.60 and is not subject to the deadlines 
established by sections 402(j)(2) and (3) of the Public Health Service 
Act or 42 CFR 11.24 and 11.44.)''
2. Sec.  11.62--What requirements apply to applicable clinical trials 
for which submission of clinical trial information has been determined 
by the Director to be necessary to protect the public health?
Overview of Proposal
    The NPRM, in accordance with section 402(j)(4)(B) of the PHS Act, 
proposed in Sec.  11.62 to require submission of clinical trial 
information if the Director determines that the posting of such 
information on ClinicalTrials.gov is necessary to protect the public 
health. Section 402(j)(4)(B)(i) of the PHS Act specifically authorizes 
the Secretary to ``require by notification'' of the submission of 
clinical trial information ``in any case in which the Secretary 
determines for a specific clinical trial [. . . .] that posting in the 
registry and results data bank of clinical trial information for such 
clinical trial is necessary to protect the public health.'' This 
authority has been delegated to the Director (74 FR 19973, Apr. 30, 
2009). If the Director so determines, clinical trial information must 
be submitted for that clinical trial in accordance with sections 
402(j)(2) and (3) of the PHS Act, except with regard to timing 
requirements. With respect to timing, such clinical trial information 
must be submitted to ClinicalTrials.gov ``not later than 30 days after 
the date specified by the [Director] in the notification,'' unless the 
responsible party submits a certification for delayed results 
information submission under section 402(j)(3)(E)(iii) of the PHS Act 
(see section 402(j)(4)(B)(i)(II) of the PHS Act).
    The NPRM proposed in Sec.  11.62(a) to implement this provision by 
requiring the responsible party for an applicable clinical trial who 
receives notification pursuant to section 402(j)(4)(B) of the PHS Act 
that the Director has determined that posting of clinical trial 
information is necessary to protect the public health to submit such 
information to ClinicalTrials.gov in accordance with proposed Sec.  
11.62(c) (79 FR 69650).
    The NPRM proposed in Sec.  11.62(b) to implement section 
402(j)(4)(B)(ii) of the PHS Act, which specifies that the types of 
clinical trials subject to this provision are limited to those that 
are: (1) ``an applicable clinical trial for a drug that is approved 
under section 505 of the Federal Food, Drug, and Cosmetic Act or 
licensed under section 351 of [the PHS Act] or for a device that is 
cleared under section 510(k) of the Federal Food, Drug, and Cosmetic 
Act or approved under section 515 or section 520(m) of [the FD&C Act], 
whose completion date is on or after the date 10 years before the date 
of the enactment of the Food and Drug Administration Amendments Act of 
2007'' (i.e., September 27, 1997) or (2) an applicable clinical trial 
that is subject to registration under section 402(j)(2)(C) of the PHS 
Act and studies a drug or device that is unapproved, unlicensed, or 
uncleared regardless of whether or not approval, licensure, or 
clearance was sought as described in section 402(j)(3)(D)(ii)(II) of 
the PHS Act (79 FR 69650).
    Section 11.62(c) of the NPRM specified that such clinical trial 
information must be submitted to ClinicalTrials.gov not later than 30 
calendar days after the date specified by the Director in the 
notification, unless the responsible party submits a certification for 
delayed results submission, as specified in Sec.  11.44(b) or (c). It 
further proposed that if the responsible party submitted clinical trial 
registration information prior to the date on which the notification is 
sent to the responsible party, the responsible party must then make all 
necessary updates, if any, to the submitted information not later than 
30 calendar days after the date specified in the notification (79 FR 
69650). The Agency invited public comment on the types of situations in 
which the posting of clinical trial information might be necessary to 
protect the public health and on the criteria that the Director should 
consider when making such a determination, but no comments were 
received on the types of trials that should be included.
Comments and Response
    One commenter addressed proposed Sec.  11.62. The comment suggested 
that the Agency should describe the criteria to be used by the Director 
to determine when applicable clinical trials subject to Sec.  11.62 
would be required to submit clinical trial information to 
ClinicalTrials.gov. The Agency will issue guidance at a later date on 
factors that the Director intends to consider in determining whether 
clinical trial information subject to Sec.  11.62 must be posted on 
ClinicalTrials.gov. We expect this authority to be rarely invoked and 
limited to extraordinary circumstances including those in the interest 
of public health or in the interest of national security.
Final Rule
    Taking into consideration the commenter's suggestion and the 
statutory requirements for applicable clinical trials for which 
submission of clinical trial information has been determined by the 
Director to be necessary to protect the public health, the final rule 
maintains the proposed Sec.  11.62 approach, except we clarify that 
``drug'' means ``drug product'' and ``device'' means ``device product'' 
in final Sec.  11.62(b)(1) and 11.62(b)(2). We also clarify in final 
Sec.  11.62(b)(2) that the applicable clinical trial is subject to this 
section ``regardless of whether approval, licensure, or clearance was, 
is, or will be sought, and that is not otherwise subject to results 
information submission in accordance with the regulation.'' As 
explained in the discussion of Sec.  11.10 of this preamble (Section 
IV.A.5), approval status of a product studied in an applicable clinical 
trial (i.e., either ``unapproved, unlicensed, or uncleared'' or 
``approved, licensed, or cleared'') is interpreted to be the approval 
status of the product on the primary completion date. In this context, 
the approval status

[[Page 65108]]

of the product is the approval status on the estimated or actual 
primary completion date on the date that the Director notifies the 
responsible party that clinical trial information must be submitted to 
ClinicalTrials.gov for an applicable clinical trial under Sec.  11.62.
    The clinical trials specified in Sec.  11.62(b)(1) would consist of 
applicable clinical trials of approved, licensed, or cleared drugs 
(including biological products) or devices that reached their primary 
completion dates on or after September 27, 1997. We note that this set 
of clinical trials would include applicable clinical trials that reach 
their primary completion dates on or after the date of enactment of 
FDAAA, many of which already would be subject to the registration and 
results information submission requirements of section 402(j) of the 
PHS Act, with the exception of applicable clinical trials that were 
initiated prior to the date of enactment of FDAAA (i.e., September 27, 
2007) and were not ongoing as of December 26, 2007.
    The clinical trials specified in Sec.  11.62(b)(2) would consist of 
applicable clinical trials that are required to register at 
ClinicalTrials.gov pursuant to Sec.  11.22(a) of this rule and that 
study drugs (including biological products) or devices that are 
unapproved, unlicensed, or uncleared by the FDA (regardless of whether 
or not approval, licensure, or clearance was sought). This set of 
clinical trials would consist of registered applicable clinical trials 
that would not otherwise be required to submit clinical trial results 
information to ClinicalTrials.gov.
    Section 11.62(c) specifies which information must be submitted to 
ClinicalTrials.gov and the timelines for submitting such information. 
In general, we interpret the references to ``clinical trial 
information'' and submission ``in accordance with paragraphs (2) and 
(3)'' in section 402(j)(4)(B)(i)(I) of the PHS act to mean registration 
information and results information as required in Sec. Sec.  11.28(a) 
and 11.48(a), respectively. Consistent with section 402(j)(4)(B)(i)(II) 
of the PHS Act, such information must generally be submitted not later 
than 30 calendar days after the date specified by the Director in the 
notification. We note that section 402(j)(4)(B)(i)(II) of the PHS Act 
permits an exception to the submission deadline for results information 
if a responsible party submits a certification for delayed results 
information submission not later than 30 days after the submission date 
specified by the Director in the notification. We also note that if the 
responsible party has submitted such a certification under Sec.  
11.44(b) or (c), only the submission of results information will be 
delayed. Accordingly, if a responsible party for an unregistered 
applicable clinical trial subject to Sec.  11.62 submits a 
certification not later than 30 calendar days after the submission date 
specified in the Director's notification, the responsible party still 
would be required to submit registration information not later than 30 
calendar days after the submission date specified in the notification, 
although results information would be required to be submitted by the 
applicable deadline established under Sec.  11.44(b) or (c).
    To clarify the submission requirement in situations in which 
registration information was submitted to ClinicalTrials.gov before a 
notification was sent to the responsible party, Sec.  11.62(c)(3) 
indicates that the registration information must be updated, if 
necessary, not later than 30 calendar days after the submission date 
specified in the notification. Notwithstanding this initial update, the 
requirements of Sec.  11.64 would apply to clinical trial information 
submitted pursuant to Sec.  11.62.
    All clinical trial information submitted to ClinicalTrials.gov 
under Sec.  11.62 will be subject to the quality control procedures 
described in Sec.  11.64(b)(1). The Agency intends to post such 
information as soon as practicable after it has completed the quality 
control review process. The timeline for posting would apply to all 
clinical trial information submitted under Sec.  11.62, including 
registration information for an applicable clinical trial of a device 
that has not previously been approved or cleared by the FDA. Section 
402(j)(4)(B) of the PHS Act applies equally to applicable clinical 
trials of drugs and devices that are approved, licensed, or cleared or 
are unapproved, unlicensed, or uncleared. It applies to ``any case'' in 
which the Director, as delegated by the Secretary, determines that 
posting of clinical trial information on ClinicalTrials.gov (not just 
submission of the information to ClinicalTrials.gov) is necessary to 
protect public health. Although section 402(j)(4)(B) of the PHS Act 
specifically allows for a delay in submission of results information if 
the responsible party submits a certification for delayed results 
information submission under section 402(j)(3)(E)(iii) of the PHS Act, 
it does not specifically delay or prohibit posting submitted 
registration information until a device is cleared or approved. 
Therefore, the Agency believes that registration information for all 
applicable clinical trials under Sec.  11.62 may be posted after 
quality control review has concluded, regardless of the approval, 
licensure, or clearance status of the device products studied. Of note, 
we do not interpret section 402(j)(4)(B) of the PHS Act to permit a 
responsible party to request a waiver of the requirement to submit 
clinical trial information pursuant to a notification from the Director 
under Sec.  11.62. The language of section 402(j)(4)(B) of the PHS Act 
states ``Notwithstanding paragraphs (2) and (3)'' (note that waivers 
are in paragraph (3)), and only makes the exception for trials with a 
certification for delayed results information submission, as described 
above. Therefore, it does not make an exception for trials for which a 
waiver was granted.
3. Sec.  11.64--When must clinical trial information submitted to 
ClinicalTrials.gov be updated or corrected?
    Proposed Sec. Sec.  11.64 and 11.66, which described the 
requirements and procedures for clinical trial information updates and 
corrections respectively, are combined in the final rule under the new 
Sec.  11.64--When must clinical trial information submitted to 
ClinicalTrials.gov be updated or corrected?, described herein.
Overview of Proposal
When must clinical trial information submitted to ClinicalTrials.gov be 
updated?
    Section 402(j)(3)(D)(v)(IV) of the PHS Act provides that the 
regulations shall also establish ``the appropriate timing and 
requirements for updates of clinical trial information, and whether 
and, if so, how such updates should be tracked.'' Section 402(j)(4)(C) 
of the PHS Act separately requires responsible parties to submit 
updates of clinical trial registration information to 
ClinicalTrials.gov not less than once every 12 months (except for 
certain specified data elements for which more rapid updates are 
required) and the Director to post such updates publicly in the data 
bank. With regard to the requirement in section 402(j)(3)(D)(v)(IV) of 
the PHS Act to establish, by regulation, ``the appropriate timing and 
requirements for updates of clinical trial information . . .,'' we 
noted in the NPRM that we interpret the term ``clinical trial 
information'' to mean both clinical trial registration information and 
clinical trial results information, consistent with the definition of 
``clinical trial information'' in section 402(j)(1)(A)(iv) of the PHS 
Act. In addition, our proposed requirements for updates

[[Page 65109]]

apply to adverse event information because adverse event information is 
deemed to be clinical trial results information under section 
402(j)(3)(I)(v) of the PHS Act (79 FR 69587).
    Proposed Sec.  11.64(a)(1) established a general requirement for 
responsible parties to update clinical trial information not less than 
once every 12 months if there are changes to any of the data elements 
previously submitted. Section 11.64(a)(2) emphasized that this 
requirement to update clinical trial information not less than once 
every 12 months includes a requirement to update the estimated Primary 
Completion Date data element, unless there have been no changes in the 
preceding 12 months. We noted that, in our view, the public should be 
able to rely upon the accuracy of this date to assist them in 
determining when results information may be available on 
ClinicalTrials.gov. In general, we recommended that the complete 
clinical trial record on ClinicalTrials.gov be reviewed not less than 
once every 12 months to help ensure that the clinical trial information 
it contains remains accurate. Proposed Sec.  11.64(a)(3) specified that 
updates to clinical trial information must be submitted until the date 
on which all required clinical trial results information has been 
submitted to ClinicalTrials.gov, meaning results for all primary and 
secondary outcome measures and all adverse events collected in 
accordance with the protocol. After that time, the proposed rule 
stated, submitted clinical trial information would continue to be 
subject to the corrections provisions in proposed Sec.  11.66 of the 
NPRM, and responsible parties would be required to submit corrected 
information when the responsible party or the NIH becomes aware of any 
errors or needed corrections in the clinical trial information (79 FR 
69651).
    Proposed Sec.  11.64(b) identified data elements that must be 
updated not later than 30 calendar days after a change occurs, 
including those already specified in section 402(j)(4)(C)(i) of the PHS 
Act (i.e., Recruitment Status and Clinical Trial Completion Status). 
Additional data elements identified for more frequent updates were: 
Study Start Date; Intervention Name(s); Availability of Expanded 
Access; Expanded Access Status; Overall Recruitment Status and, if the 
status changes to suspended, terminated, withdrawn, an explanation 
about why the study was stopped; and if the status change is terminated 
or active, not recruiting, the actual enrollment data; Individual Site 
Status; Human Subjects Protection Review Board Status; Completion Date; 
Responsible Party, by Official Title; and Responsible Party Contact 
Information. Furthermore, Sec.  11.64(b) proposed an even more frequent 
update timeline of not later than 15 calendar days for updating the 
U.S. FDA Approval, Licensure, or Clearance data element, and stated 
that the Record Verification Date must be updated any time the 
responsible party reviews the complete record for accuracy, even if no 
other updates are submitted at that time (79 FR 69653). It also 
specified that if a protocol is amended in such a manner that changes 
are communicated to participants in the clinical trial, updates to 
relevant clinical trial information must be submitted no later than 30 
calendar days after the protocol amendment is approved by the human 
subjects protection review board (79 FR 69587).
    We noted that the above exceptions to the 12-month period for 
updates are considered important for patients using the data bank to 
search for clinical trials for which they might qualify and for the 
Agency in administering other provisions of section 402(j) of the PHS 
Act. In addition, proposed Sec.  11.64(c) would require a responsible 
party to update, as necessary, any previously submitted clinical trial 
information at the time results information is submitted to 
ClinicalTrials.gov (the responsible party would then be required to 
update the Record Verification Date data element). The NPRM suggested 
that doing so will improve the accuracy of information that is used by 
ClinicalTrials.gov to automatically prepopulate some elements of 
results information. As set forth in proposed Sec.  11.64(d)(2), 
submitted clinical trial information that is posted in accordance with 
Sec. Sec.  11.35 and 11.52, including past updates of posted 
submissions, are tracked in the ClinicalTrials.gov archive, in which 
the history of changes to clinical trial information for any clinical 
trial is accessible to the public (79 FR 69587).
What are the requirements for corrections of clinical trial 
information?
    Proposed Sec.  11.66 of the NPRM set out requirements for 
responsible parties to correct clinical trial information submitted to 
ClinicalTrials.gov. This included clinical trial information 
voluntarily submitted under section 402(j)(4)(A) of the PHS Act and/or 
proposed Sec.  11.60, as well as clinical trial information necessary 
to protect the public health and submitted under section 402(j)(4)(B) 
of the PHS Act and/or proposed Sec.  11.62. Proposed Sec.  11.66 
addressed several types of corrections (i.e. correction of errors, 
correction of falsified data and other corrections). The discussion in 
the NPRM preamble regarding Sec.  11.66 indicated that some errors and 
other deficiencies are expected to be detected during quality review 
procedures conducted by the Director (79 FR 69654). Section 
402(j)(3)(D)(v)(III) of the PHS Act states that regulations shall 
establish ``procedures for quality control . . . with respect to 
completeness and content of clinical trial information under this 
subsection, to help ensure that data elements are not false or 
misleading and are non-promotional.'' The discussion of ``Quality 
Control Procedures'' in Section III.C.12 of the NPRM outlined the 
quality control process that would occur with clinical trial 
information as part of submission. This included a two-step process by 
which an automated system-based check would occur prior to submission 
followed by a detailed, manual review after submission. This detailed 
review would be based on quality review criteria for identifying 
apparent errors, deficiencies, or inconsistencies that are not detected 
by the automated checks. If any such problems are identified in the 
detailed, manual review, the proposed rule stated, the Director would 
send an electronic notification to the responsible party, indicating 
that the submission contains apparent errors, deficiencies, and/or 
inconsistencies listing such issues and requesting correction. 
Consistent with proposed Sec.  11.66 on correction of errors, the NPRM 
further outlined that responsible parties would be required to correct 
the errors, deficiencies, and/or inconsistencies in clinical trial 
information not later than 15 calendar days after being informed of 
them by the Agency (or otherwise becoming aware of them), whichever is 
later. The NPRM also recognized that because clinical trial information 
will have to be posted not later than the 30 day posting deadlines 
specified in Sec. Sec.  11.35 and 11.52, there may be some situations 
in which submitted clinical trial information is posted before it has 
been corrected. We noted that it would be necessary to include 
information indicating that such information has not completed the 
quality control process as well as implementing other mechanisms to 
help users of ClinicalTrials.gov identify such clinical trial records 
(79 FR 69586).
    Although the statute did not establish timelines for correcting 
errors, Sec.  11.66 proposed that corrections needed to be submitted 
after the responsible party becomes aware that submitted clinical trial 
information is incorrect or falsified or that corrections are needed 
for other

[[Page 65110]]

reasons. Section 11.66(a) required responsible parties to correct 
errors not later than 15 calendar days after the error is discovered. 
Section 11.66(b) covered falsified data and proposed to require 
notification to the Director of the falsification and submission of 
corrected information not later than 15 calendar days after the 
corrected information becomes available or notification not later than 
15 calendar days after determining that the information cannot be 
corrected or is correct. Section 11.66(c) addressed ``other corrections 
of clinical trial information'' which were identified as ``various 
other deficiencies'' including but not limited to ``inconsistencies in 
submitted data, for example, a mismatch between the reported number of 
subjects enrolled in a clinical trial and the sum of reported number of 
subjects assigned to different arms . . .''(79 FR 69655) and stated 
that a responsible party who becomes aware or is informed by NIH that 
such corrections are needed must make them as soon as possible but not 
later than 15 calendar days after becoming aware or being informed of 
the problem.
Comments and Response
When must clinical trial information submitted to ClinicalTrials.gov be 
updated?
    Commenters addressed the update provisions in Sec.  11.64, with 
some in support of the proposed approach, while others suggested 
changes to the required updates and the proposed timelines. Among those 
who suggested changes, commenters suggested that the specific timelines 
for updates were too short. Some commenters suggested alternative 
timelines for updates, including that the general timeline for updates 
should be extended from not less than once every 12 months to once 
every 18 months; the 30-day timeframe for rapid updates should be 
extended to 45 or 60 days; and that all the timelines for each rapid 
update element should be consistent (i.e., the timeline for updating 
the U.S. FDA Approval, Licensure, or Clearance data element should also 
be 30 calendar days). Although commenters suggested extending the 
timelines, the 12 month general timeline is established by section 
402(j)(4)(C)(i)(I) of the PHS Act. Similarly, the 30 day timeline 
following changes to Overall Recruitment Status and Completion Date is 
established by section 402(j)(4)(C)(i)(III) and section 
402(j)(4)(C)(i)(IV) of the PHS Act. While the statute would allow for 
modifying the 30 day timeline for other data elements, sufficient 
evidence of burden was not provided by the public comments indicating 
that these deadlines would be difficult to meet. Moreover, we believe 
it makes sense, in the interest of simplicity (as has also been sought 
by commenters), to keep the timeline for updates consistent to the 
extent possible. Finally, rapid updating of this information is 
consistent with the stated purpose of ClinicalTrials.gov set forth in 
section 402(j)(2)(A)(i) of the PHS Act to ``enhance patient enrollment 
and provide a mechanism to track subsequent progress of clinical 
trials.'' If such key changes were not reflected in the record in 
ClinicalTrials.gov for as long as 12 months after the change, then the 
Agency believes that the value of ClinicalTrials.gov as a source of 
reliable, accurate information for the public and potential 
participants in clinical trials would be compromised.
    Commenters also raised issues regarding specific data element 
update requirements. One disagreed with the requirement that actual 
enrollment data be provided when the Overall Recruitment Status changes 
(i.e., trial's recruitment status changes to ``terminated'' or 
``active, not recruiting'') and suggested that the NIH continue to 
allow submission of actual enrollment data at the time of overall study 
completion (e.g., LPLV). The Agency believes that submission of actual 
enrollment information at the time that recruitment is no longer 
occurring (Overall Recruitment Status is ``terminated'' or ``active, 
not recruiting'') would permit users of ClinicalTrials.gov to know more 
quickly whether the clinical trial achieved its target enrollment. 
However, we also recognize the potential burden and some of the 
challenges with providing such information in a more rapid manner. In 
the final rule, therefore, we modify the requirement to be consistent 
with current practice at ClinicalTrials.gov by requiring actual 
enrollment to instead be updated within 30 calendar days of reaching 
the Primary Completion Date.
    Another commenter opposed the requirement that the status of 
individual sites be updated because of concerns about burden on large 
international trials. The Agency believes that changes in recruitment 
status should be communicated promptly so that potential human subjects 
can know whether or not a clinical trial is currently recruiting 
subjects. In addition, prompt updates to Overall Recruitment Status as 
well as Individual Site Status support the purpose of 
ClinicalTrials.gov to enhance patient enrollment by assisting potential 
human subjects who search for clinical trials by location and wish to 
retrieve information about only those trials that are open to 
recruitment in specified locations. We clarify that when the Overall 
Recruitment Status is other than ``recruiting,'' the Individual Site 
Status no longer needs to be updated because a change in the Overall 
Recruitment Status would apply to each individual site and the 
Individual Site Status will no longer be displayed by 
ClinicalTrials.gov on the publicly posted study record. We also note 
that the update burden to responsible parties is reduced by tools 
available in the PRS that allow for easily changing the Individual Site 
Status (e.g., from ``recruiting'' to ``active, not recruiting'') for 
many sites at once.
    Another commenter raised a question about which IRB approval date 
is relevant in a multi-site trial involving multiple IRBs in response 
to the requirement to update the record not later than 30 calendar days 
after an amended protocol is approved by an IRB that involves changes 
that are communicated to participants. We clarify that the date of the 
first IRB approval for the amendment should be used. We note that we 
invited public comment on other thresholds (other than those changes 
that are communicated to enrolled participants) that could be used to 
determine which protocol changes are significant enough to warrant 30-
day updating of affected clinical trial information, but none was 
received.
    Comments were also raised in opposition to the proposal to require 
voluntarily registered trials to comply with the update and correction 
timelines due to the burden involved. It was suggested that the 
requirement may have the unintended consequence of decreasing voluntary 
submissions and, thereby, transparency. The Agency believes that in 
order to maintain the value of ClinicalTrials.gov as a source of 
accurate and up-to-date clinical trial information each record, 
including voluntary submissions, must be updated in accordance with the 
timelines outlined in the final rule. Other commenters requested that a 
mechanism be included in the PRS to make clear to responsible parties 
when they have fulfilled all obligations to update the study record, 
and no further updates are required. Proposed Sec.  11.64(a)(3) 
indicated that the responsible party must continue to submit updates 
until complete ``clinical trial results information specified in Sec.  
11.48 has been submitted for all primary and secondary outcomes and all 
adverse events that were collected in accordance with the protocol.'' 
We agree with the commenters on the need for

[[Page 65111]]

being able to identify when the obligation to update and/or correct 
clinical trial information has ended. As one component of this 
determination, we have added to Sec. Sec.  11.10(a) and 11.28, the 
Study Completion Date data element to identify ``the date the final 
subject was examined or received an intervention for purposes of final 
collection of data for the primary and secondary outcome measures and 
adverse events (e.g., last subject's last visit) . . .'' Providing the 
Study Completion Date as clinical trial information and including it as 
a data element that must be updated within 30 calendar days of a change 
is consistent with the stated purpose of ClinicalTrials.gov to ``. . . 
provide a mechanism to track subsequent progress of clinical trials'' 
(see section 402(j)(2)(A) of the PHS Act). Further, it establishes the 
date on which the final subject was examined (or received an 
intervention) for purposes of final data collection, thereby 
identifying the maximum date under Sec.  11.44(d) by which partial 
results information must be submitted (i.e., no later than one year 
after the Study Completion Date).
    The NPRM indicated that the obligation to update ends after 
submission of complete clinical trial results information. We clarify 
that the obligation to submit updates ends after all required clinical 
trial results information has been submitted as specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or as specified in Sec.  
11.48, as applicable, and after any corrections have been made or 
addressed as required under Sec.  11.64(b). We note that one reason it 
is important for the update requirements to continue through the 
conclusion of the quality control process is to ensure that the 
Responsible Party and Responsible Party Contact Information remains 
accurate during that process. We also have clarified that for any 
clinical trials that are not subject to the clinical trial results 
information submission requirements, the obligation to update ends on 
the date on which all required clinical trial registration information 
has been submitted as specified in section 402(j)(2)(A)(ii) of the PHS 
Act or Sec.  11.28, as applicable, and corrections have been made or 
addressed in response to any electronic notice received under Sec.  
11.64(b)(1).
What are the requirements for corrections of clinical trial 
information?
    Commenters addressing the proposed quality control procedures and/
or the corrections provisions proposed in Sec.  11.66 commented on the 
amount of time a responsible party has to correct clinical trial 
information, timing of posting of clinical trial information in 
relationship to quality control procedures, and the falsified data 
provisions. Each of these topics is discussed in turn.
    Commenters submitting input on the corrections provisions in Sec.  
11.66 of the NPRM expressed general support for the requirement to 
correct errors and some commenters also supported the 15 day timeline 
for addressing corrections. Other commenters expressed concern about 
the timeline for correction of errors, as they found it too short and 
suggested that it was insufficient, unrealistic, and burdensome. 
Commenters suggested that a rush by responsible parties to meet the 
deadline might result in the unanticipated submission of more errors. 
Alternative timeframes were proposed by commenters, who suggested 
extending the correction of error timeline to 30 days, 45 days, and 60 
days. One commenter proposed allowing 15 days for the responsible party 
to notify the NIH from the time an error is discovered followed by a 30 
day timeline to make any corrections. As noted in the NPRM discussion 
of quality control procedures (Section III.C.12), the Agency expects to 
conduct a quality control review and also aims to receive submission of 
corrected clinical trial information prior to the deadlines for posting 
such information publicly as specified in Sec. Sec.  11.35 and 11.52 
(i.e., not later than 30 calendar days after submission). We are, 
therefore, maintaining the proposed timeline of 15 calendar days for 
the responsible party to correct clinical trial registration 
information after a notification is sent by the Director, but we are 
extending the timeline for correction of clinical trial results 
information to ``25 calendar days.'' These timelines are in place for 
two reasons: (1) To allow, in some cases, corrected clinical trial 
information to be submitted by the responsible party in a timeline that 
would allow for quality control review and posting in accordance with 
the timelines in Sec. Sec.  11.35 or 11.52; and, (2) to minimize the 
amount of time that posted clinical trial information is available 
without conclusion of the quality control review process. In our 
experience in operating the registry component of ClinicalTrials.gov, 
we have found that clinical trial registration information can be 
reviewed quickly and that responsible parties can submit corrected 
information, if necessary, in a matter of days. However, allowing for a 
longer timeline for corrections of clinical trial results information 
acknowledges the inherent difference in complexity of the information 
as compared to clinical trial registration. To better distinguish 
between corrections that may be needed based on quality control by the 
Director and other corrections that are needed based on identification 
by the responsible party, we are modifying the corrections provisions 
in the final rule to address these separately. When a responsible party 
becomes aware of errors, the timelines to correct or address such 
errors are 15 calendar days for registration information and 25 
calendar days for results information. We clarify in the discussion of 
the final rule requirements for corrections, the steps that can be 
taken when the Director notifies a responsible party of issues.
    As initially discussed in the context of Sec. Sec.  11.35 and 
11.52, a number of commenters expressed the importance of quality 
control and suggested that both registration and results information 
should be posted only when quality control review criteria have been 
fulfilled. Commenters expressed concern about the potential to 
misinform those using the publicly posted study record and suggested 
only posting sections that have fulfilled quality control criteria. 
Some commenters suggested that the harm of posting information that has 
not passed quality control review is greater than posting the 
information in a timely manner. While we understand these concerns, 
section 402(j)(3)(G) of the PHS Act established for applicable clinical 
trials that the Director of NIH is required to post results information 
``publicly in the registry and results database not later than 30 days 
after such submission.'' In addition, because there may be cases in 
which clinical trial information is posted without conclusion of the 
quality control review process, a shorter timeline for corrections will 
minimize the amount of time such records are posted. In the event that 
a study record is posted in accordance with the statutory posting 
deadline, and the quality control review has not concluded, the 
clinical trial record will contain information that will be visible to 
the public explaining that the quality control review process for the 
posted clinical trial information has not concluded.
    Regarding the proposed statements on a study record, commenters 
were concerned that users of ClinicalTrials.gov may not understand such 
notices and may make decisions based on information that is inaccurate, 
unclear, or incomplete. To address this concern, we will evaluate 
whether there are ways in which the notices for each

[[Page 65112]]

record could specify the data element(s) identified by the Agency that 
may contain errors, deficiencies, and/or inconsistencies, and aim to 
employ other measures to ensure that the notice is clear and limited to 
the relevant sections. We note that the quality control review process 
will continue even after the information is posted with a notice 
indicating the process has not concluded. The general quality control 
review process and the specific criteria utilized by the Director to 
evaluate submitted results will be available at https://prsinfo.clinicaltrials.gov (or successor site), prior to the effective 
date, for responsible parties and the public to have a better 
understanding of the types of issues reviewed.
    Responsible parties must correct or address apparent errors, 
deficiencies, and/or inconsistencies within 15 calendar days (clinical 
trial registration information) or 25 calendar days (clinical trial 
results information) of the date the Director provides electronic 
notification to the responsible party. Quality control review 
procedures will be followed for any subsequent submission of revised 
clinical trial information. When the responsible party submits revised 
clinical trial information, or provides explanatory information that 
addresses the apparent errors, deficiencies, and/or inconsistencies, 
any revised information will be posted after quality control review. 
Further, when all apparent errors, deficiencies, and/or inconsistencies 
have been addressed, the statement that the quality control review 
process had not concluded will be removed from the posted record. 
However, the clinical trial information that was initially posted will 
appear in the archived history for that clinical trial record, and the 
archived version will indicate that it had been posted with a notice. 
The electronic notification sent to the responsible party indicating 
that the quality control review process has concluded will inform 
responsible parties of these facts. We hope this notification further 
encourages those with posted records that contain such a statement to 
correct the information or address the issues raised by the quality 
control review process as soon as possible, to help ensure that users 
of ClinicalTrials.gov may rely on the information in the trial records, 
as intended.
    Some commenters requested more information, such as additional 
guidance regarding quality control processes, while others made 
suggestions, such as NIH development of common standards for quality 
control or development of a process that involves domain experts. To 
assist responsible parties in avoiding such errors, deficiencies, and 
inconsistencies prior to this final rule, we developed and continued to 
refine documentation explaining how to meet the quality review 
criteria; identified and compiled lists of frequent errors, 
deficiencies, and inconsistencies in submitted results information; 
and, provided system support to help responsible parties minimize such 
errors, deficiencies, and inconsistencies. We also have provided 
intensive user support for responsible parties who are new to the 
online submission process, particularly for results information, 
whether through data entry using Web-based forms or automated uploading 
of data files. In particular, we provide one-on-one assistance to 
support a responsible party in submitting their clinical trial results 
information. We have developed and posted draft educational materials, 
such as tips on improving results information submissions and ways to 
avoid common errors, deficiencies, and inconsistencies observed in 
submissions to date. All such documents are available at https://prsinfo.clinicaltrials.gov (or successor site). We will continue to 
provide such support to responsible parties and, based on these 
interactions, develop new or updated materials in order to facilitate 
and streamline preparation of clinical trial information for submission 
to ClinicalTrials.gov and to help ensure that the submissions meet the 
quality review criteria.
    Commenters also addressed the falsified data correction provision 
proposed in Sec.  11.66(b) and suggested that it was vague and unclear 
about when errors should be reported as falsified data and how 
responsible parties are to determine when sufficient credible evidence 
exists to warrant a falsification report. They noted that no guidelines 
were provided for what events should trigger a presumption that data 
may be false and what constitutes a suitable investigation, and no 
distinctions were made about materiality, e.g., inaccuracies about the 
recruitment status versus inaccuracies about the validity of safety 
data. Commenters inquired about the sanctions that would go with each 
determination (error versus falsification) and asserted that a more 
clearly defined and formal process would need to be in place to ensure 
a thorough investigation is conducted before inaccuracies are reported 
as falsified data. In addition, commenters suggested that the 
falsification provision could result in depriving responsible parties 
of their right to due process under the Fifth Amendment because it 
would require companies to report falsification without establishing 
clear parameters for what constitutes falsification. One commenter 
asserted that, given that there are criminal penalties for making false 
statements to the Government, the offense must be sufficiently explicit 
to inform those who are bound by the law of the specific conduct that 
will subject them to criminal penalties. A commenter suggested that it 
was inappropriate to incorporate into the NPRM a definition of 
falsification from FDA's proposed Reporting Information Regarding 
Falsification of Data regulation (Docket No. FDA-2008-N-0115, 75 FR 
7412 (Feb. 19, 2010)). Commenters also suggested that the certification 
and falsification provisions should undergo a separate rulemaking 
process to determine what constitutes falsification and intent, and 
such process should be used and carried out in conjunction with FDA and 
other federal biomedical research stakeholders to propose a system for 
addressing the important and complicated issues related to intentional 
research falsification. Another commenter suggested that a disclaimer 
should be included in clinical trial records to inform the public that 
ClinicalTrials.gov is not responsible for the accuracy of the study 
results. Based on consideration of these comments, the final rule 
eliminates the distinctions between the types of errors (i.e. errors, 
falsifications, other errors) and simplifies the regulatory approach 
for correction of errors as described below and in Sec.  11.64(b). From 
a database integrity standpoint, the distinction between an inadvertent 
and a deliberate error is not material, and eliminating this 
distinction is responsive to concerns raised by public comments. 
However, we emphasize existing mechanisms that address scientific 
misconduct (see Sec.  11.6 and Section IV.A.3 of this preamble).
Final Rule
    Taking into consideration commenters' suggestions regarding both 
updates (proposed Sec.  11.64) and corrections (proposed Sec.  11.66), 
as well as the statutory requirements, the final rule combines these 
sections into the new Sec.  11.64--When must clinical trial information 
submitted to ClinicalTrials.gov be updated or corrected? While both the 
updates and corrections provisions in these sections include specific 
timelines by which clinical trial information must be updated or 
corrected, we encourage responsible parties to update or correct

[[Page 65113]]

information as soon as possible to help the ensure that posted clinical 
trial information is accurate and up-to-date for those that rely on the 
information on ClinicalTrials.gov. Additionally, final Sec.  11.64(a) 
clarifies that ``drug'' means ``drug product.''
    Required updates are described in Sec.  11.64(a), which generally 
retains the NPRM proposal for required updates but modifies the 
requirement for the timing of updating actual enrollment information. 
Consistent with the revisions discussed in preceding sections of this 
preamble, Sec.  11.64(a) also adds a requirement to update Study 
Completion Date and clarifies the requirements for data elements 
related to expanded access. In addition, we clarify how a responsible 
party indicates that there were no changes to clinical trial 
information in the previous 12 month period. Modifications were also 
made to clarify when a responsible party's obligation to update and 
correct clinical trial information ends. In addition, consistent with 
the discussion in section IV.F of this preamble, we made revisions to 
address the differing requirements that apply to applicable clinical 
trials (and, if voluntarily submitted, other clinical trials).
    For clinical trials initiated before the effective date of the 
final rule, Sec.  11.64(a)(1)(i)(A) establishes a general requirement 
for responsible parties to update clinical trial registration 
information specified in section 402(j)(2)(A)(ii) not less than once 
every 12 months if there are changes to any of the data elements 
previously submitted. Section 11.64(a)(1)(i)(B) and (a)(1)(i)(C) detail 
the requirement to update the Overall Recruitment Status data element 
not later than 30 calendar days after any change in overall recruitment 
status and the Primary Completion Date data element not later than 30 
calendar days after the clinical trial reaches its actual primary 
completion date.
    For clinical trials initiated on or after the effective date of the 
final rule, Sec.  11.64(a)(1)(ii)(A) establishes a general requirement 
for responsible parties to update clinical trial registration 
information specified in Sec.  11.28 not less than once every 12 months 
if there are changes to any of the data elements previously submitted. 
Section 11.64(a)(1)(ii)(B) through (a)(1)(ii)(O) establish requirements 
for a responsible party to update certain clinical trial registration 
information more rapidly after a change in the status or conduct of a 
clinical trial or pediatric postmarket surveillance of a device 
product. The NIH recognizes that it would be impractical and 
potentially burdensome to responsible parties to require rapid updates 
to all clinical trial information data elements each time a change 
occurs, but we believe that changes to certain data elements beyond 
those required to be rapidly updated in section 402(j) of the PHS Act 
are sufficiently time-sensitive to require updates more rapidly than 
once every 12 months.
    Section 11.64(a)(1)(ii) outlines the requirements for updating the 
following 14 data elements:
    (1) Study Start Date. The Study Start Date data element must be 
updated from estimated to actual not later than 30 calendar days after 
the first human subject is enrolled in the clinical trial. This 
requirement applies to clinical trials for which an estimated study 
start date is provided at the time of registration, rather than an 
actual study start date, i.e., clinical trial registration information 
was submitted prior to enrollment of the first human subject. The 
update ensures that potential human subjects know in a timely fashion 
that recruitment has begun. It also ensures that the record reflects 
the actual start date, as opposed to an estimated start date, and it 
provides a mechanism to demonstrate whether a clinical trial has been 
registered not later than 21 calendar days after enrollment of the 
first subject.
    (2) Intervention Name(s). The Intervention Name(s) data element 
must be updated to a non-proprietary name not later than 30 calendar 
days after a non-proprietary name is established for an intervention 
studied in a clinical trial. Intervention Name is frequently used as a 
search term to identify and retrieve clinical trials of interest. If it 
is not updated for as long as a year, users of ClinicalTrials.gov will 
not be able to accurately retrieve trials of interest during that time 
or to easily compare information among multiple trials of the same 
intervention.
    (3) Availability of Expanded Access. Clinical trial information 
submitted under the Availability of Expanded Access data element in 
Sec.  11.28(a)(2)(ii)(H) must be updated by the responsible party who 
is both the manufacturer of the drug and the sponsor of the applicable 
clinical trial not later than 30 calendar days after expanded access 
becomes available. Similarly, the data element must be updated not 
later than 30 calendar days after the date on which the responsible 
party receives an NCT number for the expanded access record. This data 
element informs patients whether access to an investigational drug 
product (including a biological product) to treat serious or life-
threatening diseases or conditions is available outside of the 
applicable clinical trial. Expanded access may not be available at the 
time clinical trial registration information is submitted, and expanded 
access may no longer be available on a date other than the primary 
completion date of the applicable clinical trial. Therefore, there are 
specific update requirements:
    First, when expanded access for a particular investigational drug 
product (including a biological product) becomes available after 
registration information has been submitted for applicable clinical 
trial(s) of that investigational product, if the responsible party for 
the applicable clinical trial(s) is both the manufacturer of the 
investigational product and the sponsor of the applicable clinical 
trial, the responsible party must update the Availability of Expanded 
Access data element in Sec.  11.28(a)(2)(ii)(H) not later than 30 
calendar days after expanded access becomes available.
    Second, not later than 30 calendar days after expanded access 
becomes available, if the responsible party is both the manufacturer of 
the investigational drug product and the sponsor of the applicable 
clinical trial, the responsible party must create an expanded access 
record by submitting the data elements required under Sec.  11.28(c), 
unless an expanded access record for the investigational drug product 
has already been created. The responsible party is required to enter 
the NCT number of the expanded access record in the relevant clinical 
trial record(s) not later than 30 calendar days after the date on which 
the responsible party receives such NCT number. We note that we have 
removed the NPRM proposal to also require a responsible party to update 
the Availability of Expanded Access data element not later than 30 
calendar days after termination of the expanded access program. The 
provision of the NCT number of the expanded access record as well as 
the requirement to update the Expanded Access Record data element as 
described in Sec.  11.64(a)(1)(ii)(E) will allow for ClinicalTrials.gov 
to ensure that information on the availability of expanded access is 
accurately displayed on the relevant posted record(s), while reducing 
the update burden on a responsible party.
    We note that, as discussed below, Sec.  11.64(a)(3) establishes 
when a responsible party's obligation to submit updates for clinical 
trial information ends. Even if an investigational product has not been 
approved or licensed at the time the updating requirement ends, we 
strongly encourage responsible parties to continue to update the 
Expanded Access Record until the product is approved or licensed or 
expanded

[[Page 65114]]

access is no longer available. Updating this information will provide 
patients with accurate and up-to-date information about the 
availability of investigational products, which we believe will 
facilitate access to such products. Second, updating expanded access 
records may reduce the burdens on responsible parties who are both the 
manufacturer and the sponsor of the applicable clinical trial, because 
patients who are interested in expanded access will be able to rely on 
the information in ClinicalTrials.gov, rather than having to contact 
the responsible party in order to obtain this information.
    (4) Expanded Access Record. The Expanded Access Status data element 
in Sec.  11.28(c)(2)(iv) must be updated not later than 30 calendar 
days after a change in the status of the availability of expanded 
access, to indicate whether access to the investigational drug product 
is currently available. This data element plays a role in providing 
information about expanded access that is similar to the role of 
Overall Recruitment Status in applicable clinical trials, indicating 
whether expanded access is currently available to patients. Expanded 
Access Type in Sec.  11.28(c)(1)(x) must be updated not later than 30 
calendar days after a change in the type of expanded access that is 
available to patients. The timely update of these data elements is 
important to have reflected in the data bank and is consistent with 
statutory requirements.
    (5) Overall Recruitment Status. This data element must be updated 
not later than 30 calendar days after a change in the overall 
recruitment status of the clinical trial. Changes in recruitment status 
should be communicated promptly so that potential human subjects can 
know whether or not a clinical trial is currently recruiting subjects. 
In addition, if Overall Recruitment Status is updated to ``suspended,'' 
``terminated,'' or ``withdrawn,'' the responsible party must at the 
same time provide information for the Why Study Stopped data element. 
Suspension, termination, and withdrawal of a clinical trial are 
significant changes that should be communicated promptly to prospective 
human subjects, along with the reason for the change. The responsible 
party will be allowed to enter this information as free-text so that he 
or she has flexibility to explain the reason(s) why a clinical trial 
stopped prematurely.
    (6) Individual Site Status. This data element must be updated not 
later than 30 calendar days after a change in status for any individual 
site. It also supports the purpose of ClinicalTrials.gov to enhance 
patient enrollment by assisting potential human subjects who search for 
clinical trials by location and wish to retrieve information about only 
those trials that are open to recruitment in specified locations.
    (7) Human Subjects Protection Review Board Status. This data 
element must be updated not later than 30 calendar days after a change 
in Human Subjects Protection Review Board Status. Because such 
information is intended to demonstrate to potential human subjects 
whether a registered applicable clinical trial or other clinical trial 
has undergone necessary human subjects protection review board review, 
has received necessary approvals for human subjects research, or was 
exempt from such review, it must be updated in a timely fashion.
    (8) Primary Completion Date. This data element must be updated not 
later than 30 calendar days after a clinical trial reaches its actual 
primary completion date. In addition, at the time the date is changed 
to ``actual,'' the responsible party must also update the Enrollment 
data element to actual and specify the actual number of participants 
enrolled.
    (9) Study Completion Date. This data element must be updated not 
later than 30 calendar days after a clinical trial reaches its actual 
study completion date.
    (10) Responsible Party, by Official Title. This data element must 
be updated not later than 30 calendar days after a change in either the 
name of the responsible party or in the responsible party's official 
title. This update is necessary to enable NIH and other users of the 
data bank to accurately identify the responsible party for the clinical 
trial.
    (11) Responsible Party Contact Information. Consistent with updates 
required to the Responsible Party data element, the Responsible Party 
Contact Information must be updated not later than 30 calendar days 
after a change in the responsible party or the responsible party's 
contact information. Given that the responsible party must make updates 
to clinical trial information and, in general, must submit clinical 
trial results information, it is essential for the Agency to know of 
changes to the responsible party and to responsible party contact 
information in a timely manner. Up-to-date information about the 
responsible party ensures that the Agency has contact information for 
the appropriate person responsible for submitting clinical trial 
information about the applicable clinical trial or clinical trial.
    (12) Device Product Not Approved or Cleared by U.S. FDA. This data 
element must be updated not later than 15 calendar days after a change 
in the approval or clearance status of one or more device products 
studied in the applicable clinical trial. A change in the approval or 
clearance status of a device product can trigger a requirement for the 
Agency to post previously-submitted clinical trial registration 
information within 30 calendar days of the change in status as further 
discussed in Section IV.B.5 of this preamble. The 15 day deadline is a 
procedural necessity to provide the Agency timely notice that it must 
post publicly clinical trial registration information within 30 
calendar days of the change in status, as required by law.
    (13) Record Verification Date. This data element must be updated 
any time the responsible party reviews the complete set of submitted 
clinical trial information for accuracy, even if no other updated 
information is submitted at that time. The record verification date is 
intended to demonstrate when the information in ClinicalTrials.gov for 
a particular clinical trial was last checked for accuracy. As noted in 
Sec.  11.28, the responsible party will be required to update the 
Record Verification Date if he or she examines the complete set of 
submitted clinical trial information (e.g., as part of a monthly or 
annual review), even if he or she determines that no additional or 
updated information needs to be submitted. Similarly, the responsible 
party will be required to update the Record Verification Date data 
element if he or she updates a data element and reviews the rest of the 
record for accuracy. However, the responsible party is not required to 
update the Record Verification date if he or she submits updates to one 
or more data elements without reviewing the accuracy of the rest of the 
record. We clarify that the Record Verification Date must be updated 
not less than once every 12 months, even if no other updated 
information is submitted at that time. This approach does not require a 
responsible party to review records more frequently or regularly than 
will be needed in order to update submitted information as otherwise 
required by Sec.  11.64(a), but it does require that the Record 
Verification Date be updated if the complete record were reviewed for 
accuracy during such an update and not less than once every 12 months. 
Doing so indicates to users of ClinicalTrials.gov the currency of the 
information and provides an additional assurance that it is up-to-date.
    (14) Subsection 11.64(a)(1)(ii)(O) details that relevant clinical 
trial

[[Page 65115]]

registration information be updated not later than 30 calendar days 
after a protocol amendment is approved by a human subjects protection 
review board, if the protocol is amended in such a manner that changes 
are communicated to participants in the applicable clinical trial or 
other clinical trial.
    In addition, Sec.  11.64(a)(1)(iii) requires that responsible 
parties update clinical trial registration information at the time they 
submit clinical trial results information to ClinicalTrials.gov (unless 
there are no changes to the clinical trial registration information). 
If the clinical trial was initiated before the effective date of the 
final rule, updates to clinical trial registration information must be 
submitted as described in Sec.  11.64(a)(1)(i). If the clinical trial 
was initiated on or after the effective date of the final rule, updates 
must be submitted in accordance with Sec.  11.64(a)(1)(ii). As 
discussed further in Section IV.F, this approach is consistent with the 
Agency's interpretation of the differing requirements that apply to 
applicable clinical trials initiated before the effective date of the 
final rule and those initiated on or after the effective date of the 
final rule. This requirement is intended to help ensure the consistency 
and accuracy of information in the registry and results portions of the 
data bank. Updated registration information will be used to pre-
populate certain data elements in the clinical trial record so that 
responsible parties do not have to enter them again. Because the 
submission and subsequent posting of clinical trial results information 
is often a reason for users to retrieve the record for a particular 
clinical trial, the additional update requirement will also ensure that 
users have access to complete registration and results information that 
is up-to-date.
    For clinical trials that have a primary completion date on or after 
the effective date of the final rule, Sec.  11.64(a)(2)(i) establishes 
a general requirement for responsible parties to update clinical trial 
results information not less than once every 12 months if there are 
changes to any of the data elements previously submitted. The final 
rule also clarifies that the protocol and statistical analysis plan 
specified in Sec.  11.48(a)(5) and certain agreements specified in 
Sec.  11.48(a)(6)(ii) are excluded from this general requirement as any 
changes to this content will be submitted as partial results 
information in Sec.  11.44(d)(3). Section 11.64(a)(2)(ii) requires for 
applicable device clinical trials of unapproved or uncleared device 
products that the following data elements, as the data elements are 
defined in Sec.  11.10(b), be updated not later than 30 calendar days 
after the relevant changes have occurred: Intervention Name(s), Primary 
Completion Date, Study Completion Date, and Overall Recruitment Status. 
The Record Verification Date must be updated any time the responsible 
party reviews the complete set of submitted clinical trial information 
for accuracy and not less than every 12 months. As described in Section 
IV.C.4 of this preamble for Sec.  11.48(a)(7), we interpret the statute 
to provide the Secretary the authority to require, through rulemaking, 
for applicable device clinical trials of unapproved or uncleared device 
products this additional descriptive information that is similar to the 
type of information required to be submitted under section 
402(j)(2)(A)(ii) of the PHS Act.
    Section 11.64(a)(3) specifies that updates to clinical trial 
information must be submitted until the date on which all required 
clinical trial results information has been submitted as specified in 
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or Sec.  11.48 
(as applicable), and all corrections have been made or addressed in 
response to any electronic notice received under Sec.  11.64(b)(1). 
Until that point in time, submitted clinical trial information will 
continue to be subject to the corrections provisions in Sec.  11.64(b), 
and responsible parties will be required to submit corrected 
information when the responsible party becomes aware of any errors in 
the clinical trial information. We have clarified that if no clinical 
trial results information is required to be submitted, a responsible 
party's obligation to submit updates ends on the date on which all 
required clinical trial registration information has been submitted as 
specified in section 402(j)(2)(A)(ii) of the Public Health Service Act 
or Sec.  11.28, as applicable, and corrections have been made in 
response to any electronic notice received under Sec.  11.64(b)(1).
    We note that the updating requirements under Sec.  11.64(a) are 
prompted by changes in the clinical trial and not by changes in the 
format in which data must be submitted to ClinicalTrials.gov. For 
example, if the Agency were to make administrative changes to the 
format in which clinical trial information is submitted to 
ClinicalTrials.gov after the responsible party had submitted clinical 
trial information as required, the Agency's revisions to 
ClinicalTrials.gov would not themselves give rise to a requirement that 
the responsible party update the previously submitted applicable 
clinical trial information. For example, if the Agency added additional 
options to a drop-down menu for a particular data element, even if one 
of the additional options is more appropriate with respect to an 
applicable clinical trial, the responsible party would not be required 
to update its previously-submitted clinical trial information, although 
the responsible party it could choose to do so on an optional basis. 
However, if a responsible party makes a required update to previously 
submitted clinical trial information, for example, to reflect a change 
in the conduct or progress of a clinical trial, the responsible party 
is required to submit the updated information in the format required by 
ClinicalTrials.gov at the time the update is submitted. For example, if 
the set of options in a drop-down menu had changed since the 
information had previously been submitted, the responsible party is 
required to select from the new set of options. We also note that if 
such options were modified, we would provide prior notice and seek 
public comment as described in Section IV.A.4, as needed.
    Updates to clinical trial registration information and clinical 
trial results information will be posted in accordance with Sec. Sec.  
11.35 and 11.52, respectively. Previously posted clinical trial 
information will remain publicly available through the 
ClinicalTrials.gov archive. The availability of updates is codified in 
Sec.  11.64(a)(4).
    With regard to the requirements for corrections of clinical trial 
information, the final rule eliminates the distinction between the 
three types of corrections described in the NPRM: Errors, falsified 
data, and other corrections. We clarify, however, that the elimination 
of ``falsification'' as a type of error does not reflect a lack of 
concern about data integrity or tolerance by the Agency for 
falsification of information, and we emphasize the existing mechanisms 
that address scientific misconduct and falsifying information submitted 
to the Government in Sec.  11.6. Instead, Sec.  11.64(b) of the final 
rule requires a responsible party to correct or address (1) apparent 
errors, deficiencies, and/or inconsistencies identified by the Director 
during quality control review of submitted clinical trial information; 
and, (2) errors in previously submitted information identified by the 
responsible party. We also reiterate the procedures for quality control 
review that were originally described in the NPRM in Section III.C.12 
and that are directly related to the corrections provisions of this 
final rule. Overall, we consider corrections of information to be 
different from updates to

[[Page 65116]]

information, as described in Sec.  11.64(a). While updates are 
modifications to clinical trial information that reflect changes in the 
status or conduct of a clinical trial or the associated analysis, 
corrections are used to revise submitted clinical trial information 
that contains errors or appears to be invalid, incorrect, inconsistent, 
or incomplete. Because problems in clinical trial information that is 
(or will soon be) posted publicly need to be addressed in a timely 
manner in order to ensure that accurate information is available to the 
public, the final rule requires responsible parties to correct or 
address all such problems not later than 15 calendar days for clinical 
trial registration information and 25 calendar days for clinical trial 
results information after electronic notification is sent by the 
Director or are otherwise identified by the responsible party. A 
responsible party must then either correct and resubmit the clinical 
trial information to ClinicalTrials.gov or address each identified 
issue, such as replying by electronic notification to the Director 
explaining why the information is correct as submitted or why such 
information cannot be corrected.
    Section 11.64(b)(1) specifies the requirements for correcting 
apparent errors, deficiencies, and/or inconsistencies identified based 
on quality control review procedures established by the Director 
(materials explaining how to meet the quality review criteria are 
available at https://prsinfo.clinicaltrials.gov or successor site). Our 
quality control review process is intended to help ensure that clinical 
trial information posted on ClinicalTrials.gov has facial validity and 
is free from obvious errors. Examples of errors, deficiencies, and/or 
inconsistencies that may be identified during the quality control 
review process include, but are not limited to, inadvertent, 
typographical errors, such as transpositions of numbers or characters; 
inadvertent omissions of data, such as omission of one component of set 
of participant exclusion criteria; inconsistencies in submitted data, 
for example, a mismatch between the reported number of subjects 
enrolled in a clinical trial and the sum of reported number of subjects 
assigned to different arms; and, incomplete entries that are 
insufficient to convey their intended meaning, such as a description of 
an outcome measure that does not describe the measurement scale being 
used. They also include submitted values that are demonstrably wrong, 
such as a mean age of participants of 624 years.
    At the time of submission of clinical trial registration 
information, clinical trial results information, and any related 
updates or changes, the Agency will conduct quality control review 
procedures that are similar to the procedures in place before the final 
rule and will not affect the statutory deadlines for the submission and 
updating of clinical trial information (as specified in Sec. Sec.  
11.24, 11.44, and 11.64(a)) or publicly posting submitted clinical 
trial information (as specified in Sec. Sec.  11.35 and 11.52). In 
general, we aim to complete the quality control review process and to 
receive submissions of corrected clinical trial information prior to 
the statutory deadlines for posting submitted clinical trial 
information publicly. We recognize that in some situations, the quality 
control review process may not be concluded prior to the statutory 
posting deadlines, and the Agency will post submitted information that 
may need to be corrected. Clinical trial information posted without 
having concluded the quality control review process, including any 
necessary corrections by the responsible party, will include a 
statement indicating that the quality control review process has not 
concluded. In addition, as also mentioned in Section IV.B.5 of this 
preamble, if the quality control review process has not concluded but 
the clinical trial registration information is posted to the 
ClinicalTrials.gov Web site based on the statutory posting deadline, an 
NCT number will not be assigned until the quality control review 
process has concluded. We believe additional precautions must be taken 
with such clinical trial registration information because it is used by 
the public, including by patients and healthcare providers who are 
considering enrollment in a clinical trial. This approach is generally 
consistent with the practice that has been in effect since 
ClinicalTrials.gov was launched in 2000. This approach helps ensure 
that the existence of an NCT number for a specific clinical trial 
remains an indicator both that a publicly posted clinical trial has 
been registered and that the clinical trial information has gone 
through the quality control review process. Use of NCT numbers is 
required in certain submissions to FDA and in reports to NIH and other 
HHS agencies from relevant grantees and contractors as evidence that 
clinical trials have been publicly registered, as required by section 
402(j) of the PHS Act, and by other stakeholders, including journal 
editors, as evidence of public disclosure of certain protocol 
information. Users searching ClinicalTrials.gov will be able to elect 
to include or exclude posted study records containing clinical trial 
information that has not concluded the quality control review process. 
In addition, because the quality control review process cannot ensure 
the veracity of the data submitted, all entries in ClinicalTrials.gov 
will carry a disclaimer to that effect.
    The quality control review process will continue even after 
submitted information is posted, with a notice that the quality control 
review process has not concluded. Specifically, responsible parties 
must correct or address apparent errors, deficiencies, and/or 
inconsistencies within 15 calendar days (clinical trial registration 
information) or 25 calendar days (clinical trial results information) 
of notification sent by the Director. For example, if quality control 
review identifies two or more data elements within a clinical trial 
record that are internally inconsistent, the responsible party will be 
notified that submitted clinical trial information does not appear to 
meet specified quality review criteria, including the identity of the 
particular elements involved. When the responsible party submits 
revised clinical trial information or provides explanatory information 
that addresses the apparent errors, deficiencies, and/or 
inconsistencies, any revised information will be posted after the 
quality control review. Further, when all apparent errors, 
deficiencies, and/or inconsistencies have been addressed, the statement 
that the quality control review process for that clinical trial record 
has not concluded will be removed from the posted record. However, the 
information that was initially posted will appear in the archived 
history for that clinical trial entry, and the archived version would 
indicate that it had been posted with a notice. The electronic 
notification sent to the responsible party would inform responsible 
parties of these facts.
    We further explain that the quality control review process consists 
of two sequential components as follows: (1) An automated system-based 
check followed by (2) a manual review. In the first component, the 
ClinicalTrials.gov system alerts responsible parties to machine-
detectable errors in the data entered (e.g., certain types of missing 
information that is required, certain types of impossible values, 
certain types of internally inconsistent data). The number of automated 
checks the system performs has increased over time as we have gained 
experience with the types of errors that occur and devised additional 
automated rules for detection. We will continue to refine the

[[Page 65117]]

automated checks in order to assist submitters in detecting and 
minimizing errors, deficiencies, and inconsistencies in the information 
they are submitting. Following resolution of any errors identified by 
the automated system prior to submission, ClinicalTrials.gov staff then 
manually reviews data submissions to identify, based on detailed 
quality control review criteria, additional apparent errors, 
deficiencies, and/or inconsistencies not detected by the automated 
checks. As noted previously, if problems are identified during the 
manual review, an electronic notification will be sent to the 
responsible party, indicating that the submission contains apparent 
errors, deficiencies, and/or inconsistencies with a listing of the 
specific issues that were identified with a request for correction 
within 15 calendar days (clinical trial registration information) or 25 
calendar days (clinical trial results information).
    In the proposed rule, we detailed the steps taken to satisfy the 
pilot quality control project under section 402(j)(5)(C)(i) of the PHS 
Act that directed HHS to develop a process to help ensure that clinical 
trial results information submitted to ClinicalTrials.gov is non-
promotional and is not false or misleading. The quality control study 
consisted of two parts as follows: (1) Review of the results of more 
than 4,500 clinical trials submitted under section 402(j)(3)(C) of the 
PHS Act after September 27, 2008; and (2) an initial validation study 
of the ClinicalTrials.gov results data bank with trial results reported 
in the published literature, conducted under contract by researchers at 
the Oregon Health Science University [Ref. 13].
    Since publication of the NPRM, we have completed a third part of 
the QC pilot study: A validation study of the ClinicalTrials.gov 
results data bank with trial results reported in FDA review documents 
that are publicly available on the Drugs@FDA Web site, conducted under 
contract by researchers at The Dartmouth Institute for Health Policy 
and Clinical Practice [Ref. 111a]. The study determined that primary 
outcome descriptions for sampled trials with results available in both 
sources were generally consistent. However, other information could not 
be directly compared (e.g., adverse events are reported per trial at 
ClinicalTrials.gov, but are sometimes aggregated across multiple trials 
on Drugs@FDA to summarize the overall adverse event profile of a 
particular product).
    Given the limitations of, and differences in, the databases 
identified in this study and the findings from the other parts of the 
quality control study, we have determined that comparisons with 
external sources of information could not be used to validate results 
information submissions. Our experience reviewing submissions to date 
leads us to conclude that the most appropriate approach for 
implementing quality control procedures at ClinicalTrials.gov is to 
have all submissions undergo the two-stage quality control review 
process developed during the pilot study. This quality control review 
process focuses on the content within a study record and includes 
automated validation rules followed by a detailed, manual review of 
submitted information.
    The quality control review process is conducted to help identify 
``apparent errors, deficiencies, and/or inconsistencies'' in the 
submitted information. That process, however, cannot ensure that the 
submitted information is truthful and non-misleading. Therefore, 
compliance with the quality control review process, including the 
requirements set forth in Sec.  11.64, does not constitute a legal 
defense to enforcement pursuant to section 301(jj) of the FD&C Act (21 
U.S.C. 331(jj)), section 303(f)(3) of the FD&C Act (21 U.S.C. 
333(f)(3)), or any other Federal law. A provision has been added to 
Sec.  11.64 of the final rule to clarify this point.
    Section 11.64(b)(2) specifies the requirements for correcting 
errors identified by a responsible party. It is anticipated that 
responsible parties may become aware of needed corrections through 
their own reviews of submitted data or from other parties. We, 
therefore, define procedures similar to those in Sec.  11.64(b)(1) for 
correcting or addressing such errors, including specifying the general 
timeline for corrections as not later than 15 calendar days (clinical 
trial registration information) or 25 calendar days (clinical trial 
results information) after the responsible party becomes aware of any 
such errors. In addition, for errors that are determined by the 
responsible party and the Director to be uncorrectable, information 
will be posted on the record regarding the uncorrectable information. 
As specified in Sec.  11.64(b)(2)(ii), a responsible party's obligation 
to submit correction of errors will end on the date on which complete 
clinical trial results information has been submitted as specified in 
section 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or Sec.  11.48, as 
applicable, and corrections have been made, or addressed, in response 
to any electronic notice received under Sec.  11.64(b)(1). We also have 
clarified that for any clinical trials that are not subject to the 
clinical trial results information submission requirements, the 
obligation to correct errors ends on the date on which complete 
clinical trial registration information has been submitted as specified 
in section 402(j)(2)(A)(ii) of the PHS Act or Sec.  11.28, as 
applicable, and corrections have been made in response to any 
electronic notice received under Sec.  11.64(b)(1).

E. Subpart E--Potential Legal Consequences of Non-Compliance

1. Sec.  11.66--What are potential legal consequences of not complying 
with the requirements of this part?
Overview of Proposal
    Other than the requirement that a responsible party not submit 
false or misleading information and the associated notice of potential 
liabilities for doing so (see Sec.  11.6), the proposed codified text 
did not describe the potential legal consequences of failing to comply 
with the requirements of the rule. Although we did include in the 
preamble to the proposed rule a general discussion of the statutory 
procedures and penalties related to non-compliance (79 FR 69570), we 
did not otherwise discuss in detail the legal ramifications of failure 
to comply with the requirements of section 402(j) of the PHS Act, 
including these regulations.
Comments and Response
    As discussed in Section III.A above, we received a number of 
comments about enforcement of the rule. Within the context of the FDAAA 
Title VIII statutory enforcement provisions, commenters proposed that 
NIH and FDA take certain approaches to enforcing the section 402(j) 
requirements. Commenters proposed specific penalty structures, such as 
only penalizing the responsible party and not the institution and 
making all intentional violations criminal with mandatory prison 
sentences. They also proposed incentives, such as providing easier 
submission mechanisms and citable credit for shared data sets. As 
previously stated, the specifics of how and under what circumstances 
the agencies will seek to enforce section 402(j), including the 
requirements of this final rule, are beyond the scope of this 
rulemaking. We expect that the clarification of responsibilities and 
obligations in this final rule will lead to a high level of voluntary 
compliance with these requirements. However, we believe that it also is 
important that responsible parties be more fully aware of the 
procedures and penalties to which non-compliance could subject them. 
Therefore, although the

[[Page 65118]]

procedures and penalties for non-compliance would be applicable 
regardless of whether they are included in the codified text, we have 
decided to add new Sec.  11.66, which describes the potential legal 
consequences set forth in the FDAAA Title VIII enforcement provisions.
Final Rule
    The final rule includes new Subpart E--Potential Legal Consequences 
of Non-compliance and Sec.  11.66--What are potential legal 
consequences of not complying with the requirements of this part? This 
new section describes potential civil or criminal actions, civil 
monetary penalty actions, and grant funding actions that may be taken 
because of responsible parties' failure to comply with Part 11. Not all 
potential legal consequences are included. For example, as discussed in 
relation to Sec.  11.6, other federal laws also govern the veracity of 
information submitted to the Federal Government, such as 18 U.S.C. 1001 
(making it a crime to make certain false statements to the executive, 
legislative, or judicial branch of the U.S. government). Accordingly, 
new Sec.  11.66 should not be understood as describing the exclusive 
means of enforcement that the Government might undertake with respect 
to compliance with FDAAA Title VIII, including these regulations.
    New Sec.  11.66(a) describes certain non-compliant activities that 
can lead to civil or criminal judicial actions against the responsible 
parties. FDAAA Title VIII amended the FD&C Act by adding a new 
subsection 301(jj) (21 U.S.C. 331(jj)) to the prohibited acts 
provisions. New Sec.  11.66(a)(1) describes that, under 301(jj)(1) of 
the FD&C Act, failure to submit the certification required by section 
402(j)(5)(B) of the PHS Act, or knowingly submitting a false 
certification under that section, is a prohibited act. Section 
402(j)(5)(B) requires submissions of new drug applications under 
section 505 of the FD&C Act, premarket approval applications under 
section 515 or 520(m) of the FD&C Act, biologics license applications 
under section 351 of the PHS Act, or reports under section 510(k) of 
the FD&C Act to be accompanied by a certification that all applicable 
requirements of section 402(j) of the PHS Act have been met. The 
applicable requirements of section 402(j) now include the requirements 
in Part 11.
    New Sec.  11.66(a)(2) describes that failure to submit clinical 
trial information required under section 402(j) of the PHS Act is a 
prohibited act under section 301(jj)(2) of the FD&C Act. The clinical 
trial information required to be submitted under Part 11 is clinical 
trial information required under section 402(j).
    New Sec.  11.66(a)(3) describes that submission of clinical trial 
information under section 402(j) that is false or misleading is a 
prohibited act under section 301(jj)(3) of the FD&C Act. Section 11.6 
specifically provides that information submitted by a responsible party 
under this part ``shall not be false or misleading in any particular.'' 
This language in Sec.  11.6 reflects the precise language of section 
402(j)(5)(D) of the PHS Act, which is then incorporated by reference in 
section 301(jj)(3) of the FD&C Act's prohibited act section. Violating 
Sec.  11.6 would thus be a prohibited act under section 301(jj)(3).
    Judicial remedies for violations of section 301 of the FD&C Act 
include injunctions and criminal penalties. Under section 302 of the 
FD&C Act (21 U.S.C. 332), U.S. district courts have jurisdiction to 
restrain violations of section 301. Under section 303 of the FD&C Act 
persons who violate section 301 can be imprisoned or fined. Pursuant to 
18 U.S.C. 3571, current generally applicable fines are (1) for 
individuals, up to $100,000 for a misdemeanor, up to $250,000 for a 
felony violation and (2) for organizations, up to $200,000 for a 
misdemeanor, up to $500,000 for a felony violation. Such remedies could 
be accomplished through judicial proceedings initiated by FDA and 
brought to court by the Department of Justice.
    New section 11.66(b) describes generally that any person who 
violates section 301(jj) of the FD&C Act is subject to civil monetary 
penalties under section 303(f)(3) of the FD&C Act (21 U.S.C. 
333(f)(3)). Under FDAAA Title VIII's addition of 303(f)(3) to the FD&C 
Act, a person who commits any of the prohibited acts described in 
section 301(jj)(1),(2), or (3) would be subject to a civil monetary 
penalty of ``not more than $10,000 for all violations adjudicated in a 
single proceeding'' (21 U.S.C. 333(f)(3)(A)). Under 402(j)(5)(C)(ii), 
if the Secretary determines that any clinical trial information was not 
submitted as required, or was false or misleading, the Secretary shall 
notify the responsible party and give them an opportunity to remedy the 
non-compliance within 30 days. As part of the civil monetary penalties 
provision, if the violation is not corrected within 30 days following 
such notification, the person is subject to an additional civil 
monetary penalty of ``not more than $10,000 for each day of the 
violation'' until the violation is corrected (21 U.S.C. 333(f)(3)(B)). 
With respect to the dollar amounts for the civil monetary penalties, 
separate laws provide for periodically adjusting for inflation the 
maximum civil monetary penalty amounts (the Federal Civil Penalties 
Inflation Adjustment Act of 1990 (28 U.S.C. 2461 note 2(a)), as amended 
by the Federal Civil Penalties Inflation Adjustment Act Improvements 
Act of 2015 (section 701 of Public Law 114-74)). FDA's procedures for 
administrative imposition of civil monetary penalties are in 21 CFR 
part 17.
    New Sec.  11.66(c) describes the FDAAA Title VIII provisions 
related to grant funding. Under section 402(j)(5)(A) of the PHS Act, if 
an applicable clinical trial is funded in whole or part by HHS, any 
required grant or progress report forms must include a certification 
that the responsible party has made all required registration and 
results submissions. If it is not verified that the required 
registration and results clinical trial information has been submitted 
for each applicable clinical trial for which a grantee is the 
responsible party, any remaining funding for a grant or funding for a 
future grant to such grantee will not be released. If the head of an 
HHS agency verifies that a grantee has not submitted such clinical 
trial information, the agency head will provide notice to the grantee 
of the non-compliance and allow the grantee 30 days to correct the non-
compliance and submit the required clinical trial information. As with 
other matters, the head of the agency may delegate this authority to 
other agency officials. Registration and results information 
submissions required under Part 11 are required submissions for 
purposes of these grant funding provisions.
    Although not included in Sec.  11.66, there is a statutory 
provision that directs NIH to include notices in the registry and 
results data bank containing certain non-compliance information. Under 
section 402(j)(5)(E), these notices, including specified statements, 
alert the public to: Instances of failure to submit required 
information; submission of false or misleading information; penalties 
imposed, if any; whether the information has been corrected in the data 
bank; and, failure to register the primary and secondary outcomes.

F. Effective Date, Compliance Date, and Applicability of Requirements 
in This Part

Overview of Proposal
    Section 402(j) of the PHS Act does not establish time periods for 
the effective date or compliance date of the rule, or the length of 
time between them. In the

[[Page 65119]]

NPRM, the effective date was 45 calendar days after the date on which 
the final rule is published (79 FR 69592). As of that date, the 
ClinicalTrials.gov system would be modified to allow responsible 
parties to comply with the rule. We further proposed that the 
compliance date would be 90 calendar days after the effective date (79 
FR 69592), meaning that a responsible party would have until the 
compliance date of the rule to come into compliance with the 
requirements of the rule.
    For applicable clinical trials, the NPRM also described in Section 
III.D how clinical trial records at the time of the effective date 
would be handled. For registration information, for information 
submitted on or after the effective date, the information would need to 
comply with the rule. For a trial ongoing as of the effective date, 
with registration information submitted before the effective date, the 
NPRM stated that the information would have to comply with Sec.  11.28 
of the rule by the compliance date. Under this proposal, responsible 
parties would have been required to revise and/or add registration 
information to comply with the rule. For an applicable clinical trial 
that reached its completion date prior to the effective date, the 
responsible party would not have been required to comply with the rule, 
but would have been expected to have provided registration information 
as required by section 402(j)(2)(A)(ii) of the PHS Act. The responsible 
party would also have been required to update any information 
necessary, consistent with section 402(j)(4)(C) of the PHS Act.
    With respect to results information, section 402(j)(3)(D)(iv)(II) 
requires the Secretary to determine in rulemaking whether certain 
clinical trial information (i.e., technical and non-technical 
summaries, full protocols, and other categories, as appropriate) 
``should be required to be submitted for an applicable clinical trial 
for which the clinical trial information described in subparagraph (C) 
[basic results] is submitted to the registry and results data bank 
before the effective date of the regulations . . .'' The NPRM provided 
that the responsible parties for applicable clinical trials for which 
results information was submitted under section 402(j)(3)(C) of the PHS 
Act before the effective date would not be required to provide the 
results information specified in proposed Sec.  11.48 of the rule. For 
an applicable clinical trial that reached its completion date prior to 
the effective date of the final rule, the proposal would have required 
the responsible party to submit all of the results information 
specified in proposed Sec.  11.48 if the responsible party had not 
submitted results information under section 402(j)(3)(C) of the PHS Act 
prior to the effective date of the rule. For an applicable clinical 
trial with a completion date before the effective date and for which 
partial results were submitted prior to the effective date, but the 
remaining partial results were neither due nor submitted until on or 
after the effective date, the proposal would have required the 
responsible party to submit clinical trial results information under 
proposed Sec.  11.48 for all outcome measures, including modifying the 
primary outcome measure(s) submitted before the effective date to be in 
accordance with the requirements specified in proposed Sec.  11.48 (79 
FR 69593). For applicable clinical trials completed before the 
effective date of products that are never approved, licensed, or 
cleared, results information would not have been required to be 
submitted. For applicable clinical trials completed before the 
effective date of unapproved, unlicensed, or cleared products that are 
subsequently approved, licensed, or cleared after the effective date, 
it was proposed that results information would be due by the earlier of 
1 year after completion of the trial or 30 calendar days after FDA 
approval, licensure, or clearance of the studied drug or device (79 FR 
69594).
    The NPRM addressed how voluntary submissions under Sec.  11.60 (for 
applicable clinical trials for which registration clinical trial 
information were not required to be submitted or clinical trials of 
FDA-regulated drugs or devices that are not applicable clinical trials) 
would be handled at the time of the effective date. It was proposed 
that voluntary submissions made on or after the effective date must 
comply with the final rule, regardless of trial completion date (79 FR 
69594).
    The NPRM also addressed how updates and corrections to submitted 
clinical trial information (Sec. Sec.  11.64 and 11.66) would be 
handled:
     For clinical trial registration or clinical trial results 
information due on or after the effective date, the responsible party 
would be required to comply with proposed Sec.  11.64 for updating the 
information.
     For clinical trial information due prior to the effective 
date, the responsible party would be required only to update the 
information in accordance with section 402(j)(4)(C) of the PHS Act.
     For an applicable clinical trial that reaches its 
completion date prior to the effective date, but for which results 
information are due after the effective date, the responsible party 
would be required to update registration information according to 
section 402(j)(2)(A)(ii) of the PHS Act, but update results information 
(submitted after the effective date) according to proposed Sec.  11.64.
     For an applicable clinical trial that is registered in 
accordance with section 402(j)(2) of the PHS Act but is ongoing as of 
the effective date, because the responsible party would be required to 
submit registration information consistent with proposed Sec.  11.28 by 
the compliance date, updates would also be required according to 
proposed Sec.  11.64.
    The NPRM also stated that if the responsible party is aware of 
clinical trial information that contains errors, the responsible party 
would be required to submit corrections according to Sec.  11.66, 
regardless of when that information was originally submitted (79 FR 
69594).
Comments and Response
    Commenters expressed opinions on a variety of points related to the 
proposed effective and compliance dates of the rule. Regarding the 
timeline, commenters suggested an effective date later than the 
proposed 45 calendar days after the rule's publication, such as 90 
calendar days after the rule's publication. Similarly, commenters 
suggested an compliance date later than the proposed 90 calendar days 
after the effective date, such as 180 calendar days after the effective 
date. Others supported a phased implementation of the rule's 
requirements to permit increased institutional readiness and to allow 
HHS to address practical compliance barriers that might arise during 
the early stages of the rule's implementation, including the updating 
of ClinicalTrials.gov to accommodate clinical trial information from 
new types of trials.
    First, we have extended the effective date from 45 calendar days to 
provide at least 120 calendar days after filing for public inspection 
of this rule by the Office of the Federal Register. However, but the 
compliance date will remain 90 calendar days after the effective date. 
This extended effective date will allow responsible parties subject to 
the rule more time to review the new requirements and prepare, update, 
and reconfigure their institutional operations and databases 
appropriately. It will also allow ClinicalTrials.gov additional time to 
ensure system readiness by the effective date (e.g., update the PRS 
online forms to incorporate the new data elements, update the automated 
validation rules,

[[Page 65120]]

and revise the user guide and other documentation to reflect the 
requirements of the final rule). While the period of time between the 
effective date and compliance date remains as proposed, responsible 
parties can use the longer time between publication of the rule and the 
effective date to prepare for any submissions needed to comply with the 
final rule.
    Commenters responded to the Agency's proposals on how clinical 
trial records at the time of the effective date of the rule would be 
handled. They disagreed with the approach to require results 
information for all outcome measures to comply with the rule in 
situations for which results information for primary outcome measures 
were submitted prior to the effective date, but results information for 
other measures are neither due nor submitted until on or after the 
effective date. Commenters suggested that the NPRM proposal, which 
would require updating the previously submitted information, might be 
burdensome, and researchers may not have designed or budgeted for such 
updates.
    Others opposed the requirement to comply with the rule when a trial 
was completed before the effective date and, regardless of its due 
date, results information was not submitted prior to the effective 
date. They highlighted burden and additional workload as reasons for 
their opposition. One commenter opposed application of the rule to 
ongoing trials, suggesting that it disrupts the investment-backed 
expectations in place during early development of studied products.
    Other commenters outlined alternatives to the proposal, including 
that new registration provisions only apply to trials registered after 
the effective date, and that new results provisions only apply to new 
results posted after the effective date, and to clinical trials with 
completion dates after the effective date. Another commenter suggested 
the burden caused by the proposal when the First Subject First Visit or 
Primary Completion Date is before the effective date--reporting on 
these studies would require reworking to accommodate the new criteria. 
This commenter noted a particular burden on small entities and 
suggested that the rule only apply to studies with First Subject First 
Visit or Primary Completion Dates after the effective date. As 
mentioned above, we have simplified the requirements for information 
submission during the transition, and this is discussed in more detail 
below.
    One commenter suggested that applying regulations retroactively 
does not comport with typical legal standards of due process that favor 
prospective, as opposed to retroactive, application. Another commenter 
noted that if NIH does apply the rule retroactively to previously 
registered trials, responsible parties may need more time to address 
updates. We have considered the effects of the requirements in the 
final rule and do not believe that there are any impermissible 
retroactive effects that flow from the final rule. We believe that the 
revised approach being adopted alleviates the concerns expressed by 
commenters in this regard.
    While we received no comments suggesting that the handling of 
clinical trial records on and immediately after the effective date be 
made explicit in the regulatory text, we did receive comments 
indicating that the rules are confusing. To resolve that general 
concern, we have restructured the requirements for which applicable 
clinical trials must be registered, whether results information 
submission is required for a particular applicable clinical trial, and 
whether the applicable registration and results information submission 
requirements are those specified in section 402(j) of the PHS Act or 
are those specified in these regulations. In making these changes, our 
aim is to be as clear as possible about the obligations of responsible 
parties.
Final Rule
    The final rule differs from the proposal the NPRM in two important 
ways. First, we have extended the effective date from 45 calendar days 
to at least 120 calendar days after filing for public inspection of 
this rule by the Office of the Federal Register. However, the 
compliance date will remain the same, at 90 calendar days after the 
effective date. Second, the rule simplifies the process for determining 
which applicable clinical trials and information are subject to the 
rule's reporting requirements. Specifically, the registration 
requirements that apply to an applicable clinical trial are determined 
by the date on which the trial is initiated (i.e., the actual study 
start date as defined in Sec.  11.10(b)(16)), and the results 
information submission requirements that apply to an applicable 
clinical trial are determined by the date on which the trial reaches 
its actual primary completion date. We believe that this framework 
provides a logical approach to registering and submitting results 
information, in that it relies on what are, in the simplest terms, and 
for purposes of section 402(j) of the PHS Act and these regulations, 
the start date and the primary completion date of a trial.
    Under this approach, the registration and results information 
submission requirements that apply to any given applicable clinical 
trial also depend on whether the trial is of an approved, licensed, or 
cleared product, or an unapproved, unlicensed, or uncleared product. We 
have reconsidered the approach described in the NPRM (79 FR 69593) with 
respect to determining whether an applicable trial involves an 
approved, licensed, or cleared product, or whether it involves an 
unapproved, unlicensed, or uncleared product. For purposes of this 
final rule, the marketing status of a product will be determined based 
on its marketing status on the primary completion date. Thus, if a drug 
product (including a biological product) or a device product is 
approved, licensed, or cleared for any use as of the primary completion 
date, we will consider that applicable clinical trial to be a trial of 
an approved, licensed, or cleared product. Similarly, if a drug product 
(including a biological product) or a device product is unapproved, 
unlicensed, or uncleared for any use as of the primary completion date, 
regardless of whether it is later approved, licensed, or cleared, we 
will consider that applicable clinical trial to be a trial of an 
unapproved, unlicensed, or uncleared product.
    As a result of this interpretation, whether results information 
submission is required for an applicable clinical trial of an 
unapproved, unlicensed, or uncleared product depends on whether the 
primary completion date for that trial falls before or after the 
effective date of the regulations. If it falls before the effective 
date, then no results information is required to be submitted for that 
applicable clinical trial, regardless of whether the product studied in 
that clinical trial is later approved, licensed, or cleared. If the 
primary completion date is after the effective date of the final rule, 
then results information submission is required as specified in the 
final rule.
    We recognize that there are responsible parties who submitted 
results information pursuant to the provisions in sections 402(j)(3)(C) 
and (E) for applicable clinical trials of products that were not 
approved, licensed, or cleared at the time the trial was ongoing, but 
which were approved after the primary completion date. Notwithstanding 
the fact that, under the interpretation in the final rule, results 
information for these trials was not required to be submitted, we do 
not consider the results information for these trials to have been 
submitted

[[Page 65121]]

pursuant to section 402(j)(4)(A). Although the previously submitted 
information will remain in the PRS system and will be publicly 
available, it is not subject to either the provisions of Sec.  11.60 
regarding voluntary submissions or the requirements in Sec.  11.64 with 
respect to updates and corrections of information. The Agency does, 
however, encourage responsible parties to update such previously 
submitted results information and would not consider such updates to be 
subject to the voluntary submission requirements in Sec.  11.60.
    The applicable registration and results information submission 
requirements are summarized in the following table:

                                                     Applicability of Requirements in 42 CFR Part 11
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                        Registration information  submission required?       Results information  submission required?
                                                   -----------------------------------------------------------------------------------------------------
       Initiation date         Primary  completion                                                                                        Unapproved,
                                       date           Approved,  licensed, or    Unapproved,  unlicensed,   Approved,  licensed, or     unlicensed, or
                                                         cleared products         or  uncleared products        cleared products      uncleared products
--------------------------------------------------------------------------------------------------------------------------------------------------------
On or before September 27,     After December 26,   Yes, as specified in        Yes, as specified in       Yes, as specified in       No.
 2007.                          2007 and before      section 402(j)(2)(A)(ii)    section 402(j)(2)(A)(ii)   section 402(j)(3)(C) and
                                Effective Date of    of the PHS Act.             of the PHS Act.            section 402(j)(3)(I) of
                                Final Rule.                                                                 the PHS Act.
After September 27, 2007 and   Before Effective     Yes, as specified in        Yes, as specified in       Yes, as specified in       No.
 before the Effective Date of   Date of Final Rule.  section 402(j)(2)(A)(ii)    section 402(j)(2)(A)(ii)   section 402(j)(3)(C) and
 the Final Rule.                                     of the PHS Act.             of the PHS Act.            section 402(j)(3)(I) of
                                                                                                            the PHS Act.
After September 27, 2007 and   On or after          Yes, as specified in        Yes, as specified in       Yes, as specified in 42    Yes, as specified
 before Effective Date of       Effective Date of    section 402(j)(2)(A)(ii)    section 402(j)(2)(A)(ii)   CFR part 11.               in 42 CFR part
 Final Rule.                    Final Rule.          of the PHS Act.             of the PHS Act.                                       11.
On or after Effective Date of  On or after          Yes, as specified in 42     Yes, as specified in 42    Yes, as specified in 42    Yes, as specified
 Final Rule.                    Effective Date of    CFR part 11.                CFR part 11.               CFR part 11.               in 42 CFR part
                                Final Rule.                                                                                            11.
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The table above does not apply to voluntary submissions under Sec.  
402(j)(4)(A) of the PHS Act and Sec.  11.60. The registration and 
results information submission requirements for the voluntary 
submission of clinical trial information are addressed in Sec.  11.60.
    We recognize that there will be some situations that arise in the 
months leading up to and following the effective date where a 
responsible party's obligations may shift depending on a variety of 
factors. For example, there may be a small number of applicable 
clinical trials for which the study start date (i.e., the date of 
initiation) changes after the trial is registered and that that change 
may result in a shift in the registration and/or results information 
submission requirements for that applicable clinical trial. For 
example, if a responsible party initially registered an applicable 
clinical trial two months before the effective date of the final rule 
and entered an estimated study start date that fell one month before 
the effective date of the final rule, the responsible party's 
understanding at the time of registration would be that it would need 
to submit registration information as specified in section 
402(j)(2)(A)(ii) of the PHS Act. However, if the trial is not initiated 
until after the effective date of the final rule, the responsible party 
will be required to comply with the registration provisions as 
specified in the final rule and to update the registration information 
for that applicable clinical trial. In a situation such as this, we 
would expect clinical trial registration information to be updated 
promptly, but in any case no later than as required under Sec.  
11.64(a) of the final rule. We note that in this scenario the 
responsible party will have been on notice since the publication date 
of the final rule both that the registration requirements will be 
changing as of the effective date and what those changes will be.
    Similarly, if a responsible party initially registered an 
applicable clinical trial two months before the effective date of the 
final rule and entered an estimated study start date that fell one 
month after the effective date of the final rule, the responsible 
party's understanding at the time of registration would be that it 
would need to submit registration information as specified in the final 
rule (although we note that, because of the work needed to update the 
ClinicalTrials.gov data bank to accommodate the changes in the final 
rule, it may not be possible to enter information required as specified 
in the final rule prior to the effective date). However, if the 
applicable clinical trial actually was initiated one week before the 
effective date of the final rule, the trial would instead be subject to 
the registration requirements as specified in section 402(j)(2)(A)(ii) 
of the PHS Act and not the final rule.
    Further, it is our understanding that, because of the complexities 
of how clinical research activities are managed at larger institutions, 
in some situations an applicable clinical trial might have been 
initiated but the individual who is responsible for submitting 
registration information regarding that trial might not have received 
notice of that initiation. If this scenario were to occur shortly after 
the effective date of the final rule, it is possible that the trial 
would be registered under the assumption that the requirements in the 
final rule apply and, therefore, more clinical trial information would 
be submitted than would be required. In this situation, the responsible 
party would not be required to update that additional registration 
information (although the information itself would remain available in 
the PRS system).
    We also recognize that because a responsible party has 21 days 
after

[[Page 65122]]

initiation in which to register an applicable clinical trial, it is 
possible that a trial might be initiated before the effective date of 
the final rule but the responsible party might not submit registration 
information for it until after the effective date of the final rule. In 
this situation, notwithstanding the fact that the registration 
information for that applicable clinical trial was submitted after the 
effective date of the final rule, the Responsible Party would only be 
required to submit registration information as specified in section 
402(j)(2)(A)(ii) of the PHS Act, not the final rule.
    We appreciate that the possibility that situations such as these 
may arise will be of concern to affected responsible parties, and we 
are committed to assisting them in understanding their responsibilities 
and determining which requirements apply to particular applicable 
clinical trials. We would like to emphasize, however, that it has been 
clear since the proposed rule was issued in 2014 (and, in our view, 
since the enactment of FDAAA, with both its requirement that the 
rulemaking address the issue of results information submission and the 
provision that the Secretary may modify the registration requirements) 
that changes to the registration and results information submission 
requirements were both possible and highly probable.
    While we believe that the NPRM provided a logical approach for 
handling records in transition, we understand that the approach might 
have been confusing to responsible parties. We believe that these 
changes will address the concerns of many commenters, such as those who 
did not believe primary outcome measures should have to be resubmitted 
when secondary outcome measures were due and submitted after the 
effective date. This change is simpler and clearer for those who were 
compliant under section 402(j) of the PHS Act. In addition, with the 
change to a later effective date, responsible parties who are subject 
to the registration and/or results information submission requirements 
in the final rule will have more time to plan accordingly.

V. Regulatory Impact Statement

    The Agency has examined the impacts of this final rule under 
Executive Order 12866, Regulatory Planning and Review, Executive Order 
13563, Improving Regulation and Regulatory Review, the Regulatory 
Flexibility Act (5 U.S.C. 601-612) (RFA), the Unfunded Mandates Reform 
Act of 1995 (Pub. L. 104-4), and Executive Order 13132, Federalism. 
Executive Order 12866, as amended by Executive Order 13563, directs 
agencies to assess all costs and benefits of available regulatory 
alternatives and, when regulation is necessary, to select regulatory 
approaches that maximize net benefits (including potential economic, 
environmental, public health and safety, and other advantages; 
distributive impacts; and equity). A regulatory impact analysis must be 
prepared for major rules with economically significant effects ($100 
million or more in any single year). The Agency estimates that the 
total cost of the requirements to regulated entities is approximately 
$59.6 million annually. We anticipate the potential for significant 
scientific and public health benefits, in the form of improvements in 
clinical trial designs, human subjects' protections, and improved 
evidence base to inform product development and clinical care. In 
addition, enhanced access to information about clinical trials may 
increase public trust in the research enterprise. We estimate that this 
rule is not an economically significant regulatory action as defined by 
Executive Order 12866. Because of the interest in this rule among 
regulated entities and others involved in conducting or using the 
results of clinical trials, we have, nevertheless, prepared an analysis 
that, to the best of our ability, estimates the costs and benefits of 
this rule. The RFA requires agencies to analyze regulatory options that 
would minimize any significant impact of a rule on a substantial number 
of small entities. The rule is estimated to impose costs of 
approximately $17,907 per applicable clinical trial (see Table 1 and 
Section V.G for additional information). Based on the RFA analysis (see 
Section V.G), we estimated that most small entities would be expected 
to be responsible for no more than one applicable clinical trial per 
year and that the per applicable trial cost to them would in general 
represent a small fraction of their revenues. This analysis forms the 
basis of the Agency's certification that the final rule will not have a 
significant economic impact on a substantial number of small entities.
    Section 202 of the Unfunded Mandates Reform Act of 1995 requires, 
among other things, that agencies prepare a written statement, which 
includes an assessment of anticipated costs and benefits, before 
proposing ``any rule that includes any Federal mandate that may result 
in the expenditure by State, local, and tribal governments, in the 
aggregate, or by the private sector, of $100,000,000 or more (adjusted 
annually for inflation) in any one year'' (2 U.S.C. 1352(a)). The 
current threshold, adjusted for inflation using the 2015 Implicit Price 
Deflator for the Gross Domestic Product, is $146 million. The Agency 
does not expect this rule to result in any 1-year expenditure that 
would meet or exceed this amount. As explained above, however, the 
Agency has conducted an analysis of the costs that could result from 
this rule.
    Executive Order 13132 (Federalism) establishes certain requirements 
that an Agency must meet when it promulgates a proposed rule (and 
subsequent final rule) that imposes substantial direct requirement 
costs on State and local governments, preempts State law, or otherwise 
has Federalism implications.

A. Comments and Response

    Commenters responded to the economic analysis in the NPRM of the 
estimates of the costs and benefits of the rule. While some commenters 
found the analysis appropriate overall and considered a 40 hour 
estimate for results information submission to be accurate, other 
commenters suggested that the time estimates used to calculate 
registration, results, and updates burden were lower than they should 
be. Some argued that the burden of entering information into the 
database is greater for smaller research institutions because, unlike 
larger research organizations, they are less likely to have dedicated 
and trained personnel to manage clinical trial information reporting. 
Others suggested the rule will be equally burdensome to small and large 
organizations. We recognize that some members of the regulated 
community may spend more hours than others to develop, process, and 
maintain clinical trial records. However, we believe our estimates of 8 
hours for registration information, 40 hours for results information 
and 16 hours for updates of information are a reasonable representation 
of the overall average time required to complete all registration and 
results requirements by all respondents.
    Commenters also suggested that ClinicalTrials.gov harmonize its 
clinical trial reporting requirements with existing international 
regulations in order to decrease the burden on institutions. It was 
suggested that reporting unique numbers of individuals with adverse 
events by organ system differs from the EU reporting standards and 
increases the burden of the rule. In consideration of the commenters' 
concerns, the final rule no longer requires the reporting of numbers of 
people with adverse events at the organ system level. We anticipate

[[Page 65123]]

that this change will decrease the burden of the rule.
    One commenter suggested that the rule would also have an economic 
impact on biopharmaceutical development because of competitive harms 
associated with premature disclosure of confidential commercial 
information. As discussed in Section III.B of this preamble and Sec.  
11.44, this rule requires only summary level results information to be 
submitted, and it allows for delayed submission with certification in 
order to minimize any perceived competitive disadvantages for 
unapproved, unlicensed, or uncleared products (see Sec.  11.44(b) and 
(c)) and delayed posting of registration information for unapproved or 
uncleared device products (see Sec.  11.35(b)(2)(i)). Submission of 
clinical trial results information for applicable clinical trials of 
approved, licensed, or cleared products and applicable clinical trials 
of unapproved, unlicensed, or uncleared products, according to 
deadlines established by the final rule, ensures consistent and timely 
public access to comprehensive summary results for all applicable 
clinical trials. Furthermore, we are not persuaded that economic harms 
will result from the public posting of the required data elements.
    Commenters also suggested that the cost estimates understated the 
burden associated with bringing previously submitted registration 
information into compliance with the final rule. One commenter 
suggested that the cost of compliance will not go down over time, while 
another suggested that in order to decrease this burden, the rule 
should only apply to those trials that had their First Subject First 
Visit or Primary Completion Date after the effective date of the rule. 
In consideration of commenters' concerns, the final rule eliminates 
virtually all additional burden associated with updating previously 
submitted trial information by requiring only registration as specified 
in the final rule for applicable clinical trials for which the date of 
initiation is after the effective date of the final rule and by only 
requiring results information submission as specified in the final rule 
for applicable clinical trials that reach their primary completion date 
after the effective date of the final rule. In light of these changes, 
which are discussed in more detail in Section IV.F of this preamble, 
there are very few applicable clinical trials registered or submitted 
partial results prior to the effective date of the final rule that will 
need to be updated as a consequence of the rule. As such, we expect the 
burden associated with such situations to be minimal because they will 
arise relatively infrequently. In addition, we anticipate that the 
occurrence of such situations will decrease over the next three years 
because, ultimately, there will be very few ongoing applicable clinical 
trials that were initially registered prior to the effective date of 
the final rule.
    Another commenter suggested that the correction procedures proposed 
in Sec.  11.66 could cause further economic burden because they thought 
that no clear distinction in the definitions of errors and 
falsifications was provided, which they said could lead to unnecessary 
and costly preemptive actions by the responsible party. The final rule 
no longer distinguishes between different types of errors (see Sec.  
11.64), and, thus, the potential economic burden of differentiating the 
type of error has been eliminated.
    Commenters also suggested that the Agency should calculate actual 
burden and include other costs such as reprograming of institutional 
systems, increased medical review, and management oversight. They 
suggested that we had not sufficiently considered the costs associated 
with activities carried out by organizations that may invest 
substantial resources to avoid the negative consequences of violating 
the legal and regulatory requirements, e.g., loss of federal grant 
support and/or monetary penalties. We agree that our cost estimate did 
not attempt to isolate the cost and burden that an institution as a 
whole might absorb in order to facilitate and monitor compliance among 
clinical investigators subject to the rule who are employed by the 
institution. Because overhead costs (i.e., costs not related to direct 
labor or direct materials) varies among different industries and 
occupations, we attempted to approximate those overhead costs by 
doubling the average hourly wages in the personnel cost calculations. 
We took this approach in part because the cost of this rule is likely 
to vary significantly among institutions and organizations due to 
differences in institution's sizes, frequency of clinical trials 
performed per year and variation in the need to update or create 
information technology tools or application used to support clinical 
trial registration and results information submission and also because 
of the lack of data on the cost of institutional compliance. 
Nonetheless, in response to public comments, we have developed a 
separate estimate of the costs that institutions may assume in order to 
facilitate and monitor compliance among employees with responsibilities 
under the rule. The estimate is described in Section E below.
    Commenters suggested that the Agency should allow financial burden 
of registration and results reporting to be covered as a direct cost in 
grants, whether incurred by the investigator or shared with a central 
administration unit. The Agency has previously clarified for NIH 
awardees that ``[g]iven the nature of registration and result 
information report requirement and that the project staff will 
generally be in the best position to submit and maintain these data, 
the costs of compliance with section 402(j) of the PHS Act will be 
generally allowable as direct charges to NIH grants. While it is 
expected that these costs will be covered by the funds provided with 
the grant, administrative supplements could also be considered'' [Ref. 
112].

B. The Final Rule

    The final rule codifies in federal regulation the provisions for 
the mandatory registration and submission of results information for 
applicable clinical trials to ClinicalTrials.gov, as required by 
section 402(j) of the PHS Act. This rule both clarifies the existing 
statutory requirements for submission of registration and results 
information, including adverse events information, and implements the 
expansion of the registry and results data bank by rulemaking as 
required by section 402(j)(3)(D) of the PHS Act.

C. Need for the Final Rule

    The Agency is promulgating this rule to fulfill the requirements of 
section 402(j) of PHS Act in a manner that will provide broad public 
access to pertinent clinical trial registration and results 
information. Section 402(j)(2)(A)(i) of the PHS Act requires the 
Secretary to expand the clinical trials registry data bank with respect 
to clinical trial information to ``enhance patient enrollment and 
provide a mechanism to track subsequent progress'' of the clinical 
trials. Sections 402(j)(3)(B) and 402(j)(3)(C) of the PHS Act instruct 
the Secretary to expand the clinical registry data bank not later than 
1 year after enactment of FDAAA to include the results information 
specified in section 402(j)(3)(C) for certain applicable clinical 
trials. Section 402(j) of the PHS Act also requires responsible parties 
to submit to the expanded data bank specified registration information 
(i.e., descriptive information, recruitment information, location 
information, and administrative information) summarizing key aspects of 
applicable clinical trials that are subject to the law and specified 
results information

[[Page 65124]]

describing the outcomes of applicable clinical trials for which the 
drugs or devices under study have been approved, cleared, or licensed 
by FDA. Section 402(j) of the PHS Act further establishes deadlines by 
which such information must be submitted and establishes penalties for 
non-compliance. This final rule implements the statutory requirements 
and clarifies the Agency's interpretation of them. It explains the 
meaning of terms defined in the section 402(j) of the PHS Act (e.g., 
responsible party and applicable clinical trial) and of several data 
elements that are required to be submitted to the data bank (e.g., 
study design, eligibility criteria). It also exercises the authority 
given to the Secretary in section 402(j)(2)(iii) of the PHS Act to 
modify by regulation the requirements for clinical trial registration 
information. This final rule specifies several modifications to the 
clinical trial registration information that the Agency believes meet 
the statutory criteria of improving and not reducing the statutorily 
specified clinical trial registration information.
    In addition, this rule is necessary to implement provisions of 
section 402(j) of the PHS Act that are specifically required to be 
addressed by regulation. Section 402(j)(3)(I) of the PHS Act, requires 
the Secretary to determine by regulation the ``best method'' for 
including in the registry and results data bank appropriate results 
information on serious adverse and other adverse events collected for 
certain applicable clinical trials. Section 402(j)(3)(D) of the PHS Act 
requires, among other things, the Secretary to further expand the 
registry and results data bank through rulemaking to ``provide more 
complete results information and to enhance patient access to and 
understanding of the results of clinical trials.'' Section 402(j)(3)(D) 
of the PHS Act specifies several topics that the rule is to address, 
including whether to require the submission of results information for 
applicable clinical trials of drugs and devices that have not been 
approved, licensed, or cleared by FDA; whether technical or lay 
summaries of a clinical trial can be included in the data bank without 
being misleading or promotional; and whether to require responsible 
parties to submit the protocol or ``such information on the protocol . 
. . as may be necessary to help evaluate the results of the trial.'' 
This rule addresses each of these topics and others specified in 
section 402(j) of the PHS Act.

D. Benefits of the Final Rule

    As discussed in Section I of this preamble, the overarching aim of 
the final rule is to provide public access to a standardized set of 
information describing the conduct and results of certain clinical 
trials of FDA-regulated drugs (including biological products) and 
devices. Access to clinical trial information has significant 
scientific, and public health benefits, which we describe in Section I. 
These benefits accrue to potential and enrolled clinical trial 
participants, clinical researchers, systematic reviewers, disease and 
patient advocacy groups, regulators, drug and device manufacturers, 
healthcare providers, patients and their family members. Public access 
to clinical trial information can help patients find trials for which 
they might be eligible, enhance the design of clinical trials and 
prevent duplication of unsuccessful or unsafe trials, improve the 
evidence base that informs clinical care, increase the efficiency of 
drug and device development processes, improve clinical research 
practice, and build public trust in clinical research.
    Access to clinical trial information assists individuals in finding 
trials in which they may be eligible to enroll. It can help people in 
making more informed decisions about participating in a clinical trial 
by providing them and their care providers with information about the 
results of a broader set of clinical trials of various interventions 
that have been studied for a disease or condition of interest. The 
highly structured data and search engine allows members of the public 
to search for trials for which they may be eligible [Ref. 19]. It also 
enables third parties to use the information describing the clinical 
trial to meet other specific needs [Ref. 35], such as reformatting the 
data for constituents of various patient advocacy groups (e.g., 
patients with breast cancer) [Ref. 36], data mining for associations 
among interventions and diseases studied worldwide, and for use in 
semi-automated data collection for conducting critical appraisals and 
systematic reviews to support evidence-based medicine. For example, 
while ClinicalTrials.gov does not itself match potential participants 
with relevant trials, the rule ensures the timely posting of 
registration information about trials currently enrolling participants. 
This information is used by third parties to provide matching services 
that help patients find trials that might be appropriate for them.
    Increased clinical trial transparency has the potential to drive 
scientific progress by informing future research, identifying knowledge 
gaps and opportunities, improving study designs, and preventing 
replication of unsuccessful trials and initiation of unsafe trials. 
Accessibility of clinical trial information may accelerate the drug 
discovery and development process by reducing redundancies and 
facilitating the identification and validation of new drug targets or 
surrogate endpoints, and it allows for improved understanding of the 
safety and efficacy of new therapies. The information provides a more 
robust evidence base for new research, which reduces systematic bias 
and leads to better science. Strengthening the evidence base also 
maximizes returns on the contributions of clinical trial participants 
as well as the time and financial investments of investigators, study 
funders, and sponsors.
    Access to clinical trial information enables IRBs [Ref. 25], 
researchers, funding agencies, systematic reviewers [Ref. 26, 27], 
bioethicists [Ref. 28], science and public policy makers [Ref. 29], and 
others to see the landscape of trials on a given topic, by a particular 
funder, by geography [Ref. 30], by population [Ref. 9], or other 
relevant criteria. Providing these users with such a capability informs 
their judgments about the potential value of new trials. It also helps 
ensure that assessments of the risks and benefits of a potential 
intervention for a particular use reflect the totality of evidence from 
all prior trials. Such information also enhances scientific and 
financial accountability of sponsors. Landscape analyses such as these 
also provide feedback and insights for the clinical research community, 
by informing the design and analysis of future trials [Ref. 11, 31, 
32].
    Access to clinical trial results information helps fill substantial 
gaps in the database left by the non-publication (or very delayed 
publication) of a substantial portion of clinical trials in the medical 
literature [Ref. 42, 43]. Access to results from clinical trials of 
unapproved, uncleared, or unlicensed products is expected to alleviate 
the concerns regarding bias in the literature and selective 
publication. The complete set of results for all primary and secondary 
outcome measures supplements the more limited set of results data found 
in the published literature [Ref. 13, 37]. The availability of results 
information will help prevent the evidence base that is the foundation 
of systematic reviews and clinical practice guidelines from being 
skewed.
    The availability of results information for trials of unapproved 
products may inform the assessment of risks and benefits that potential 
participants

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might face in subsequent studies of those same or similar products; it 
may also contribute to the overall assessments that are made of similar 
marketed products [Ref. 46]. Trials of products that are unapproved, 
unlicensed, and uncleared are unlikely to be published if the results 
of these trials are insufficient to support applications for product 
approvals (e.g., because the study resulted in negative findings or was 
inadequately designed or executed).
    Clinical trials are expensive to initiate and carry out, and they 
are a significant national investment. Phase 2, 3, and 4 clinical 
trials cost on average, $13 million, $20 million, and $20 million 
respectively [Ref. 113], and it takes an average of $1.4 billion in 
clinical trial costs to develop 1 new compound [Ref. 114]. In FY 2016, 
NIH invested an estimated $3.3 billion in clinical trials and 
supportive activities [Ref. 115]. Access to more complete information 
about clinical trials helps conserve resources and, for federally 
funding trials, optimize the public investment in research. It helps 
avoid a suboptimal return on the financial resources invested by study 
funders and sponsors [Ref. 47] and can reduce costs by minimizing 
redundant trials.
    Finally, another benefit of the rule is that it helps individual 
investigators, the clinical trial enterprise, and society as a whole 
fulfill an ethical obligation to trial participants. Individuals 
participate in clinical trials with the understanding that the research 
will contribute to the expansion of knowledge pertaining to human 
health. When trial information is withheld from public scrutiny and 
evaluation, the interpretation of the data and the public's trust in 
the research may be compromised. The rule helps to further the goal of 
ensuring that participation in research leads to accountability via the 
public reporting of information. The importance of trust in clinical 
research and public trust in the enterprise is promoted when we 
establish a public record of the trials in which people participate.

E. Costs Associated With the Final Rule

    The costs associated with the final rule consist of the time and 
effort necessary for responsible parties to comply with the rule 
requirements to register applicable clinical trials; submit specified 
results information (including adverse event information); update and 
correct submitted registration and results information, as needed; 
submit certifications and/or extension requests to delay the deadline 
for submitting results information; submit information describing 
expanded access programs for drugs studied in an applicable clinical 
trial, and request waivers to any of the requirements for results 
information submission. We do not intend this rule to cause responsible 
parties to collect any information that was not already intended to be 
collected during the clinical trial, nor do we intend this rule to 
cause responsible parties to analyze such information in ways that were 
not intended under the protocol or the associated SAP. Rather, the rule 
specifies those elements of the collected results information that must 
be submitted to the data bank and the format in which that information 
must be submitted.
    The calculations below present our estimates of the time and cost 
associated with meeting the information submission requirements of the 
final rule, including the burden associated with assembling the 
required information, formatting the information for submission, 
submitting it to the data bank, and correcting or updating it over 
time. The calculations break out the estimated annual costs associated 
with: (1) Registering a trial; (2) submitting results information; (3) 
submitting certifications, extension requests and appeals to delay the 
results information submission deadline; (4) submitting clinical trial 
information that is triggered by a voluntary submission; and, (5) 
creating expanded access records for drugs studied in an applicable 
clinical trial. The estimates include the costs associated with 
updating submitted information and with correcting errors detected by 
NIH. These are shown in the table below and, in the text below the 
table in Sections 1-5, we described these costs in more detail. We also 
estimate the costs of compliance to institutions that elect to devote 
resources to help investigators in their institutions who are subject 
to the rule to comply with its requirements. These additional resources 
mainly involve the hiring or reassignment of personnel to support the 
submission of registration and results information submission to 
ClinicalTrials.gov. The approach we took to estimate these costs is 
described below in Section 6. In the NPRM, we estimated cost of this 
final rule to be $32 million. Our higher estimate of $59.6 million is 
largely due to the more detailed consideration of costs that 
organizations may incur to ensure compliance on the part of responsible 
parties they employ.
1. Registration of Applicable Clinical Trials
    To estimate the costs of trial registration, we first estimated the 
number of applicable clinical trials that would be initiated in a given 
year and be subject to the provisions of this final rule. Using the 
approach described below, we estimate that a total of 7,400 applicable 
clinical trials of drug products (including biological products) and 
device products per year would be subject to the registration 
requirement of this final rule. This estimate is based on information 
from FDA indicating that it receives approximately 5,150 clinical trial 
protocol submissions annually for applicable clinical trials (76 FR 
256). This figure includes protocol submissions to CDER, CBER, and 
CDRH; it does not include clinical trials that were not conducted under 
an IND or IDE. To estimate the number of such clinical trials, we 
examined the number of clinical trials registered with 
ClinicalTrials.gov that appear to meet the criteria for an applicable 
clinical trial but do not appear to have been conducted under an IND or 
IDE, e.g., because they are exempt from the requirement to submit an 
IND or IDE. We found approximately 1,700 and 2,000 such clinical trials 
in 2012 and 2013, respectively. We increased this figure to 2,250 to 
accommodate further growth in the number of such clinical trials that 
would be registered following publication of the final rule. The sum of 
these figures (i.e., 5,150 plus 2,250 equals 7,400) provides an 
estimate of the number of applicable clinical trials that will be 
subject to the registration requirement of this final rule each year.
    To calculate the burden associated with registering 7,400 clinical 
trials, we estimated the time required to submit complete clinical 
trial registration information for an applicable clinical trial. We 
estimate this time to be 8 hours, including time to extract information 
from the study protocol, reformat it, and submit it to 
ClinicalTrials.gov. This figure accounts for the estimated time needed 
to submit the 5 additional data elements that will be required by this 
final rule. Applying this time estimate to the estimated number of 
applicable clinical trials yields a burden of 59,200 hours per year for 
registering applicable clinical trials. Based on our previous 
experience, we estimate that each registration record will be updated 
an average of eight times during the course of the study (e.g., to 
reflect changes in the conduct of the clinical trial, additions of 
investigational sites, recruitment status updates). Although clinical 
trials of long duration and with multiple sites will likely submit more 
updates during the course of the trial, we have found that many 
applicable clinical trials have a

[[Page 65126]]

relatively short duration and a limited number of study sites, which 
lowers the average per clinical trial. The time required for subsequent 
updates of clinical trial registration information is expected to be 
significantly less than for the original registration as less 
information must be provided) and is estimated to be 2 hours per 
update, resulting in a total of 16 hours of additional time attributed 
to updates per trial. Using these figures, we calculated the total 
annual hour burden for updates to clinical trial registration 
information for all applicable clinical trials to be 118,400 hours. 
Combining this figure with the estimated time for initial registrations 
(59,200 hours) yields an estimate of the total hour burden associated 
with the submission and updating of clinical trial registration 
information of 177,600 hours per year. These estimates include the time 
involved in addressing any issues identified during quality control 
review of submitted registration information.
    To calculate the cost of registration, we examined May 2015 data 
from the U.S. Bureau of Labor Statistics on the average wages of life, 
physical, and social science workers in the pharmaceuticals and 
medicine manufacturing and medical scientists (except epidemiologists) 
also working in the pharmaceutical and medicine manufacturing 
industries. During the time we have operated ClinicalTrials.gov, we 
have found that this task is generally performed by junior-level 
researchers or administrative staff. For purposes of this estimate, we 
used an average hourly wage rate of $36.02, which is the average wage 
of life, physical, and social science workers in the pharmaceuticals 
and medicine manufacturing industries and is significantly higher than 
the median wage of other administrative staff in those sectors who are 
typically tasked with submitting registration information to 
ClinicalTrials.gov. Because overhead costs vary among different 
industries and organizations, we approximate overhead costs by doubling 
the average hourly wages (to $72.04 per hour). Using this adjusted wage 
figure, we calculated an estimated total annual cost of registration 
under the final rule, including updates over the course of a clinical 
trial, of $12,794,304 (Table 1). This figure represents an incremental 
increase of $533,096 per year above the estimated cost of registration 
prior to the rule.
2. Results Information Submission
    To estimate the burden associated with submission of clinical trial 
results information, we started with the premise that every clinical 
trial required to register in a given year would be required 
subsequently to submit results information. The statute requires 
results information submission for all applicable clinical trials that 
study drugs (including biological products) or devices that are 
approved, cleared, or licensed by FDA. The rule requires, in addition, 
the submission of clinical results information for applicable clinical 
trials of drug products (including biological products) and device 
products that are not approved, cleared, or licensed by FDA. We, 
therefore, estimate the burden associated with results information 
submission for a total of 7,400 applicable clinical trials of drug 
products (including biological products) and device products per year, 
recognizing that in most cases, such clinical trial results information 
will not be submitted in the same year as the associated clinical trial 
registration information but in accordance with the deadlines specified 
in Sec.  11.44. We expect, however, that on average the number of 
clinical trials for which clinical trial results information is 
submitted in any given year will approximate the number of new trials 
for which clinical trial registration information is submitted.
    To estimate an average amount of time required to submit clinical 
trial results information, we reviewed a variety of data sources, 
including publicly available information from various organizations 
about results information submission times [Ref. 116], comments made at 
the April 2009 public meeting [Ref. 64], responses to the burden 
estimates included in the current and previous OMB clearance documents 
(77 FR 22579, Apr. 16, 2012; 73 FR 58972, Oct. 8, 2008), feedback from 
respondents who tested preliminary versions of the data entry system 
during the summer of 2008, and feedback from those submitting data to 
the existing ClinicalTrials.gov system. These sources contain a wide-
range of estimates, from as little as 6 hours to as long as 60 hours. 
We believe the differences in these estimates reflect a number of 
factors, including the significant variation in the complexity of 
applicable clinical trials, in terms of the study design, number of 
outcome measures (primary and secondary), statistical analyses, and 
adverse event information. The estimates also reflect differences in 
the responsible party's familiarity with the clinical trial results 
information and the ClinicalTrials.gov submission process and the time 
they attribute to assembling the information for submission. Shorter 
estimates may be indicative of situations in which the responsible 
party already has assembled (and analyzed) the clinical trial results 
information for purposes of preparing a journal article or other 
summary report, while longer estimates may assume the clinical trial 
results information needs to be calculated and compiled. We expect 
that, in most situations, the responsible party would have ready access 
to the necessary information because it is information that the 
clinical trial is conducted to collect and analyze (i.e., the 
information for submission would have been collected during the trial, 
as specified in the protocol). Nevertheless, for purposes of this 
analysis, we selected an average time of 40 hours for initial 
submission of clinical trial results information, which corresponds to 
the higher range of estimates contained in several industry surveys and 
in other comments the Agency received. This figure represents an 
increase of 15 hours over our 2015 estimate of 25 hours and reflects 
the additional information that is required to be submitted under this 
final rule. We expect the hour burden will decline as responsible 
parties become more familiar with ClinicalTrials.gov and implement 
procedures for streamlining data collection, analysis, and formatting.
    This final rule requires submission of the full protocol and SAP 
(if a separate document) at the time results are submitted and allows 
redaction by the responsible party if confidential commercial 
information or personally identifiable information is included. Because 
protocol and SAP documents already exist, we do not expect that the 
requirement to upload them will impose a significant burden that is not 
already accounted for in the results submission burden. In addition, we 
anticipate that the need for redaction will be very rare, so those 
costs should also be minimal.
    Prior to this final rule, we estimated that results information 
would be submitted for 3,700 applicable clinical trials per year, which 
is the estimated number of clinical trials that would have been 
included in marketing applications for drug products, biological 
products, and device products that were initially approved, licensed, 
or cleared by the FDA and subject to the basic results reporting 
provisions of section 402(j) of the PHS Act. Under the final rule, 
results information is required to be submitted as specified in the 
final rule for all applicable clinical trials that are subject to the 
registration requirement and that reach their completion date after the 
effective date of the final rule (i.e., an

[[Page 65127]]

estimated 7,400 clinical trials per year). Applying the 40 hour figure 
to 7,400 applicable clinical trials per year produces a total estimated 
burden of 296,000 hours per year for submitting clinical trial results 
information. Our 2015 estimate was 92,500 hours.
    We also estimated that, on average, each results record will be 
updated 2 times after the initial submission to reflect changes in data 
analysis or the submission of additional results from other pre-
specified outcome measures (e.g., submitting partial results). This 
estimate is based on user data collected to date, which indicates that 
each result record is updated, on average, 1.25 times after initial 
submission. We estimated that each such update will take 10 hours, on 
average. This figure is 2 hours over our 2015 estimate of 8 hours and 
reflects ongoing experience with data submission to ClinicalTrials.gov. 
Applying these estimates to 7,400 applicable clinical trials per year 
produces an estimate of 148,000 hours per year for updates to clinical 
trial results information (2 updates per trial), compared to 59,200 
hours for the 3,700 applicable clinical trials estimated under the 
existing information collection. Combining the figure for updates with 
the estimate of the initial burden of submitting clinical trial results 
information, produces a total estimated annual hour burden for results 
information submission under the final rule of 444,000 hours, compared 
with 151,700 hours under the existing information collection. These 
estimates include the time involved in addressing any issues identified 
during quality control review of submitted results information.
    To calculate the economic cost of clinical trial results 
information submission, we examined the average wages of workers in the 
pharmaceuticals and medical equipment industries who typically are 
involved in submitting clinical trial results information. Based on our 
experience in operating the results database and our consultations with 
data submitters, we believe that this task is performed generally by 
clinical researchers who are more experienced than those involved in 
registration. Based on May 2015 data from the U.S. Bureau of Labor 
Statistics, we identified the average hourly wage rate of $55.02, which 
corresponds to the mean hourly wage of a medical scientist (except 
epidemiologists) working in the pharmaceutical and medicine 
manufacturing industries. We doubled this wage rate (to $110.04) to 
account for benefits and overhead. Using this adjusted wage rate, we 
estimate a total annual cost of results information submission under 
this final rule, including updates, of $48,857,760 (Table 1). This 
represents an increase of $32,162,692 per year over our 2015 estimate 
of $16,693,068.
3. Delayed Submission of Results via Certification or an Extension 
Request
    We also have estimated the average time and cost associated with 
the submission of certifications and extension requests to delay 
results information submission, consistent with Sec.  11.44(b), (c) and 
(e). Responsible parties for applicable clinical trials may submit a 
certification to delay results information submission for an applicable 
clinical trial provided that initial approval, licensure, or clearance 
or approval, licensure, or clearance of a new use for the studied 
product is sought. We estimate that the number of clinical trials that 
will qualify for delayed submission of results in a given year will not 
exceed the estimated number of newly initiated applicable clinical 
trials per year that are conducted under an IND or IDE. Such clinical 
trials study drug products (including biological products) and device 
products that are unapproved, unlicensed, or uncleared or that are 
already approved, licensed, or cleared for one use but are seeking 
approval, licensure, or clearance of a new use. While some responsible 
parties might elect to submit clinical trial results information 1 year 
after the primary completion date instead of certifying for delayed 
submission, for purposes of this estimate, we assume that they all will 
elect to submit a certification to delay results information 
submission. (Note that the subsequent burden of submitting clinical 
trial results information is captured by the calculations in Section 2 
above.) Using the same FDA data we used to estimate the number of 
applicable clinical trials subject to the registration requirements of 
this final rule, we estimate that certifications will be submitted for 
5,150 trials per year. We estimate that it will take no more than 30 
minutes for a responsible party to determine that an applicable 
clinical trial is eligible for a certification (and to verify the 
eligibility with a sponsor or manufacturer, if necessary) and to submit 
the necessary information to ClinicalTrials.gov. Using this figure 
produces an estimated annual hour burden of 2,575 hours for 
certifications. We estimate that the hourly wage of personnel who would 
submit the certification is the same as that for submitting clinical 
trial results information, or $55.02. Doubling this wage rate to 
account for benefits and overhead produces an annual estimated cost of 
$283,353 per year.
    To estimate the number of good-cause extension requests, we 
considered several factors, including the rate of submission of 
requests between 2008 and 2015. A total of 192 requests were submitted 
during those 8 years (i.e., 24 requests per year on average). Many of 
these requests were not needed in order to delay results information 
submission because the estimated primary completion date of the 
applicable clinical trial had changed. An extension request is not 
needed in such these situations because a responsible party need only 
update the estimated primary completion date to reflect changes in the 
progress of the trial. Other extension requests were submitted for 
clinical trials that were not applicable clinical trials subject to 
section 402(j) of the PHS Act. Under the rule, the approach outlined in 
Sec.  11.22(b) and described in Section IV.B.2 of this preamble can be 
used to determine that the clinical trial is not an applicable clinical 
trial that is subject to this final rule. When these unnecessary 
requests are excluded, we received about 20 requests per year to delay 
results information submission for applicable clinical trials for which 
the actual primary completion date had passed. We have not attempted to 
estimate the number of responsible parties who may have thought they 
had a good cause for delaying submission but, rather than seeking the 
extension, chose instead to not submit results on time.
    Under the final rule, we expect that the number of extension 
requests will increase as responsible parties gain more clarity about 
the deadlines for submitting clinical trial results information. We, 
thus, estimate that approximately 200 requests will be submitted per 
year, which represents a 10-fold increase over the annual rate of 
submissions to date. The estimated 200 requests is equivalent to 3 
percent of all applicable clinical trials for which clinical trial 
results information is to be submitted in a given year (i.e., 200 out 
of 7,400). It also represents about 10 percent of the applicable 
clinical trials that do not certify for delayed results information 
submission. We believe the 10-fold increase will also account for any 
responsible parties who will now seek an extension rather than simply 
not submitting results on time. While responsible parties may request 
an extension request even after they have filed a certification, we do 
not expect this to happen frequently. Moreover, as explained in Section 
IV.C.3 of this preamble, we expect that extensions will be granted in 
only a limited set of

[[Page 65128]]

circumstances where ``good cause'' has been demonstrated. In cases 
where an extension request is denied, the responsible party will have 
the opportunity to appeal the denial. If we estimate that 50 percent of 
extension requests are denied and that 50 percent of denials result in 
an appeal, we expect to receive 50 appeals per year.
    We estimate that the time required for gathering the information 
for a good-cause extension request or appeal and submitting it to 
ClinicalTrials.gov will be no more than 2 hours. Using this figure, we 
estimate that the annualized hourly burden for extension requests and 
appeals will be 500 hours. We expect that requests will be submitted by 
individuals familiar with the results information submission 
requirements and, therefore, use an hourly wage of $55.02. Doubling 
this wage rate (to $110.04) to account for benefits and overhead brings 
the annualized cost of extension requests to $55,020. Combining the 
estimated costs for certification and extension requests produces a 
total cost of $338,373 per year (Table 1). Prior to the rule, we 
estimated that 3,700 certifications would be submitted by responsible 
parties seeking initial approval, licensure, or clearance or approval, 
licensure, or clearance of a new use of a drug product (including 
biological product) or device product studied in an applicable clinical 
trial and that 200 extension requests would be submitted per year. 
These figures yield an estimated annual cost of $245,114 meaning that 
the incremental cost attributable to this rule is $93,259 per year.
    We note that under Sec.  11.54, responsible parties may also seek a 
waiver from any applicable requirement of the rule. Such waivers are 
available only under extraordinary circumstances that must be 
consistent with the protection of the public health or in the interest 
of national security. We expect the need for such waivers to be 
exceedingly rare. As such, we are subsuming the costs of waiver 
requests in the extension request estimates.
4. Triggered Submission of Clinical Trial Information Following a 
Voluntary Submission
    Section 11.60 of the final rule implements section 402(j)(4)(A) of 
the PHS Act and stipulates that if a responsible party voluntarily 
registers or submits results information for a clinical trial of an 
FDA-regulated drug product or device product that is not an applicable 
clinical trial subject to the mandatory clinical trial information 
submission requirements, that responsible party must, under specified 
circumstances, also submit information for other applicable clinical 
trials that are included in a marketing application or premarket 
notification that is submitted to FDA and for which clinical trial 
information has not already been submitted to ClinicalTrials.gov. The 
types of trials for which the voluntary submission of clinical trial 
information would invoke this requirement include, e.g., phase 1 trials 
of drug products, small feasibility studies of device products (neither 
of which is considered to be applicable clinical trial) or applicable 
clinical trials that are not otherwise subject to section 402(j) of the 
PHS Act because they were initiated prior to the date of enactment of 
FDAAA and were no longer ongoing as of December 26, 2007. The voluntary 
submission of clinical trial information for such trials will trigger a 
requirement to submit clinical trial information for other applicable 
clinical trials that are included in the marketing application for a 
drug product or device product only if the entity submitting the 
marketing application or premarket notification is the same as the 
responsible party for those other trials and still has access to and 
control over the necessary data.
    In practice, we expect that the requirement under section 
402(j)(4)(A) of the PHS Act to submit clinical trial information for 
applicable clinical trials not otherwise registered in 
ClinicalTrials.gov will be triggered infrequently. In most cases, when 
clinical trial information is submitted voluntarily, we expect that the 
applicable clinical trials required to be submitted in a marketing 
application that includes the voluntarily-submitted clinical trial 
would be registered in ClinicalTrials.gov consistent with section 
402(j)(2)(C) of the PHS Act and Sec.  11.60. For example, the voluntary 
submission of information for a phase 1 trial of an unapproved drug 
product would trigger the submission of information for an applicable 
clinical trial that was not previously submitted only if the 
responsible party for the voluntarily-submitted trial is the same as 
the entity submitting the marketing application, the applicable 
clinical trial is required to be submitted in that marketing 
application, and the marketing application is for the same use studied 
in the voluntarily submitted trial. For purposes of this analysis, we 
estimate that 1 percent of the clinical trials registered voluntarily 
with ClinicalTrials.gov each year could trigger the submission of 
clinical trial information for an applicable clinical trial for which 
clinical trial information was not otherwise required to be submitted 
to ClinicalTrials.gov. Of the 19,170 clinical trials that are 
registered every year, on average, with ClinicalTrials.gov, we estimate 
that 11,770 are voluntary or do not fall under the rule (i.e. non-
regulated) submissions (all but the 7,400 that are applicable clinical 
trials). Using 1 percent estimate and this figure, we calculate that 
voluntary registrations will trigger the required submission of 
clinical trials information for an estimated 118 clinical trials per 
year. Based on our experience to date with voluntary submissions, we 
expect that for at least three-quarters of those triggered trials (88 
total) registration information only will need to be submitted; for the 
other quarter, results information will need to be submitted. For those 
clinical trials for which only registration information is required, we 
estimate that it will take a data submitter with an average hourly wage 
rate of $36.02 (consistent with the figures used for registration of 
applicable clinical trials) 8 hours to register the clinical trial. 
Doubling the wage rate to account for benefits and overhead produces an 
estimated cost of $50,716 per year. Submitted information will not 
generally need to be updated because the clinical trial will, in 
general, have reached its primary completion date by the time the 
requirement to submit clinical trial information is triggered. For the 
remaining quarter of the triggered clinical trials (30 total), we 
estimate that the hourly burden would equal the 40 hours estimated for 
results information submission for other applicable clinical trials 
plus 5 hours to account for the additional data elements that are 
specified in Sec.  11.60(b)(2)(i)(B) and (c)(2)(i)(B). Using these 
figures and doubling the estimated average hourly rate of $55.02, we 
estimate the annual cost of submission as $148,554. Combining this 
figure with the $50,716 figure for triggered clinical trials that 
submit only registration information produces a total annual estimated 
cost of $199,270 for the submission of clinical trial information 
triggered by the voluntary submission of information under Sec.  11.60 
(Table 1). Because the submission of clinical trial information 
triggered by the voluntary submission of information was not required 
prior to the rule, the incremental cost attributable to this rule will 
be the full estimated cost of $199,270 per year. We note that each year 
a number of studies will likely be registered in ClinicalTrials.gov 
that are not subject to section 402(j) of the PHS Act.

[[Page 65129]]

Investigators may choose to register such studies in order to assist in 
the recruitment of subjects or to follow other policies, e.g., 
scientific journal publication requirements, or for other reasons. 
Examples of such studies include studies of surgical or behavioral 
interventions. It is also possible that investigators may choose to 
register studies and report results information for clinical trials not 
subject to section 402(j) of the PHS Act because the final rule may 
bring about greater awareness of the registration or results 
information submission process.
    Because we are not able to distinguish the portion of voluntary 
submissions of information to the database attributed to increased 
awareness of the final rule, the cost to entities that submit clinical 
trial information, but are not required to do so under section 402(j) 
of the PHS Act, as implemented by this final rule, are not included in 
this cost estimate. We do, however, account for them in the discussion 
of the PRA clearance of the requirements under this rule because we 
expect submissions to increase as a result of some combination of this 
rule and the contemporaneous NIH policy document, both of which are 
associated with the same OMB control number.
5. Expanded Access Records
    As specified in Sec.  11.28(a), if an expanded access record is 
available for an investigational drug product (including a biological 
product) that is studied in an applicable drug clinical trial, the 
responsible party for that applicable clinical trial must, if it is 
both the manufacturer of the investigational product and the sponsor of 
the applicable clinical trial, include the NCT number of the expanded 
access record with the clinical trial information submitted at the time 
of registration. If an expanded access record for the investigational 
drug product (including a biological product) being studied in the 
applicable clinical trial has not yet been submitted to 
ClinicalTrials.gov, and if the responsible party is both the 
manufacturer of the investigational product and the sponsor of the 
applicable clinical trial, the responsible party must create an 
expanded access record by submitting data elements in Sec.  11.28(c). 
To determine the cost and burden associated with the creation of this 
record, we relied on information from FDA. Each year, an estimated 135 
investigational drug products (including biological products) that were 
not previously available for expanded access use will be made available 
for individual patient expanded access (including emergency use) by 
responsible parties who are required to create an expanded access 
record. FDA estimates that 10 treatment INDs or treatment protocols are 
initiated annually and that expanded access use for intermediate size 
patient populations is initiated 68 times annually. These are the three 
types of expanded access for which information in Sec.  11.28(c) must 
be submitted to ClinicalTrials.gov under this final rule for an 
expanded access record. We estimate the time required to submit the 
required information for an expanded access record to be 2 hours, which 
is one-quarter of the estimated time to register an applicable clinical 
trial. Compared to the number of data elements required under the rule 
for applicable clinical trials, only about half as many data elements 
are required for an expanded access record for expanded access use 
under treatment INDs, treatment protocols and for intermediate-size 
patient populations, and still fewer for expanded access records for 
individual patient expanded access use. The rule also does not require 
some of the more detailed data elements, such as Primary Outcome 
Measure, Secondary Outcome Measure, Individual Site Status, and 
Facility Location information. We also estimate an average of 2 updates 
per expanded access record per year, each taking which 15 minutes. We 
estimate the total hour burden associated with 213 expanded access 
records (i.e., 135 investigational drug products available for single 
patient access, 68 for intermediate size patient populations and 10 
treatment INDs or treatment protocols) to be 533 hours per year (426 
hours for initial information submission plus 107 hours for information 
updates). We expect that expanded access records are submitted by staff 
with the same qualifications as those registering applicable clinical 
trials and, hence use an estimated hourly wage of $36.02. Doubling this 
wage rate to $72.04 to account for benefits and overhead results in a 
total estimated annual cost of $38,361 (Table 1). Because the 
submission of expanded access records was not included prior to 
rulemaking, the incremental cost attributable to this rule is the full 
estimated cost of $38,361 per year.
6. Institutional Compliance Costs
    Organizations such as academic institutions may decide to devote 
more resources to ensure that applicable clinical trials being 
conducted in their organizations are compliant with the final rule. 
They may elect to do so in order to avoid the consequences of non-
compliance, which, for an organization receiving federal funding for 
the clinical trial, could include suspension of grant funding were 
there to be a finding of non-compliance. These additional resources 
would primarily involve additional staff support to help facilitate and 
monitor compliance on the part of responsible parties within the 
organization.
    Institutions of higher education that receive federal funding 
generally cover compliance activities under indirect costs rates that 
are negotiated for each institution. Although the final rule may cause 
an increase in compliance costs, the increase is anticipated to be 
incremental. Institutions can obtain up to 26 percent of their 
administrative costs to pay for administrative support.
    To estimate the costs that institutions may bear because of the 
final rule, we estimated the current compliance costs (FDAAA pre-rule). 
We first identified the number of industry and non-industry sponsors of 
probable applicable clinical trials (pACTs) who submitted results to 
ClinicalTrials.gov in 2015 and separated them into three categories 
based on volume of pACTs submitted per year. The categories were low 
volume, defined as 1 to 5 pACTs per year; medium volume, defined as 6 
to 10 pACTs per year; and high volume, defined as 11 or more pACTs per 
year. We identified 363 non-industry sponsors (312 low volume, 29 
medium volume, 22 high volume) and 277 industry sponsors (238 low 
volume, 17 medium volume, 22 high volume) who submitted pACT results 
information in 2015. We then multiplied the current number of full time 
employees (FTEs) per organization, a figure estimated to be 0.5 FTEs 
[Ref. 117], by the total number of industry and non-industry sponsors 
who submitted pACT results information in 2015. We then multiplied the 
estimated total FTEs by the estimated annual salary costs, using U.S. 
Bureau of Labor Statistics data on average wages from May 2015 of 
medical scientists (except epidemiologists) in the pharmaceuticals and 
medicine manufacturing ($36.02 per hour) and medical scientists (except 
epidemiologist) in a college, university or professional school ($32.17 
per hour). We doubled these wage figures (to $72.04 and $64.34) to 
account for benefits and overhead. The final total product of the FDAAA 
pre-rule institutional yearly cost of compliance for all sponsors was 
estimated to be $45 million (Table 1).
    We next estimated the cost of the final rule and used reported 
number of compliance staff from a high volume sponsor [Ref. 118]. We 
assumed that the required number of FTEs will depend

[[Page 65130]]

on the number of trials to be overseen and thus estimated that low 
volume sponsors will need 0.5 FTEs. We assumed that, in most cases, low 
volume sponsors will not need to hire additional FTEs because reporting 
responsibilities will be fulfilled by the responsible parties 
themselves (as detailed and calculated in Sections 1-3 above). We also 
estimated that medium volume sponsors will need 2 FTEs and high volume 
sponsors will require an estimated 3 FTEs. We calculated the product of 
the total institutional cost with the adjusted increase in compliance 
staff is estimated to be $70.3 million (Table 1). The difference 
between the cost estimate of the final rule and the estimate of the 
amount spent currently on compliance (FDAAA pre-rule) is $25.2 million. 
We believe these estimates are likely to be overestimates because FTEs 
involved in FDAAA final rule compliance activities at many institutions 
will be engaged in other compliance activities that relate to other 
federal and state laws and regulations governing clinical research 
(e.g., FDA IND/IDE and IRB regulations, Common Rule) as well as 
compliance activities due to non-governmental clinical trial-related 
policies (e.g., journal editors require trial registration before the 
first participant is enrolled as a condition for the publication 
results after study completion) [Ref. 98]. We also assumed that the 
FTEs will spend some time up front engaged in developing programs or 
systems to facilitate institutional compliance efforts, and that they 
will later shift their focus to compliance monitoring activities. 
Therefore, the number of attributable FTEs is constant over time and 
the cost of updating existing IT programs/systems is already included. 
We also did not differentiate between industry and non-industry 
organizations to reflect the fact that industry organizations have 
well-established regulatory affairs operations, the functions of which 
include compliance monitoring and oversight. We believe that many of 
these operations are already engaged in oversight activities to support 
compliance with the statutory requirements. Thus, the costs for 
industry organizations are likely an overestimate.
    We estimate the annualized cost to the Federal Government due to 
the final rule data collection requirements is approximately $1.4 
million for ClinicalTrials.gov activities. This figure includes the 
increased cost associated with contractors required to develop software 
and operate the database and senior scientists, analysts, and other 
staff needed to carry out and oversee ClinicalTrials.gov operations as 
well as other costs including database equipment and maintenance.
    We estimate the total annual cost of the final rule to be $59.6 
million. We expect that over time the cost of complying with the final 
rule will decline notably as responsible parties become more familiar 
with the registration and results information submission requirements 
as well as the data submission and review processes. Many institutions 
may have already developed systems and procedures to support 
investigators in fulfilling their reporting responsibilities under the 
statute. Also, a number of clinical trial data management software 
tools currently allow users to output registration information for 
automatic uploading of files in bulk to ClinicalTrials.gov. We expect 
that by clarifying the requirements for submission of clinical trial in 
this final rule, responsible parties will automate portions of the data 
extraction and formatting processes for required results information, 
significantly reducing the burden and associated cost of compliance 
with this final rule.

                                  Table 1--Estimated Annual Cost of Final Rule
----------------------------------------------------------------------------------------------------------------
                                                                     Estimated       Estimated      Incremental
                                                                    annual cost     annual cost     cost above
              Provision                 Final rule  section(s)       prior to        under the    pre-rule  data
                                                                    rulemaking      final rule       collection
----------------------------------------------------------------------------------------------------------------
Registration of applicable clinical   11.28(a),(b), 11.64(a)....     $12,261,208     $12,794,304        $533,096
 trials, including updates.
Results information submission for    11.48, 11.64(a)...........      16,693,068      48,857,760      32,162,692
 applicable clinical trials,
 including updates.
Submission of certifications,         11.44(b), (c), (e)........         245,114         338,373          93,259
 extension requests, and appeals to
 delay results information
 submission.
Triggered registration and results    11.60.....................               0         199,270         199,270
 information submission following
 voluntary submissions.
Submission of expanded access         11.28(c)..................               0          38,361          38,361
 records.
Institutional compliance costs......  ..........................      45,042,920      70,287,277      25,244,357
Cost to the Federal Government......  ..........................       4,826,307       6,190,784       1,364,477
                                     ---------------------------------------------------------------------------
    Total...........................  N/A.......................      79,068,617     138,706,129      59,635,512
----------------------------------------------------------------------------------------------------------------

F. Alternatives to the Final Rule

    Section 402(j)(3)(D)(v)(VI) of the PHS Act requires the Secretary 
to promulgate regulations to expand the registry and results data bank 
and to address specific issues that are enumerated in the statute. 
Section 402(j)(2)(A)(iii) of the PHS Act also authorizes the Secretary 
to make additions or modifications to the statutorily enumerated 
requirements for registration of applicable clinical trials. This final 
rule implements and expands the basic provisions mandated by section 
402(j) of the PHS Act that became effective prior to rulemaking on the 
schedule established by the statute. In the NPRM, we described various 
alternatives that we considered in exercising authority to add or 
modify the statutory provisions and in addressing the topics that were 
required to be addressed through rulemaking. In developing the final 
rule, and informed by public comments, we considered alternatives 
approaches that could be taken in the final rule. We discuss two here.
    One important provision of the final rule requires results 
information from applicable clinical trials of unapproved, unlicensed, 
or uncleared products to be submitted. The Agency has concluded that 
the public health benefits of this approach, as discussed in above in 
Section D, justify the costs. In particular, trials of products that 
are unapproved, unlicensed, or uncleared are unlikely to be published 
if the

[[Page 65131]]

results of these trials would not help support applications for product 
approval, licensure, or clearance. This rule's requirements that 
responsible parties submit results information from applicable clinical 
trials of unapproved, unlicensed, or uncleared products regardless of 
whether approval, licensure, or clearance is sought, as well as the 
public posting of this information, are expected to help address bias 
in the literature and selective publication of results. The requirement 
for results information submission will make information public that 
otherwise likely would not have reached the public domain. The 
availability of results information from such applicable clinical 
trials will help to prevent the evidence base, which serves as a 
foundation for future research, systematic reviews, and clinical 
practice guidelines, from being skewed. The alternative position--not 
requiring results information submission for applicable clinical trials 
of unapproved, unlicensed, or uncleared products--would decrease the 
costs of the rule as estimated in Section V.E.2, but it would likely be 
costly to public health because of the absence of the benefits 
described in Section V.D. Therefore, the Agency believes that the 
benefits to public health justify the cost of compliance.
    The final rule also requires submission of the final research 
protocol and SAP as part of the results information (discussed in 
Section III.D of the preamble). We expect the protocol to provide users 
of ClinicalTrials.gov with more complete information about the trial. 
One of the aims of section 402(j) of the PHS Act and of the rule is to 
``provide more complete results information.'' We believe this goal 
complements the goals of increased transparency and accountability. As 
such, the submission of the protocol and SAP will provide more complete 
results information and significantly enhance the understanding of the 
trial and the context of the data fields provided. Because protocol and 
SAP documents already exist, we do not expect that the requirement to 
upload them will impose a significant burden that is not already 
accounted for in the results submission burden. The alternative--not 
requiring the submission of protocol--would have little to no effect in 
reducing the burden of the rule, but it would decrease public health 
benefits by decreasing the transparency of clinical trial results 
information.

G. Regulatory Flexibility Act

    The RFA (5 U.S.C. 601-612) requires agencies to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. This final rule will affect a number of small entities that 
conduct clinical trials of drug products and device products, but the 
Agency estimates that the costs incurred by small entities would be 
limited, especially in relation to the other costs associated with 
conducting a clinical trial. As explained below, the Agency believes 
that the final rule is not likely to have a significant economic impact 
on a substantial number of small entities.
    The companies that would be affected by this final rule are 
classified in seven separate 2012 North American Industrial 
Classification System (NAICS) categories by the Census Bureau. The 
affected industries are NAICS 325412--Pharmaceutical Preparation; NAICS 
325414--Biological Products (except diagnostic); NAICS 334510--
Electromedical and Electrotherapeutic Apparatus; NAICS 339112--Surgical 
and Medical Instrument; NAICS 339113--Surgical Appliance and Supplies; 
NAICS 339114--Dental Equipment and Supplies; NAICS 339115--Ophthalmic 
Goods [Ref. 119]. The Small Business Administration (SBA) size 
standards define small entities as those companies with a maximum 
number of employees. The 2016 size standards for all these industries 
are shown in the table below [Ref. 120]. The most recent data from the 
U.S. Census of Manufacturers that offers the level of detail for 
establishments at or near the employee size limits as defined by SBA is 
from 2012 [Ref. 121]. In each of these establishment size categories, 
large majorities (i.e., 90 percent or more) of the establishments meet 
the criteria as small entities [Ref. 122]. Even taking into account 
that many of these establishments are parts of multi-establishment 
corporations, significant numbers of companies would still qualify as 
small entities and have fewer than 100 employees across all of these 
categories (i.e., ranging from 79 percent to 96 percent of all 
establishments within a category). Although the Agency expects that 
most companies sponsoring applicable clinical trials would be larger 
than the average-sized company in their industry, the Agency concludes 
that a substantial number of companies would still qualify as small 
entities.

             Table 2--Size Standards for Affected Companies
------------------------------------------------------------------------
                                                               Size
                                                           standards in
           NAICS code and industry description               number of
                                                             employees
------------------------------------------------------------------------
NAICS 339113--Surgical Appliance and Supplies...........             750
NAICS 339114--Dental Equipment and Supplies.............             750
NAICS 339112--Surgical and Medical Instrument...........           1,000
NAICS 339115--Ophthalmic Goods..........................           1,000
NAICS 325412--Pharmaceutical Preparation................           1,250
NAICS 325414--Biological Products (except diagnostic)...           1,250
NAICS 334510--Electromedical and Electrotherapeutic                1,250
 Apparatus..............................................
------------------------------------------------------------------------

    The cost analysis presented above indicates an estimated cost of 
compliance with this final rule of $17,907 per applicable clinical 
trial ($132,515,345 for 7,400 clinical trials per year). While some 
larger firms could be the responsible party for multiple applicable 
clinical trials in the same year, we expect most small firms would be 
responsible for no more than one applicable clinical trial per year. 
Using data from the 2012 Census of Manufacturers, we used the average 
value of shipments for establishments in these industries to calculate 
the cost percentage of the rule on small entities. Assuming that small 
operations with one to four employees had one applicable clinical trial 
that was required to submit registration or results information each 
year, the costs of this final rule would representan estimated 3.4 
percent of the annual value of shipments. For establishments with 50 to 
99 employees, the costs of this final rule would represent an estimated 
0.9 percent of the value of shipments, even

[[Page 65132]]

if they were responsible for 10 applicable clinical trials administered 
annually. For establishments with 100 or more employees, the costs of 
this final rule would represent an estimated 0.1 percent of the value 
of shipments even with 10 applicable clinical trials administered 
annually. Although the figure for establishments with one to four 
employees in one industry was estimated to be 3.4 percent at most, the 
remaining figures are well below the threshold of 3 to 5 percent of the 
total revenue for small entities needed to consider that this final 
rule would have a significant economic impact on a substantial number 
of small entities. The Agency concludes and certifies that this final 
rule would not have a significant economic impact on a substantial 
number of small entities.
    In practice, we expect the burden on small firms will be 
significantly lower than this estimate. In general, the applicable 
clinical trials initiated by small firms will be less complex than the 
applicable clinical trials initiated by large firms, including, for 
example, fewer trial locations (sites), shorter duration, and fewer 
outcome measures. As a result, the amount of results information to be 
submitted--and the time and cost associated with such submissions--will 
be less than for larger entities and represent a smaller share of 
shipments. In addition, these costs would affect only a fraction of 
small firms in any given year. For example, by our estimates, 
registration information would be required to be submitted (and results 
information subsequently submitted) for approximately 500 applicable 
device clinical trials in any given year. Information from the 2012 
Economic Census of the United States indicates that there are 
approximately 11,500 companies in the U.S. that are involved in the 
manufacture of medical devices and that almost 11,000 of them have 
fewer than 100 employees. Even if no company engaged in more than one 
applicable clinical trial at the same time, then on average, less than 
10 percent of all device manufacturers would initiate a trial subject 
to the registration and results information submission requirements of 
this final rule in any given year (700 applicable device clinical 
trials per year divided by 11,500 firms equals 0.061 or 6.1 percent).

H. Unfunded Mandates Reform Act of 1995

    Section 1352(a) of the Unfunded Mandates Reform Act of 1995 
requires that the Agency prepare, among other things, a written 
statement that includes an assessment of anticipated costs and benefits 
before proposing ``any rule that includes any Federal mandate that may 
result in the expenditure by State, local, and Tribal governments, in 
the aggregate, or by the private sector, of $100,000,000 or more 
(adjusted annually for inflation) in any 1 year'' (2 U.S.C. 1532(a)). 
The current threshold, adjusted for inflation using the 2015 Implicit 
Price Deflator for the Gross Domestic Product, is $146 million. We do 
not expect the direct burden of this final rule, including the cost of 
compiling, submitting, and updating clinical trial registration and 
results information for applicable clinical trials, to result in any 1 
year expenditure that would meet or exceed this amount. Nor do we 
expect that State or local governments would bear a significant 
fraction of this cost, as most of the entities affected by the final 
regulation would be private entities. As a result, we conclude that 
this rule has no consequential effect on State, local, or tribal 
governments or on the private sector. We have determined that this 
final rule would not constitute a significant rule under the Unfunded 
Mandates Reform Act of 1995 because it would impose no mandates with 
costs exceeding the current threshold.

I. Federalism

    Executive Order 13132, Federalism, establishes certain requirements 
that an Agency must meet when it promulgates a proposed rule (and 
subsequent final rule) ``that imposes substantial direct compliance 
costs on State and local governments,'' preempts State law, or 
otherwise has federalism implications. The Agency has analyzed this 
final rule in accordance with the principles set forth in Executive 
Order 13132 and has determined that this final rule does not contain 
policies that would impose any ``substantial direct compliance costs on 
State or local governments[.]'' This final rule, does, however, have 
federalism implications.
    Section 801(d)(1) of FDAAA expressly provides a preemption 
provision as follows: ``Upon the expansion of the registry and results 
data bank under section 402(j)(3)(D) of the Public Health Service Act . 
. . no State or political subdivision of a State may establish or 
continue in effect any requirement for the registration of clinical 
trials or for the inclusion of information relating to the results of 
clinical trials in a database.'' We interpret this language to prohibit 
a State or political subdivision of a State from establishing any 
requirement for the inclusion of information in a database that is (1) 
clinical trial registration information, as that term is defined in 
Sec.  11.10, i.e., the actual registration data elements; (2) clinical 
trial results information required to be submitted under section 
402(j)(3) of the PHS Act and this part; or, (3) information that is 
otherwise collected through any data element in ClinicalTrials.gov, 
such as information relating to voluntary submissions and other 
information whether or not required to be submitted under section 
402(j) of the PHS Act and this part. We do not interpret section 
801(d)(1) of FDAAA to preempt other types of reporting and/or data 
collection that States may require related to public health, disease 
surveillance, clinical care, or the practice of medicine such as 
patient and disease registries or public health surveillance 
registries.

VI. Paperwork Reduction Act of 1995

    This final rule contains requirements that are subject to review by 
OMB under the PRA (44 U.S.C. 3501-3520). Sections 11.28, 11.48, 11.60, 
11.62, and 11.64 of this rule contain information collection 
requirements that are subject to OMB approval. A revision of the 2015 
PRA clearance for clinical trial registration and results information 
submission (OMB 0925-0586) to meet the requirements of this final rule 
will be submitted to OMB for review. It will also be updated to request 
approval to collect clinical trial registration and results information 
under a final policy that NIH is issuing in tandem with the final rule 
that will apply to all NIH-funded clinical trials, including those not 
subject to the rule [Ref. 65].
    Section VII of the NPRM, the Agency provided an estimate of the 
annualized burden hours associated with the information collection 
requirements included in the proposed rule, and we invited comments on: 
(1) Whether the proposed collection of information is necessary for the 
proper performance of the functions of NIH, including whether the 
information will have practical utility; (2) the accuracy of the 
estimate of the burden of the proposed collection of information by 
NIH, including the validity of the methodology and assumptions used; 
(3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology (79 FR 69663). The comments we received are 
discussed in Section V.A of the final rule.
    A description of the information collection requirements included 
in this rule is provided in the Regulatory

[[Page 65133]]

Impact Statement (Section V of this preamble) and is summarized in this 
section of the preamble with an estimate of the annualized burden 
hours. Included in this estimate is the time for reviewing 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing, reviewing, updating, and 
correcting each collection of information.
    Organizations and individuals desiring to submit comments on the 
information collection and submission requirements should send their 
comments by October 21, 2016 to (1) Ms. Mikia Currie, Project Clearance 
Officer, National Institutes of Health, Rockledge Centre 1, 6705 
Rockledge Drive, Room 3509, Bethesda, Maryland 20817, telephone 301-
594-7949 (not a toll-free number); and (2) the Office of Information 
and Regulatory Affairs, OMB, [email protected], or by fax to 
202-395-6974, and mark ``Attention: Desk Officer for the National 
Institutes of Health, Department of Health and Human Services.'' After 
we obtain OMB approval, we will publish the OMB control number in the 
FR.
    The estimate includes the annual hourly burden for submission, 
updating, and correction of information both for applicable clinical 
trials that are subject to this rule and for the larger number of 
clinical trials for which information is submitted to 
ClinicalTrials.gov on a voluntary basis in order to recruit subjects, 
remain eligible to publish summary articles in scientific journals that 
follow the guidelines of the ICMJE, to comply with NIH or other public, 
company, or other organizational policies regarding public disclosure 
of clinical trial information, or for other purposes.
    The burden for trials that are subject to this rule follows the 
estimates presented in Section V of this preamble. For registration, we 
estimated 7,400 applicable clinical trials which included the number of 
clinical trials that would be subject to mandatory registration under 
the rule. This estimate reflects the number of protocols for applicable 
clinical trials that are submitted to FDA under an IND or IDE (i.e., 
5,150), as well as applicable clinical trials that are not conducted 
under an IND or IDE (i.e., 2,250). We also increased the estimated hour 
burden of registration from 7 hours in the 2015 information collection, 
to 8 hours to reflect the additional data elements that would be 
required under this rule. For results information submission, we have 
increased from 3,700 to 7,400 our estimate of the number of applicable 
clinical trials that would be subject to mandatory results information 
submission under this rule. The final rule requires the submission of 
results information for all registered applicable clinical trials, 
regardless of whether or not the drug product (including biological 
product) or device product under study in the trial is approved, 
licensed, or cleared. We have made corresponding increases in the 
estimated number of applicable clinical trials for which a 
certification to delay results information submission would be 
submitted. We have also increased the estimated hour burden for 
submitting results information from 25 hours to 40 hours to account for 
the additional results information that would be required to be 
submitted under this rule. In addition, we have added estimates of the 
burden associated with the submission of registration and results 
information that could be triggered by some voluntary submissions of 
clinical trial information under Sec.  11.60. Finally, we have included 
a separate estimate of the burden associated with the creation of an 
expanded access record if an investigational drug product (including a 
biological product) that is studied in an applicable clinical trial is 
available under expanded access. See figures in Table 3.
    As we noted in Section V, a number of trials studies will likely be 
registered in ClinicalTrials.gov that are not subject to section 402(j) 
of the PHS Act. Investigators may choose to register such studies in 
order to assist in the recruitment of subjects or to comply with 
medical journal policies that make registration in a publicly 
accessible repository a condition of publication. In addition, starting 
in 2017, clinical trial registration and results information will also 
be collected from NIH-funded investigators whether or not they are 
subject to the final rule, which will lead to an increase in the number 
of non-regulated submissions.
    In order to estimate the impact of the NIH policy, over and above 
the impact of the rule, we began by determining that 526 NIH funded 
trials that are likely not applicable clinical trials were first 
registered in 2015. These represent the likely number of trials that 
will have the additional burden of submitting results per year under 
the NIH policy. In addition, we estimated that approximately 25 percent 
of NIH-funded trials that are not applicable clinical trials have not 
been registered in the past (despite encouragement from NIH and the 
journal editors' policy). This leads to an estimate of an additional 
131 trials registered and reporting results per year. The total number 
of non-applicable clinical trials that will register and submit results 
due to the NIH policy is estimated to be 657 per year. Investigators 
subject to the NIH policy will be expected to submit the same 
information within the same timeframes as parties subject to 
402(j)(2)(C) of the PHS Act. We, thus, use the assumptions here that we 
used to estimate the burden for applicable clinical trials, i.e., 
initial submission of registration information will take an average of 
8 hours, updates of 2 hours apiece will take place 8 times during the 
course of the study and, initial results submission will take on 
average 40 hours with 2 expected updates requiring an average of 10 
hours total. Adding the registration burden to the results information 
burden yields an estimated total annual hour burden of 55,188 (Table 
3).
    In order to estimate the burden for clinical trials that are not 
subject to section 402(j) of the PHS Act, including the requirements in 
this final rule, and will not be subject to the NIH policy, we examined 
registrations to ClinicalTrials.gov in calendar year 2015 and found 
that a total of 19,170 clinical trials were registered that year. Since 
we estimate that 7,400 of these are applicable clinical trials, the 
remainder 11,770 trials, can be considered voluntary or to not fall 
under the rule. Of these, 526 were NIH funded. This leaves an estimated 
11,244 trials registered per year that do not fall under either the 
rule or the NIH policy.
    We expect that these clinical trials will submit the same clinical 
trial registration information as is submitted for applicable clinical 
trials that are subject to the rule. We expect that information 
submitted for such clinical trials will be updated as frequently as 
information for applicable clinical trials that are subject to the 
rule. Therefore, for calculating the registration burden associated 
with these clinical trials, we use the same assumptions as for 
applicable clinical trials required to register under section 
402(j)(2)(C) of the PHS Act, i.e., initial submission of registration 
information will take an average of 8 hours, updates of 2 hours apiece 
will take place 8 times during the course of the study. Applying these 
figures yields an estimated annual burden of 269,856 hours, of which 
89,952 derives from the initial registration and 179,904 derives from 
updates (Table 3).
    For clinical trials that are not subject to section 402(j) of the 
PHS Act, including the requirements in this final rule, or the NIH 
policy, we expect that often only clinical trial registration 
information, and not both registration and results information, will be

[[Page 65134]]

submitted. To estimate the number results submissions will be 
submitted, we looked at results submissions in 2015 and found that 
1,580 were for clinical trials that were neither applicable clinical 
trials nor funded by NIH. We estimate that this number will grow 
slightly, secondary to various other funder policies (e.g., PCORI). We, 
therefore, estimate that we will receive approximately 2,000 results 
per year that are not due to either the rule or the NIH policy. We 
estimate that the time required to submit clinical trial results 
information for such clinical trials would be equivalent to that for 
applicable clinical trials required to register under section 
402(j)(2)(C) of the PHS Act. Using those figures, we estimate that the 
total annual hour burden for submitting clinical trial results 
information for clinical trials that are not otherwise required to 
submit results information would be 80,000 hours, plus 40,000 hours for 
updates (Table 3).

       Table 3--Estimated Burden for Registration and Results Information Submission at ClinicalTrials.gov
----------------------------------------------------------------------------------------------------------------
                                                                                   Average time
        Type of respondents             Number of       Frequency of response      per response     Annual hour
                                       respondents                                    (hours)         burden
----------------------------------------------------------------------------------------------------------------
                                  Regulated Submissions (Subject to this Rule)
----------------------------------------------------------------------------------------------------------------
Registration.......................           7,400  1 Initial..................               8          59,200
                                     ..............  8 Subsequent Updates.......               2         118,400
Results Information................           7,400  1 Initial..................              40         296,000
                                     ..............  2 Subsequent Updates.......              10         148,000
Certifications to delay results               5,150  1..........................             0.5           2,575
 submission.
Extension requests and appeals.....             250  1..........................               2             500
Registration triggered by voluntary              88  1..........................               8             704
 submission.
Results triggered by voluntary                   30  1..........................              45           1,350
 submission.
Expanded access records............             213  1 initial..................               2             426
                                     ..............  2 Subsequent Updates.......            0.25             107
                                    ----------------------------------------------------------------------------
    Subtotal for Regulated                                             627,262
     Submissions.
----------------------------------------------------------------------------------------------------------------
                               Non-regulated Submissions Related to the NIH Policy
----------------------------------------------------------------------------------------------------------------
Registration.......................             657  1 Initial..................               8           5,256
                                     ..............  8 Subsequent Updates.......               2          10,512
Results information................             657  1 Initial..................              40          26,280
                                     ..............  2 Subsequent Updates.......              10          13,140
                                    ----------------------------------------------------------------------------
    Subtotal for Non-regulated                                          55,188
     Submissions Related to the NIH
     Policy.
----------------------------------------------------------------------------------------------------------------
                                            Non-regulated Submissions
----------------------------------------------------------------------------------------------------------------
Registration.......................          11,244  1 Initial..................               8          89,952
                                     ..............  8 Subsequent Updates.......               2         179,904
Results information................           2,000  1 Initial..................              40          80,000
                                     ..............  2 Subsequent Updates.......              10          40,000
                                    ----------------------------------------------------------------------------
    Subtotal for Non-regulated                                         389,856
     Submissions.
----------------------------------------------------------------------------------------------------------------
    Subtotal for Non-regulated                                         445,044
     Submissions and Submissions
     Related to the NIH Policy.
----------------------------------------------------------------------------------------------------------------
        Total......................                                   1,072,306
----------------------------------------------------------------------------------------------------------------

VII. Legal Authority

    These regulations are issued under the authorities contained in 42 
U.S.C. 282(i); 42 U.S.C. 282(j); 5 U.S.C. 301; 42 U.S.C. 286(a); 42 
U.S.C. 241(a); 42 U.S.C. 216(b); and sections 801(c)-(d), Public Law 
110-85, 121 Stat. 921-922 (42 U.S.C. 282 (note)).

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List of Subjects in 42 CFR Part 11

    Biologics, Clinical trial, Data bank, Drugs, Human subjects 
research, Medical devices, Medical research, Registry, Reporting and 
recordkeeping requirements, Results information.

Regulatory Text

    For the reasons stated in this preamble, the U.S. Department of 
Health and Human Services amends Title 42, Chapter I of the Code of 
Federal Regulations by adding Part 11 to subchapter A to read as 
follows:

PART 11--CLINICAL TRIALS REGISTRATION AND RESULTS INFORMATION 
SUBMISSION

Subpart A--General Provisions
Sec.
11.2 What is the purpose of this part?
11.4 To whom does this part apply?
11.6 What are the requirements for the submission of truthful 
information?
11.8 In what format must clinical trial information be submitted?
11.10 What definitions apply to this part?
Subpart B--Registration
11.20 Who must submit clinical trial registration information?
11.22 Which applicable clinical trials must be registered?
11.24 When must clinical trial registration information be 
submitted?
11.28 What constitutes clinical trial registration information?
11.35 By when will the NIH Director post clinical trial registration 
information submitted under Sec.  11.28?
Subpart C--Results Information Submission
11.40 Who must submit clinical trial results information?
11.42 For which applicable clinical trials must clinical trial 
results information be submitted?
11.44 When must clinical trial results information be submitted for 
applicable clinical trials subject to Sec.  11.42?
11.48 What constitutes clinical trial results information?
11.52 By when will the NIH Director post submitted clinical trial 
results information?
11.54 What are the procedures for requesting a waiver of the 
requirements for clinical trial results information submission?
Subpart D--Additional Submission of Clinical Trial Information
11.60 What requirements apply to the voluntary submission of 
clinical trial information for clinical trials of FDA-regulated drug 
products (including biological products) and device products?
11.62 What requirements apply to applicable clinical trials for 
which submission of clinical trial information has been determined 
by the Director to be necessary to protect the public health?
11.64 When must clinical trial information submitted to 
ClinicalTrials.gov be updated or corrected?
Subpart E--Potential Legal Consequences of Non-Compliance
11.66 What are potential legal consequences of not complying with 
the requirements of this part?


    Authority: 42 U.S.C. 282(i); 42 U.S.C. 282(j); 5 U.S.C. 301; 42 
U.S.C. 286(a); 42 U.S.C. 241(a); 42 U.S.C. 216(b).

Subpart A--General Provisions


Sec.  11.2  What is the purpose of this part?

    This part implements section 402(j) of the Public Health Service 
Act (42 U.S.C. 282(j)) by providing requirements and procedures for the 
submission of clinical trial information for certain applicable 
clinical trials and other clinical trials to the Director of the 
National Institutes of Health (NIH) to be made publicly available via 
ClinicalTrials.gov, the Internet-accessible clinical trial registry and 
results data bank established by the National Library of Medicine (NLM) 
at https://clinicaltrials.gov.


Sec.  11.4  To whom does this part apply?

    (a) This part applies to the responsible party for an applicable 
clinical trial that is required to be registered under Sec.  11.22, a 
clinical trial for which clinical trial registration information or 
clinical trial results information is submitted voluntarily in 
accordance with Sec.  11.60, or an applicable clinical trial that is 
required by the Director to have clinical trial information submitted 
to protect the public health under Sec.  11.62.
    (b) The responsible party must communicate the identity and contact 
information of the responsible party to the Director by submitting the 
Responsible Party, by Official Title and Responsible Party Contact 
Information data elements under Sec.  11.28(a)(2)(iii)(B) and 
(a)(2)(iv)(F) as part of the clinical trial information submitted at 
the time of registration. Changes must be communicated to the Director 
by updating information in accordance with Sec.  11.64(a).

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    (c) Determination of responsible party. For purposes of this part, 
each applicable clinical trial or other clinical trial must have one 
responsible party. With respect to a clinical trial, the sponsor of the 
clinical trial will be considered the responsible party unless and 
until a principal investigator has been designated the responsible 
party, in accordance with paragraph (c)(2) of this section. With 
respect to a pediatric postmarket surveillance of a device product that 
is not a clinical trial, the responsible party is the entity that the 
U.S. Food and Drug Adminstration (FDA), under section 522 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 3601), orders to 
conduct the pediatric postmarket surveillance of a device product.
    (1) Determination of sponsor. For purposes of this part, each 
applicable clinical trial or other clinical trial must have one 
sponsor.
    (i) When an applicable clinical trial or other clinical trial is 
conducted under an investigational new drug application (IND) or 
investigational device exemption (IDE), the IND or IDE holder will be 
considered the sponsor.
    (ii) When an applicable clinical trial or other clinical trial is 
not conducted under an IND or IDE, the single person or entity who 
initiates the trial, by preparing and/or planning the trial, and who 
has authority and control over the trial, will be considered the 
sponsor.
    (2) Designation of a principal investigator as the responsible 
party.
    (i) The sponsor may designate a principal investigator as the 
responsible party if such principal investigator meets all of the 
following requirements:
    (A) Is responsible for conducting the trial;
    (B) Has access to and control over the data from the trial;
    (C) Has the right to publish the results of the trial; and
    (D) Has the ability to meet all of the requirements for submitting 
and updating clinical trial information as specified in this part.
    (ii) With regard to an applicable clinical trial or other clinical 
trial, a designation by the sponsor under paragraph (c)(2)(i) of this 
section shall consist of the sponsor obtaining from the principal 
investigator an acknowledgment of the principal investigator's 
responsibilities under this part as responsible party, and the 
principal investigator acknowledging the designation as responsible 
party to the Director in the format specified at https://prsinfo.clinicaltrials.gov.
    (3) Withdrawal of the designation of a principal investigator as 
the responsible party.
    In the event that a principal investigator who has been designated 
the responsible party no longer meets or is no longer able to meet all 
the requirements for being so designated under paragraph (c)(2)(i) of 
this section, the sponsor must withdraw the designation in the format 
specified at https://prsinfo.clinicaltrials.gov, at which time the 
sponsor will be considered the responsible party unless and until the 
sponsor makes a new designation in accordance with paragraph (c)(2) of 
this section.


Sec.  11.6  What are the requirements for the submission of truthful 
information?

    The clinical trial information submitted by a responsible party 
under this part shall not be false or misleading in any particular. A 
responsible party who submits false and/or misleading information is 
subject to civil monetary penalties and/or other civil or criminal 
remedies available under U.S. law.


Sec.  11.8  In what format must clinical trial information be 
submitted?

    Information submitted under this part must be submitted 
electronically to ClinicalTrials.gov, in the format specified at 
https://prsinfo.clinicaltrials.gov.


Sec.  11.10  What definitions apply to this part?

    (a) The following definitions apply to terms used in this part:
    Adverse event means any untoward or unfavorable medical occurrence 
in a human subject, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject's participation in the research, whether or 
not considered related to the subject's participation in the research. 
See also the definition of ``serious adverse event.''
    Applicable clinical trial means an applicable device clinical trial 
or an applicable drug clinical trial. Expanded access use under section 
561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb) is 
not an applicable clinical trial.
    Applicable device clinical trial means:
    (1) A prospective clinical study of health outcomes comparing an 
intervention with a device product subject to section 510(k), 515, or 
520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 
21 U.S.C. 360e, 21 U.S.C. 360j(m)) against a control in human subjects 
(other than a small clinical trial to determine the feasibility of a 
device product, or a clinical trial to test prototype device products 
where the primary outcome measure relates to feasibility and not to 
health outcomes);
    (2) A pediatric postmarket surveillance of a device product as 
required under section 522 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 3601); or
    (3) A clinical trial of a combination product with a device primary 
mode of action under 21 CFR part 3, provided that it meets all other 
criteria of the definition under this part.
    Applicable drug clinical trial means a controlled clinical 
investigation, other than a phase 1 clinical investigation, of a drug 
product subject to section 505 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 355) or a biological product subject to section 351 of 
the Public Health Service Act (42 U.S.C. 262), where ``clinical 
investigation'' has the meaning given in 21 CFR 312.3 and ``phase 1'' 
has the meaning given in 21 CFR 312.21. A clinical trial of a 
combination product with a drug primary mode of action under 21 CFR 
part 3 is also an applicable drug clinical trial, provided that it 
meets all other criteria of the definition under this part.
    Approved drug means a drug product that is approved for any use 
under section 505 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 355) or a biological product licensed for any use under section 
351 of the Public Health Service Act (42 U.S.C. 262).
    Approved or cleared device means a device product that is cleared 
for any use under section 510(k) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C 360(k)) or approved for any use under sections 
515 or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C 
360e, 360j(m)).
    Arm means a pre-specified group or subgroup of human subject(s) in 
a clinical trial assigned to receive specific intervention(s) (or no 
intervention) according to a protocol.
    Clinical study means research according to a protocol involving one 
or more human subjects to evaluate biomedical or health-related 
outcomes, including interventional studies and observational studies.
    Clinical trial means a clinical investigation or a clinical study 
in which human subject(s) are prospectively assigned, according to a 
protocol, to one or more interventions (or no intervention) to evaluate 
the effect(s) of the intervention(s) on biomedical or health-related 
outcomes.
    Clinical trial information means the data elements, including 
clinical trial registration information and clinical trial results 
information, that the responsible party is required to submit to 
ClinicalTrials.gov, as specified in section 402(j) of the Public Health

[[Page 65140]]

Service Act (42 U.S.C. 282(j)) and this part.
    Clinical trial registration information means the data elements 
that the responsible party is required to submit to ClinicalTrials.gov, 
as specified in section 402(j)(2)(A)(ii) of the Public Health Service 
Act (42 U.S.C. 282(j)(2)(A)(ii)) or Sec.  11.28, as applicable.
    Clinical trial results information means the data elements that the 
responsible party is required to submit to ClinicalTrials.gov, as 
specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public 
Health Service Act (42 U.S.C. 282(j)(3)(C) and (I)) or Sec.  11.48, as 
applicable. If a responsible party submits clinical trial results 
information voluntarily for a clinical trial, clinical trial results 
information also means Sec.  11.60(b)(2)(i)(B) or Sec.  
11.60(c)(2)(i)(B), as applicable.
    Comparison group means a grouping of human subjects in a clinical 
trial that is or may be used in analyzing the results data collected 
during the clinical trial.
    Completion date means, for a clinical trial, including an 
applicable clinical trial, the date that the final subject was examined 
or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded 
according to the pre-specified protocol or was terminated. In the case 
of clinical trials with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data 
collection is completed for all of the primary outcomes. For a 
pediatric postmarket surveillance of a device product that is not a 
clinical trial, completion date means the date on which the final 
report of the pediatric postmarket surveillance of the device product 
is submitted to FDA. For purposes of this part, completion date is 
referred to as ``primary completion date.''
    Control or controlled means, with respect to a clinical trial, that 
data collected on human subjects in the clinical trial will be compared 
to concurrently collected data or to non-concurrently collected data 
(e.g., historical controls, including a human subject's own baseline 
data), as reflected in the pre-specified primary or secondary outcome 
measures. For purposes of this part, all clinical trials with one or 
more arms and pre-specified outcome measure(s) are controlled.
    Device means a device as defined in section 201(h) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321(h)).
    Director means the NIH Director or any official of NIH to whom the 
NIH Director delegates authorities granted in section 402(j) of the 
Public Health Service Act (42 U.S.C. 282(j)).
    Drug means a drug as defined in section 201(g) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 321(g)) or a biological product as 
defined in section 351 of the Public Health Service Act (42 U.S.C. 
262).
    Enroll or enrolled means a human subject's, or their legally 
authorized representative's, agreement to participate in a clinical 
trial following completion of the informed consent process, as required 
in 21 CFR part 50 and/or 45 CFR part 46, as applicable. For the 
purposes of this part, potential subjects who are screened for the 
purpose of determining eligibility for a trial, but do not participate 
in the trial, are not considered enrolled, unless otherwise specified 
by the protocol.
    Human subjects protection review board means an institutional 
review board (IRB) as defined in 21 CFR 50.3 or 45 CFR 46.102, as 
applicable, that is responsible for assuring the protection of the 
rights, safety, and well-being of human subjects involved in a clinical 
trial and is adequately constituted to provide assurance of that 
protection. An IRB may also be known as an ``independent ethics 
committee.''
    Interventional means, with respect to a clinical study or a 
clinical investigation, that participants are assigned prospectively to 
an intervention or interventions according to a protocol to evaluate 
the effect of the intervention(s) on biomedical or other health-related 
outcomes.
    Investigational Device Exemption (IDE) has the meaning given in 21 
CFR part 812.
    Investigational New Drug Application (IND) has the meaning given in 
21 CFR 312.3.
    NCT number means the unique identification code assigned to each 
record in ClinicalTrials.gov, including a record for an applicable 
clinical trial, a clinical trial, or an expanded access program.
    Ongoing means, with respect to a clinical trial of a drug product 
(including a biological product) or a device product and to a date, 
that one or more human subjects is enrolled in the clinical trial, and 
the date is before the primary completion date of the clinical trial. 
With respect to a pediatric postmarket surveillance of a device 
product, ongoing means a date between the date on which FDA approves 
the plan for conducting the surveillance and the date on which the 
final report is submitted to FDA.
    Outcome measure means a pre-specified measurement that will be used 
to determine the effect of an experimental variable on the human 
subject(s) in a clinical trial. See also the definitions of ``primary 
outcome measure'' and ``secondary outcome measure.''
    Pediatric postmarket surveillance of a device product means the 
active, systematic, scientifically valid collection, analysis, and 
interpretation of data or other information conducted under section 522 
of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360l) about a 
marketed device product that is expected to have significant use in 
patients who are 21 years of age or younger at the time of diagnosis or 
treatment. A pediatric postmarket surveillance of a device product may 
be, but is not always, a clinical trial.
    Primary completion date means, for purposes of this part, 
``completion date.'' See the definition of ``completion date.''
    Primary outcome measure means the outcome measure(s) of greatest 
importance specified in the protocol, usually the one(s) used in the 
power calculation. Most clinical trials have one primary outcome 
measure, but a clinical trial may have more than one. For purposes of 
this part, ``primary outcome'' has the same meaning as primary outcome 
measure.
    Principal investigator means the individual who is responsible for 
the overall scientific and technical direction of the study.
    Protocol means the written description of the clinical trial, 
including objective(s), design, and methods. It may also include 
relevant scientific background and statistical considerations.
    Responsible party means, with respect to a clinical trial, the 
sponsor of the clinical trial, as defined in 21 CFR 50.3; or the 
principal investigator of such clinical trial if so designated by a 
sponsor, grantee, contractor, or awardee, so long as the principal 
investigator is responsible for conducting the trial, has access to and 
control over the data from the clinical trial, has the right to publish 
the results of the trial, and has the ability to meet all of the 
requirements under this part for the submission of clinical trial 
information. For a pediatric postmarket surveillance of a device 
product that is not a clinical trial, the responsible party is the 
entity who FDA orders to conduct the pediatric postmarket surveillance 
of the device product.
    Secondary outcome measure means an outcome measure that is of 
lesser importance than a primary outcome measure, but is part of a pre-
specified analysis plan for evaluating the effects

[[Page 65141]]

of the intervention or interventions under investigation in a clinical 
trial and is not specified as an exploratory or other measure. A 
clinical trial may have more than one secondary outcome measure. For 
purposes of this part, ``secondary outcome'' has the same meaning as 
secondary outcome measure.
    Secretary means the Secretary of Health and Human Services or any 
other official(s) to whom the Secretary delegates the authority 
contained in section 402(j) of the Public Health Service Act (42 U.S.C. 
282(j)).
    Serious adverse event means an adverse event that results in any of 
the following outcomes: Death, a life-threatening adverse event as 
defined in 21 CFR 312.32, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may 
not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the human subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of a substance use disorder.
    Sponsor means either a ``sponsor'' or ``sponsor-investigator,'' as 
each is defined in 21 CFR 50.3.
    Study completion date means, for a clinical trial, the date the 
final subject was examined or received an intervention for purposes of 
final collection of data for the primary and secondary outcome measures 
and adverse events (e.g., last subject's last visit), whether the 
clinical trial concluded according to the pre-specified protocol or was 
terminated.
    U.S. FDA-regulated device product means, for purposes of this part, 
a device product subject to section 510(k), 515, 520(m), or 522 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 21 U.S.C. 360e, 
21 U.S.C. 360j(m), 21 U.S.C. 360l).
    U.S. FDA-regulated drug product means, for purposes of this part, a 
drug product subject to section 505 of the Federal Food, Drug, and 
Cosmetic Act or a biological product subject to section 351 of the 
Public Health Service Act (21 U.S.C. 355, 42 U.S.C. 262) .
    (b) The following definitions apply to data elements of clinical 
trial information referenced in this part, unless otherwise specified:
    (1) Brief Title means a short title of the clinical trial written 
in language intended for the lay public, including any acronym or 
abbreviation used publicly to identify the clinical trial.
    (2) Official Title means the title of the clinical trial, 
corresponding to the title of the protocol.
    (3) Brief Summary means a short description of the clinical trial, 
including a brief statement of the clinical trial's hypothesis, written 
in language intended for the lay public.
    (4) Primary Purpose means the main objective of the intervention(s) 
being evaluated by the clinical trial.
    (5) Study Design means a description of the manner in which the 
clinical trial will be conducted, including the following information:
    (i) Interventional Study Model. The strategy for assigning 
interventions to human subjects.
    (ii) Number of Arms. The number of arms in the clinical trial. For 
a trial with multiple periods or phases that have different numbers of 
arms, it means the maximum number of arms during all periods or phases.
    (iii) Arm Information. A description of each arm of the clinical 
trial that indicates its role in the clinical trial, provides an 
informative title, and, if necessary, additional descriptive 
information (including which interventions are administered in each 
arm) to differentiate each arm from other arms in the clinical trial.
    (iv) Allocation. The method by which human subjects are assigned to 
arms in a clinical trial.
    (v) Masking. The party or parties, if any, involved in the clinical 
trial who are prevented from having knowledge of the interventions 
assigned to individual human subjects.
    (6) Study Phase means, for a clinical trial of a drug product 
(including a biological product), the numerical phase of such clinical 
trial, consistent with terminology in 21 CFR 312.21, such as phase 2 or 
phase 3, and in 21 CFR 312.85 for phase 4 studies.
    (7) Study Type means the nature of the investigation or 
investigational use for which clinical trial information is being 
submitted, e.g., interventional, observational.
    (8) Pediatric Postmarket Surveillance of a Device Product means a 
clinical trial or study that includes a U.S. FDA-regulated device 
product as an intervention and is a pediatric postmarket surveillance 
of a device product ordered under section 522 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 369l).
    (9) Primary Disease or Condition Being Studied in the Trial, or the 
Focus of the Study means the name(s) of the disease(s) or condition(s) 
studied in the clinical trial, or the focus of the clinical trial. Use, 
if available, appropriate descriptors from NLM's Medical Subject 
Headings (MeSH)-controlled vocabulary thesaurus or terms from another 
vocabulary, such as the Systematized Nomenclature of Medicine--Clinical 
Terms (SNOMED CT), that has been mapped to MeSH within the Unified 
Medical Language System (UMLS) Metathesaurus.
    (10) Intervention Name(s) means a brief descriptive name used to 
refer to the intervention(s) studied in each arm of the clinical trial. 
A non-proprietary name of the intervention must be used, if available. 
If a non-proprietary name is not available, a brief descriptive name or 
identifier must be used.
    (11) Other Intervention Name(s) means other current and former 
name(s) or alias(es), if any, different from the Intervention Name(s), 
that the sponsor has used publicly to identify the intervention(s), 
including, but not limited to, past or present names such as brand 
name(s), or serial numbers.
    (12) Intervention Description means details that can be made public 
about the intervention, other than the Intervention Name(s) and Other 
Intervention Name(s), sufficient to distinguish the intervention from 
other, similar interventions studied in the same or another clinical 
trial. For example, interventions involving drugs may include dosage 
form, dosage, frequency, and duration.
    (13) Intervention Type means, for each intervention studied in the 
clinical trial, the general type of intervention, e.g., drug, 
biological/vaccine, or, device.
    (14) Device Product Not Approved or Cleared by U.S. FDA means that 
at least one device product studied in the clinical trial has not been 
previously approved or cleared by FDA for one or more uses.
    (15) Product Manufactured in and Exported from the U.S. means that 
any drug product (including a biological product) or device product 
studied in the clinical trial is manufactured in the United States or 
one of its territories and exported for study in a clinical trial in 
another country.
    (16) Study Start Date means the estimated date on which the 
clinical trial will be open for recruitment of human subjects, or the 
actual date on which the first human subject was enrolled.

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    (17) Primary Completion Date means the estimated or actual primary 
completion date. If an estimated primary completion date is used, the 
responsible party must update the Primary Completion Date data element 
once the clinical trial has reached the primary completion date to 
reflect the actual primary completion date.
    (18) Enrollment means the estimated total number of human subjects 
to be enrolled (target number) or the actual total number of human 
subjects that are enrolled in the clinical trial. Once the trial has 
reached the primary completion date, the responsible party must update 
the Enrollment data element to reflect the actual number of human 
subjects enrolled in the clinical trial.
    (19) Primary Outcome Measure Information means a description of 
each primary outcome measure, to include the following information:
    (i) Name of the specific primary outcome measure;
    (ii) Description of the metric used to characterize the specific 
primary outcome measure; and
    (iii) Time point(s) at which the measurement is assessed for the 
specific metric used.
    (20) Secondary Outcome Measure Information means a description of 
each secondary outcome measure, to include the following information:
    (i) Name of the specific secondary outcome measure;
    (ii) Description of the metric used to characterize the specific 
secondary outcome measure; and
    (iii) Time point(s) at which the measurement is assessed for the 
specific metric used.
    (21) Eligibility Criteria means a limited list of criteria for 
selection of human subjects to participate in the clinical trial, 
provided in terms of inclusion and exclusion criteria and suitable for 
assisting potential human subjects in identifying clinical trials of 
interest.
    (22) Sex/Gender means the sex and, if applicable, gender of the 
human subjects who may participate in the clinical trial.
    (23) Age Limits means the minimum and maximum age of human subjects 
who may participate in the clinical trial, provided in relevant units 
of time.
    (24) Accepts Healthy Volunteers means that human subjects who do 
not have a disease or condition, or related conditions or symptoms, 
under study in the clinical trial are permitted to participate in the 
clinical trial.
    (25) Overall Recruitment Status means the recruitment status for 
the clinical trial as a whole, based on the status of the individual 
sites. If at least one facility in a multi-site clinical trial has an 
individual site status of ``recruiting,'' then the overall recruitment 
status for the trial must be ``recruiting.''
    (26) Why Study Stopped means, for a clinical trial that is 
suspended or terminated or withdrawn prior to its planned completion as 
anticipated by the protocol, a brief explanation of the reason(s) why 
the clinical trial was stopped.
    (27) Individual Site Status means the recruitment status of each 
participating facility in a clinical trial.
    (28) Availability of Expanded Access means, for an applicable drug 
clinical trial of a drug product (including a biological product) that 
is not an approved drug product (including a biological product), and 
for which the responsible party is both the manufacturer of the drug 
product (including a biological product) and the sponsor of the 
applicable clinical trial:
    (i) An indication of whether there is expanded access to the 
investigational drug product (including a biological product) under 
section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
360bbb) for those individuals who do not qualify for enrollment in the 
applicable clinical trial, under one or more of the following types of 
expanded access programs: for individual patients, including for 
emergency use, as specified in 21 CFR 312.310; for intermediate-size 
patient populations, as specified in 21 CFR 312.315; or under a 
treatment IND or treatment protocol, as specified in 21 CFR 312.320; 
and
    (ii) If expanded access is available under section 561 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb), the NCT number 
of the expanded access record.
    (29) Name of the Sponsor means the name of the entity or individual 
who is the sponsor of the clinical trial, as defined in this part.
    (30) Responsible Party, by Official Title means an:
    (i) Indication of whether the responsible party is the sponsor of 
the clinical trial, as that term is defined in 21 CFR 50.3; the 
sponsor-investigator, as that term is defined in 21 CFR 50.3; or a 
principal investigator designated pursuant to this part; and
    (ii) Either:
    (A) The official name of the entity, if the responsible party is an 
entity; or
    (B) The official title and primary organizational affiliation of 
the individual, if the responsible party is an individual.
    (31) Facility Information means, for each participating facility in 
a clinical trial, the following information:
    (i) Facility Name, meaning the full name of the organization where 
the clinical trial is being conducted;
    (ii) Facility Location, including city, state, country and zip code 
for U.S. locations (including territories of the United States) and 
city and country for locations in other countries; and
    (iii) Either:
    (A) For each facility participating in a clinical trial, Facility 
Contact, including the name or title, telephone number, and email 
address of a person to whom questions concerning the trial and 
enrollment at that site can be addressed; or
    (B) Central Contact Person, including the name or title, toll-free 
telephone number, and email address of a person to whom questions 
concerning enrollment at any location of the trial can be addressed.
    (32) Unique Protocol Identification Number means any unique 
identifier assigned to the protocol by the sponsor.
    (33) Secondary ID means:
    (i) Any identifier(s) other than the organization's unique protocol 
identifier or NCT number that is assigned to the clinical trial, 
including any unique clinical trial identifiers assigned by other 
publicly available clinical trial registries. If the clinical trial is 
funded in whole or in part by a U.S. Federal Government agency, the 
complete grant or contract number must be submitted as a Secondary ID.
    (ii) A description of the type of Secondary ID.
    (34) U.S. Food and Drug Administration IND or IDE Number means an 
indication of whether there is an IND or IDE for the clinical trial 
and, if so, each of the following elements:
    (i) Name or abbreviation of the FDA center with whom the IND or IDE 
is filed;
    (ii) IND or IDE number assigned by the FDA center; and
    (iii) For an IND, the IND serial number, as defined in 21 CFR 
312.23(e), if any, assigned to the clinical trial.
    (35) Human Subjects Protection Review Board Status means 
information to indicate whether a clinical trial has been reviewed and 
approved by a human subjects protection review board or whether such 
review is not required per applicable law (e.g., 21 CFR part 56, 45 CFR 
part 46, or other applicable regulation). Human Subjects Protection 
Review Board Status must be listed as ``approved'' if at least one 
human subjects protection review board has approved the clinical trial.

[[Page 65143]]

    (36) Record Verification Date means the date on which the 
responsible party last verified the clinical trial information in the 
entire ClinicalTrials.gov record for the clinical trial, even if no 
additional or updated information was submitted at that time.
    (37) Responsible Party Contact Information means administrative 
information to identify and allow communication with the responsible 
party by telephone, email, and regular mail or delivery service. 
Responsible Party Contact Information includes the name, official 
title, organizational affiliation, physical address, mailing address, 
phone number, and email address of the individual who is the 
responsible party or of a designated employee of the organization that 
is the responsible party.
    (38) Studies a U.S. FDA-regulated Device Product means that a 
clinical trial studies a device product subject to section 510(k), 515, 
or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
360(k), 21 U.S.C. 360e, 21 U.S.C. 360j(m)).
    (39) Studies a U.S. FDA-regulated Drug Product means a clinical 
trial studies a drug product (including a biological product) subject 
to section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
355) or section 351 of the Public Health Service Act (42 U.S.C. 262).
    (40) Post Prior to U.S. FDA Approval or Clearance means, for an 
applicable device clinical trial of a device product that has not been 
previously approved or cleared, the responsible party indicates to the 
Director that it is authorizing the Director, in accordance with Sec.  
11.35(b)(2)(ii), to publicly post its clinical trial registration 
information, which would otherwise be subject to delayed posting, as 
specified in Sec.  11.35(b)(2)(i), prior to the date of FDA approval or 
clearance of its device product.
    (41) Study Completion Date means the estimated or actual study 
completion date. Once the clinical trial has reached the study 
completion date, the responsible party must update the Study Completion 
Date data element to reflect the actual study completion date in 
accordance with Sec.  11.64(a)(1)(ii)(J) .

Subpart B--Registration


Sec.  11.20  Who must submit clinical trial registration information?

    The responsible party for an applicable clinical trial specified in 
Sec.  11.22 must submit clinical trial registration information for 
that clinical trial.


Sec.  11.22  Which applicable clinical trials must be registered?

    (a) General specification. (1) Any applicable clinical trial that 
is initiated after September 27, 2007, must be registered.
    (2) Any applicable clinical trial that is initiated on or before 
September 27, 2007, and is ongoing on December 26, 2007, must be 
registered.
    (3) Determining the date of initiation for an applicable clinical 
trial. An applicable clinical trial, other than a pediatric postmarket 
surveillance of a device product that is not a clinical trial, is 
considered to be initiated on the date on which the first human subject 
is enrolled. A pediatric postmarket surveillance of a device product 
that is not a clinical trial is considered to be initiated on the date 
on which FDA approves the plan for conducting the surveillance.
    (b) Determination of applicable clinical trial for a clinical trial 
or study initiated on or after January 18, 2017. A clinical trial or 
study that, at any point in time, meets the conditions listed in 
paragraph (b)(1) or (2) of this section will be considered to meet the 
definition of an applicable clinical trial.
    (1) Applicable device clinical trial. A clinical trial or study 
that meets the conditions listed in either paragraph (b)(1)(i) or (ii) 
of this section is an applicable device clinical trial:
    (i) The study is a pediatric postmarket surveillance of a device 
product as required by FDA under section 522 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 3601).
    (ii) The study is a clinical trial with one or more arms that meets 
all of the following criteria:
    (A) Study Type is interventional;
    (B) Primary Purpose of the clinical trial is other than a 
feasibility study;
    (C) The clinical trial Studies a U.S. FDA-regulated Device Product; 
and
    (D) One or more of the following applies:
    (1) At least one Facility Location is within the United States or 
one of its territories,
    (2) A device product under investigation is a Product Manufactured 
in and Exported from the U.S. or one of its territories for study in 
another country, or
    (3) The clinical trial has a U.S. Food and Drug Administration IDE 
Number.
    (2) Applicable drug clinical trial. A clinical trial with one or 
more arms that meets the following conditions is an applicable drug 
clinical trial:
    (i) Study Type is interventional;
    (ii) Study Phase is other than phase 1;
    (iii) The clinical trial Studies a U.S. FDA-regulated Drug Product; 
and
    (iv) One or more of the following applies:
    (A) At least one Facility Location for the clinical trial is within 
the United States or one of its territories,
    (B) A drug product (including a biological product) under 
investigation is a Product Manufactured in and Exported from the U.S. 
or one of its territories for study in another country, or
    (C) The clinical trial has a U.S. Food and Drug Administration IND 
Number.


Sec.  11.24  When must clinical trial registration information be 
submitted?

    (a) General. Except as provided in paragraph (b) of this section, 
the responsible party for an applicable clinical trial for which 
submission of clinical trial registration information is required must 
submit the clinical trial registration information specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) or Sec.  11.28(a), as applicable, not later than 
December 26, 2007, or 21 calendar days after the first human subject is 
enrolled, whichever date is later.
    (b) Exceptions:. (1) The responsible party for an applicable 
clinical trial that is a clinical trial and for which the submission of 
clinical trial registration information is required and that is not for 
a serious or life-threatening disease or condition must submit clinical 
trial registration information as specified in section 402(j)(2)(A)(ii) 
of the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) or Sec.  
11.28(a), as applicable, not later than September 27, 2008, or 21 
calendar days after the first human subject is enrolled, whichever date 
is later.
    (2) The responsible party for an applicable device clinical trial 
that is a pediatric postmarket surveillance of a device product and is 
not a clinical trial must submit clinical trial registration 
information, as specified in section 402(j)(2)(A)(ii) of the Public 
Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) or Sec.  11.28(b), not 
later than December 26, 2007, or 21 calendar days after FDA approves 
the postmarket surveillance plan, whichever date is later.


Sec.  11.28  What constitutes clinical trial registration information?

    (a) For each applicable clinical trial that must be registered with 
ClinicalTrials.gov, other than a pediatric postmarket surveillance of a 
device product that is not a clinical trial, the responsible party must 
submit the following information:
    (1) For such applicable clinical trials that were initiated before 
January 18,

[[Page 65144]]

2017, the responsible party must submit the information specified in 
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)).
    (2) For such applicable clinical trials that are initiated on or 
after January 18, 2017, the responsible party must submit the data 
elements listed below:
    (i) Descriptive information:
    (A) Brief Title;
    (B) Official Title;
    (C) Brief Summary;
    (D) Primary Purpose;
    (E) Study Design;
    (F) Study Phase, for an applicable drug clinical trial;
    (G) Study Type;
    (H) Pediatric Postmarket Surveillance of a Device Product, for an 
applicable device clinical trial that is a Pediatric Postmarket 
Surveillance of a Device Product;
    (I) Primary Disease or Condition Being Studied in the Trial, or the 
Focus of the Study;
    (J) Intervention Name(s), for each intervention studied;
    (K) Other Intervention Name(s), for each intervention studied;
    (L) Intervention Description, for each intervention studied;
    (M) Intervention Type, for each intervention studied;
    (N) Studies a U.S. FDA-regulated Device Product;
    (O) Studies a U.S. FDA-regulated Drug Product;
    (P) Device Product Not Approved or Cleared by U.S. FDA, if any 
studied intervention is a device product;
    (Q) Post Prior to U.S. FDA Approval or Clearance, for an applicable 
device clinical trial that studies at least one device product not 
previously approved or cleared by the U.S. FDA;
    (R) Product Manufactured in and Exported from the U.S., if the 
entry for U.S. Food and Drug Administration IND or IDE Number in Sec.  
11.28(a)(2)(iv)(C) indicates that there is no IND or IDE for the 
clinical trial, and the entry(ies) for Facility Information in Sec.  
11.28(a)(2)(iii)(C) include no facility locations in the United States 
or its territories;
    (S) Study Start Date;
    (T) Primary Completion Date;
    (U) Study Completion Date;
    (V) Enrollment;
    (W) Primary Outcome Measure Information, for each primary outcome 
measure; and
    (X) Secondary Outcome Measure Information, for each secondary 
outcome measure.
    (ii) Recruitment information:
    (A) Eligibility Criteria;
    (B) Sex/Gender;
    (C) Age Limits;
    (D) Accepts Healthy Volunteers;
    (E) Overall Recruitment Status;
    (F) Why Study Stopped;
    (G) Individual Site Status; and
    (H) Availability of Expanded Access. If expanded access is 
available for an investigational drug product (including a biological 
product), an expanded access record must be submitted in accordance 
with Sec.  11.28(c), unless an expanded access record was submitted 
previously in accordance with that provision.
    (iii) Location and contact information:
    (A) Name of the Sponsor;
    (B) Responsible Party, by Official Title; and
    (C) Facility Information.
    (iv) Administrative data:
    (A) Unique Protocol Identification Number;
    (B) Secondary ID;
    (C) U.S. Food and Drug Administration IND or IDE Number;
    (D) Human Subjects Protection Review Board Status;
    (E) Record Verification Date; and
    (F) Responsible Party Contact Information.
    (b) Pediatric postmarket surveillance of a device product that is 
not a clinical trial. For each pediatric postmarket surveillance of a 
device product that is not a clinical trial, the responsible party must 
submit the following information:
    (1) For such applicable device clinical trials that were initiated 
before January 18, 2017, the responsible party must submit the 
information specified in section 402(j)(2)(A)(ii) of the Public Health 
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).
    (2) For such applicable device clinical trials that are initiated 
on or after January 18, 2017, the responsible party must submit the 
data elements listed below:
    (i) Descriptive information:
    (A) Brief Title. A short title of the pediatric postmarket 
surveillance of a device product in language intended for the lay 
public. If an acronym or abbreviation is used to publicly identify the 
surveillance, it must be provided.
    (B) Official Title. The title of the pediatric postmarket 
surveillance of a device product, corresponding to the title of the 
protocol or the FDA-approved plan for conducting the surveillance
    (C) Brief Summary. A short description of the pediatric postmarket 
surveillance of a device product, including a brief statement of the 
hypothesis or objective, written in language intended for the lay 
public, and a general description of the surveillance design, including 
relevant population information
    (D) Study Type. The type of study being registered. In the case of 
a pediatric postmarket surveillance of a device product that is not a 
clinical trial, a study type of ``observational'' is required.
    (E) Pediatric Postmarket Surveillance of a Device Product. For a 
study that includes an FDA-regulated device product as an intervention 
and is a pediatric postmarket surveillance of a device product
    (F) Primary Disease or Condition Being Studied, or the Focus of the 
Study. The name(s) of the disease(s) or condition(s) being studied in 
the pediatric postmarket surveillance of a device product, or the focus 
of the surveillance study. Use, if available, appropriate descriptors 
fromNLM's MeSH-controlled vocabulary thesaurus or terms from another 
vocabulary, such as the SNOMED CT, that has been mapped to MeSH within 
the UMLS Metathesaurus.
    (G) Intervention Name(s). A brief descriptive name used to refer to 
each intervention studied in the pediatric postmarket surveillance of a 
device product. A non-proprietary name of the intervention must be 
used, if available. If a non-proprietary name is not available, a brief 
descriptive name or identifier must be used.
    (H) Other Intervention Name(s). Any other current and former 
name(s) or alias(es), different from the Intervention Name(s), that the 
sponsor has used publicly to identify the intervention(s), including, 
but not limited to, past or present names such as brand name(s), or 
serial numbers
    (I) Intervention Description. Details that can be made public about 
each intervention, other than the Intervention Name(s) and Other 
Intervention Name(s), sufficient to distinguish the intervention from 
other, similar interventions studied in the same or another clinical 
trial or pediatric postmarket surveillance of a device product that is 
not a clinical trial
    (J) Intervention Type. For each intervention studied in the 
pediatric postmarket surveillance of a device product, the general type 
of intervention
    (K) Study Start Date. The date on which FDA approves the pediatric 
postmarket surveillance plan, as specified in 21 CFR 822.19(a).
    (L) Primary Completion Date. The estimated or actual date on which 
the final report of the pediatric postmarket surveillance of a device 
product is expected to be submitted to FDA. Once the final report has 
been submitted, this is the actual date on which the final report is 
submitted to FDA.
    (ii) Location and contact information:

[[Page 65145]]

    (A) Name of the Sponsor.
    (B) Responsible Party, by Official Title:
    (1) If the responsible party is an entity, the official name of the 
entity; or
    (2) If the responsible party is an individual, the official title 
and primary organizational affiliation of the individual.
    (C) Contact Information. The name or official title, toll-free 
telephone number, and email address of a person to whom questions 
concerning the pediatric postmarket surveillance of a device product 
can be addressed.
    (iii) Administrative data:
    (A) Unique Protocol Identification Number. The unique identifier 
assigned to the pediatric postmarket surveillance of a device product 
by the sponsor, if any.
    (B) Secondary ID: (1) Identifier(s) other than the organization's 
unique protocol identifier or NCT number that is assigned to the 
pediatric postmarket surveillance of a device product, if any, 
including any unique identifiers assigned by other publicly available 
clinical study registries. If the pediatric postmarket surveillance of 
a device product is funded in whole or in part by a U.S. Federal 
Government agency, the complete grant or contract number must be 
submitted as a Secondary ID.
    (2) For each secondary ID listed, a description of the type of 
secondary ID.
    (C) Human Subjects Protection Review Board Status. Information to 
indicate whether a pediatric postmarket surveillance of a device 
product has been reviewed and approved by a human subjects protection 
review board or whether such review is not required per applicable law 
(e.g., 21 CFR part 56, 45 CFR part 46, or other applicable regulation). 
Human Subjects Protection Review Board Status must be listed as 
``approved'' if at least one human subjects protection review board has 
approved the pediatric postmarket surveillance.
    (D) Record Verification Date. The date on which the responsible 
party last verified the clinical trial information in the entire 
ClinicalTrials.gov record for the pediatric postmarket surveillance of 
a device product, even if no additional or updated information was 
submitted at that time
    (E) Responsible Party Contact Information. Administrative 
information sufficient to identify and allow communication with the 
responsible party by telephone, email, and regular mail or delivery 
service. Responsible Party Contact Information includes the name, 
official title, organizational affiliation, physical address, mailing 
address, phone number, and email address of the individual who is the 
responsible party or of a designated employee of the organization that 
is the responsible party.
    (c) Expanded access record. If expanded access is available, as 
specified in 21 CFR 312.315 (for an intermediate-size patient 
population) or 21 CFR 312.320 (under a treatment IND or treatment 
protocol), for an investigational drug product (including a biological 
product) studied in an applicable drug clinical trial, and the data 
elements set forth in paragraphs (c)(1) through (4) of this section 
have not been submitted in an expanded access record for that 
investigational product, the responsible party, if both the 
manufacturer of the investigational product and the sponsor of the 
applicable clinical trial, must submit the clinical trial information 
specified in paragraphs (c)(1) through (4) of this section to 
ClinicalTrials.gov in the form of an expanded access record. If 
expanded access is available only as specified in 21 CFR 312.310 (for 
individual patients, including for emergency use) for an 
investigational drug product (including a biological product) studied 
in an applicable drug clinical trial, and the data elements set forth 
in paragraphs (c)(1)(i), (iii), (iv), (vi), (ix), (x), (c)(2)(iv), 
(c)(3), (c)(4)(i), (iii),(iv), and (v) of this section have not been 
submitted in an expanded access record for that investigational 
product, the responsible party, if both the manufacturer of the 
investigational product and the sponsor of the applicable clinical 
trial, must submit the clinical trial information specified in those 
paragraphs to ClinicalTrials.gov in the form of an expanded access 
record.
    (1) Descriptive information:
    (i) Brief Title. A short title identifying the expanded access, 
written in language intended for the lay public. If an acronym or 
abbreviation is used publicly to identify the expanded access, it must 
be provided.
    (ii) Official Title. The title, if any, of the expanded access 
program corresponding to the title that has been submitted to FDA for 
that program
    (iii) Brief Summary. A short description of the availability of 
expanded access, including the procedure for requesting the 
investigational drug product (including a biological product).
    (iv) Study Type. The nature of the investigation or investigational 
use for which clinical trial information is being submitted, i.e., 
``expanded access''.
    (v) Primary Disease or Condition. The name(s) of the disease(s) or 
condition(s) for which expanded access to the investigational drug 
product (including a biological product) is available. Use, if 
available, appropriate descriptors from NLM's MeSH-controlled 
vocabulary thesaurus, or terms from another vocabulary, such as the 
SNOMED CT, that has been mapped to MeSH within the UMLS Metathesaurus.
    (vi) Intervention Name(s). A brief descriptive name used to refer 
to the investigational drug product (including a biological product) 
that is available through expanded access. A non-proprietary name of 
the intervention must be used, if available. If a non-proprietary name 
is not available, a brief descriptive name or identifier must be used.
    (vii) Other Intervention Name(s). Any other current and former 
name(s) or alias(es), different from the Intervention Name(s), that the 
sponsor has used publicly to identify the intervention, including, but 
not limited to, past or present names such as brand name(s), or serial 
numbers.
    (viii) Intervention Description. Details that can be made public 
about each intervention, other than the Intervention Name(s) or Other 
Intervention Name(s), sufficient to distinguish the intervention from 
other, similar interventions that are available through expanded access 
or in clinical trials.
    (ix) Intervention Type. For each investigational drug product 
(including a biological product) for which expanded access is 
available, the general type of intervention, e.g., drug.
    (x) Expanded Access Type. The type(s) of expanded access for which 
the investigational drug product (including a biological product) is 
available, as specified in Sec.  11.10(b)(28).
    (2) Recruitment information:
    (i) Eligibility Criteria. A limited list of criteria for 
determining who is eligible to receive the investigational drug product 
(including a biological product) through expanded access, provided in 
terms of inclusion and exclusion criteria and suitable for assisting 
potential patients in identifying investigational drug products 
(including biological products) of interest for which expanded access 
is available.
    (ii) Sex/Gender. The sex and gender (if applicable) of the patients 
for whom expanded access is available.
    (iii) Age Limits. The minimum and maximum age of patients for whom 
expanded access is available, provided in relevant units of time.
    (iv) Expanded Access Status. The status of availability of the 
investigational drug product (including a biological product) through 
expanded access.
    (3) Contact information:

[[Page 65146]]

    (i) Name of the Sponsor.
    (ii) Responsible Party, by Official Title. The official name of the 
entity.
    (iii) Contact Information. The name or official title, toll-free 
telephone number, and email address of a person to whom questions 
concerning expanded access can be addressed.
    (4) Administrative data:
    (i) Unique Protocol Identification Number. Any unique identifier 
assigned by the sponsor to refer to the availability of its 
investigational drug product (including a biological product) for 
expanded access use or to identify the expanded access record.
    (ii) Secondary ID: (A) Any identifier(s) other than the Unique 
Protocol Identification Number or the NCT number that is assigned to 
the expanded access record, including any unique identifiers assigned 
by other publicly available clinical trial or expanded access 
registries.
    (B) For each Secondary ID listed, a description of the type of 
Secondary ID.
    (iii) U.S. Food and Drug Administration IND Number. An indication 
of whether there is an IND and, if so, each of the following elements:
    (A) Name or abbreviation of the FDA center with whom the IND is 
filed (i.e., CDER or CBER), if applicable;
    (B) IND number (assigned by the FDA center) under which the 
investigational drug product (including a biological product) is being 
made available for expanded access, if applicable; and
    (C) IND serial number. as defined in 21 CFR 312.23(e), if any, 
assigned to the expanded access.
    (iv) Record Verification Date. The date on which the responsible 
party last verified the information in the expanded access record, even 
if no additional or updated information was submitted at that time.
    (v) Responsible Party Contact Information. Administrative 
information sufficient to identify and allow communication with the 
responsible party entering the clinical trial information into the 
expanded access record by telephone, email, and regular mail or 
delivery service. Responsible Party Contact Information includes the 
name, official title, organizational affiliation, physical address, 
mailing address, phone number, and email address of the individual who 
is the responsible party or of a designated employee of the 
organization that is the responsible party.


Sec.  11.35  By when will the NIH Director post clinical trial 
registration information submitted under Sec.  11.28?

    (a) Applicable drug clinical trial. The Director will post publicly 
on ClinicalTrials.gov the clinical trial registration information, 
except for certain administrative data, for an applicable drug clinical 
trial not later than 30 calendar days after the responsible party has 
submitted such information, as specified in Sec.  11.24.
    (b) Applicable device clinical trial. (1) For an applicable device 
clinical trial of a device product that was previously approved or 
cleared, the Director will post publicly on ClinicalTrials.gov the 
clinical trial registration information, except for certain 
administrative data, as soon as practicable, but not later than 30 
calendar days after clinical trial results information is required to 
be posted, as specified in Sec.  11.52.
    (2) For an applicable device clinical trial of a device product 
that has not been previously approved or cleared:
    (i) The Director will post publicly on ClinicalTrials.gov the 
clinical trial registration information, except for certain 
administrative data, not earlier than the date of FDA approval or 
clearance of the device product and not later than 30 calendar days 
after the date of such approval or clearance, except as otherwise 
provided in paragraph (b)(2)(ii) of this section.
    (ii) If, prior to the date of approval or clearance of the device 
product, the responsible party for an applicable clinical trial that is 
initiated on or after January 18, 2017, indicates to the Director, by 
submitting the Post Prior to U.S. FDA Approval or Clearance data 
element under Sec.  11.28(a)(2)(i)(Q), that it is authorizing the 
Director to publicly post its clinical trial registration information, 
which would otherwise be subject to delayed posting as specified in 
paragraph (b)(2)(i) of this section, prior to the date of FDA approval 
or clearance of its device product, the Director will publicly post the 
registration information, except for certain administrative data, as 
soon as practicable.

Subpart C--Results Information Submission


Sec.  11.40   Who must submit clinical trial results information?

    The responsible party for an applicable clinical trial specified in 
Sec.  11.42 must submit clinical trial results information for that 
clinical trial.


Sec.  11.42  For which applicable clinical trials must clinical trial 
results information be submitted?

    (a) Applicable clinical trials for which the studied product is 
approved, licensed, or cleared by FDA. Unless a waiver of the 
requirement to submit clinical trial results information is granted in 
accordance with Sec.  11.54, clinical trial results information must be 
submitted for any applicable clinical trial for which the studied 
product is approved, licensed, or cleared by FDA for which submission 
of clinical trial registration information is required in accordance 
with the following:
    (1) If the primary completion date is before January 18, 2017, the 
responsible party must submit the clinical trial results information 
specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public 
Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)); 
or
    (2) If the primary completion date is on or after January 18, 2017, 
the responsible party must submit the clinical trial results 
information specified in Sec.  11.48.
    (b) Applicable clinical trials for which the studied product is not 
approved, licensed, or cleared by FDA. Unless a waiver of the 
requirement to submit clinical trial results information is granted in 
accordance with Sec.  11.54, clinical trial results information 
specified in Sec.  11.48 must be submitted for any applicable clinical 
trial with a primary completion date on or after January 18, 2017 for 
which clinical trial registration information is required to be 
submitted and for which the studied product is not approved, licensed, 
or cleared by FDA.


Sec.  11.44  When must clinical trial results information be submitted 
for applicable clinical trials subject to Sec.  11.42?

    (a) Standard submission deadline. In general, for applicable 
clinical trials subject to Sec.  11.42, clinical trial results 
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the 
Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 
282(j)(3)(I)) or in Sec.  11.48, as applicable, must be submitted no 
later than 1 year after the primary completion date of the applicable 
clinical trial.
    (b) Delayed submission of results information with certification if 
seeking approval, licensure, or clearance of a new use--(1) General 
requirements. If, prior to the results information submission deadline 
specified under paragraph (a) of this section, the responsible party 
submits a certification that an applicable clinical trial involves an 
FDA-regulated drug product (including a biological product) or

[[Page 65147]]

device product that previously has been approved, licensed, or cleared, 
for which the manufacturer is the sponsor of the applicable clinical 
trial and for which an application or premarket notification seeking 
approval, licensure, or clearance of the use being studied (which is 
not included in the labeling of the approved, licensed, or cleared drug 
product (including a biological product) or device product) has been 
filed or will be filed within 1 year with FDA, the deadline for 
submitting clinical trial results information, as specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or Sec.  11.48, as 
applicable, will be 30 calendar days after the earliest of the 
following events:
    (i) FDA approves, licenses, or clears the drug product (including a 
biological product) or device product for the use studied in the 
applicable clinical trial;
    (ii) FDA issues a letter that ends the regulatory review cycle for 
the application or submission but does not approve, license, or clear 
the drug product (including a biological product) or device product for 
the use studied in the applicable clinical trial; or
    (iii) The application or premarket notification seeking approval, 
licensure, or clearance of the new use is withdrawn without 
resubmission for not less than 210 calendar days.
    (2) Two-year limitation. Notwithstanding the deadlines specified in 
paragraph (b)(1) of this section, the responsible party must submit 
clinical trial results information specified in paragraph (b)(1) of 
this section not later than the date that is 2 years after the date 
that the certification was submitted, except to the extent that 
paragraph (d) of this section applies.
    (3) Additional requirements. If a responsible party who is both the 
manufacturer of the drug product (including a biological product) or 
device product studied in an applicable clinical trial and the sponsor 
of the applicable clinical trial submits a certification in accordance 
with paragraph (b)(1) of this section, that responsible party must 
submit such a certification for each applicable clinical trial that 
meets the following criteria:
    (i) The applicable clinical trial is required to be submitted in an 
application or premarket notification seeking approval, licensure, or 
clearance of a new use; and
    (ii) The applicable clinical trial studies the same drug product 
(including a biological product) or device product for the same use as 
studied in the applicable clinical trial for which the initial 
certification was submitted.
    (c) Delayed submission of results with certification if seeking 
initial approval, licensure, or clearance.--(1) General requirements. 
If, prior to the submission deadline specified under paragraph (a) of 
this section, a responsible party submits a certification that an 
applicable clinical trial studies an FDA-regulated drug product 
(including a biological product) or device product that was not 
approved, licensed, or cleared by FDA for any use before the primary 
completion date of the trial, and that the sponsor intends to continue 
with product development and is either seeking, or may at a future date 
seek, FDA approval, licensure, or clearance of the drug product 
(including a biological product) or device product under study, the 
deadline for submitting clinical trial results information, as 
specified in Sec.  11.48, will be 30 calendar days after the earlier of 
the date on which:
    (i) FDA approves, licenses, or clears the drug product (including a 
biological product) or device product for any use that is studied in 
the applicable clinical trial; or
    (ii) The marketing application or premarket notification is 
withdrawn without resubmission for not less than 210 calendar days.
    (2) Two-year limitation. Notwithstanding the deadlines established 
in paragraph (c)(1) of this section, the responsible party must submit 
clinical trial results information specified in paragraph (c)(1) of 
this section not later than 2 years after the date on which the 
certification was submitted, except to the extent that paragraph (d) of 
this section applies.
    (d) Submitting partial results information. (1) If clinical trial 
results information specified in sections 402(j)(3)(C) and 402(j)(3)(I) 
of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 
282(j)(3)(I)) or Sec.  11.48, as applicable, has not been collected for 
a secondary outcome measure(s) or additional adverse event information 
by the primary completion date, the responsible party must submit the 
remaining required clinical trial results information for secondary 
outcome measure(s) or additional adverse event information for that 
clinical trial by the following deadlines:
    (i) For secondary outcome measure(s), by the later of:
    (A) One year after the date on which the final subject is examined 
or receives an intervention for the purposes of final collection of 
data for that secondary outcome measure, whether the clinical trial was 
concluded according to the pre-specified protocol or was terminated; or
    (B) If a certification to delay results information submission has 
been submitted under paragraph (b) or (c) of this section, the date on 
which results information for the primary outcome measures is due 
pursuant to paragraph (b) or (c) of this section.
    (ii) For additional adverse event information, by the later of:
    (A) One year after the date of data collection for additional 
adverse event information, whether the clinical trial was concluded 
according to the pre-specified protocol or was terminated; or
    (B) If a certification to delay results information submission has 
been submitted under paragraph (b) or (c) of this section, the date on 
which results information for the primary outcome measures is due 
pursuant to paragraph (b) or (c) of this section.
    (2) Except, if clinical trial results information was submitted for 
the primary outcome measure(s) prior to the effective date of these 
regulations but data collection for all of the secondary outcome 
measure(s) or additional adverse event information is not completed 
until on or after January 18, 2017, clinical trial results information 
for all primary and secondary outcome measures and adverse event 
information for the clinical trial must be submitted as specified in 
sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act 
(42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
    (3) For each submission of partial results information for a 
clinical trial, as specified in paragraph (d)(1) of this section:
    (i) If any amendments were made to the protocol and/or statistical 
analysis plan as described in Sec.  11.48(a)(5) since the previous 
submission of partial results information, the responsible party must 
submit a copy of the revised protocol and/or statistical analysis plan; 
and
    (ii) If information about certain agreements as described in Sec.  
11.48(a)(6)(ii) has changed since the previous submission of partial 
results information, the responsible party must submit information to 
reflect the new status of certain agreements between the principal 
investigator and the sponsor.
    (e) Extensions for good cause. (1) A responsible party may request 
an extension of the deadline for submitting clinical trial results 
information subject to paragraphs (e)(1)(i) and (ii) of this section or 
section 402(j)(3)(E)(vi) of the Public Health Service Act (42 U.S.C. 
282(j)(3)(E)(vi)), as applicable, and may request more than one 
extension for the same applicable clinical trial.

[[Page 65148]]

    (i) The responsible party must submit a request for an extension to 
ClinicalTrials.gov prior to the date on which clinical trial results 
information would otherwise be due in accordance with paragraph (a), 
(b), (c), (d), (e), or (f) of this section.
    (ii) A request for an extension must contain the following:
    (A) Description of the reason(s) why clinical trial results 
information cannot be provided according to the deadline, with 
sufficient detail to allow for the evaluation of the request; and
    (B) Estimate of the date on which the clinical trial results 
information will be submitted.
    (2) Decision and submission deadline. The Director will provide a 
response electronically to the responsible party indicating whether the 
requested extension demonstrates good cause and has been granted.
    (i) If the extension request is granted, the responsible party must 
submit clinical trial results information not later than the date of 
the deadline specified in the electronic response.
    (ii) If the extension request is denied, the responsible party must 
either appeal in accordance with paragraph (e)(3) of this section or 
submit clinical trial results information specified in Sec.  11.48 by 
the later of the submission deadline specified in paragraph (a), (b), 
(c), (d), (e), or (f) of this section, as applicable, or 30 calendar 
days after the date on which the electronic notice of the denial is 
sent to the responsible party.
    (3) Appealing a denied extension request. (i) A responsible party 
who seeks to appeal a denied extension request or the deadline 
specified in a granted extension must submit an appeal to the Director 
in the format specified at https://prsinfo.clinicaltrials.gov/ not 
later than 30 calendar days after the date on which the electronic 
notification of the granting or denial of the request is sent to the 
responsible party.
    (ii) An appeal must contain an explanation of the reason(s) why the 
initial decision to deny the extension request or to grant the 
extension request with a shorter deadline than requested should be 
overturned or revised, with sufficient detail to allow for the 
evaluation of the appeal.
    (iii) The Director will provide an electronic notification to the 
responsible party indicating whether the requested extension has been 
granted upon appeal.
    (iv) If the Director grants the extension request upon appeal, the 
responsible party must submit clinical trial results information not 
later than the deadline specified in the electronic notification 
specified in paragraph (e)(3)(iii) of this section.
    (v) If the Director denies the appeal of a denied extension 
request, the responsible party must submit clinical trial results 
information by the later of the deadline specified in paragraph (a), 
(b), (c), (d), (e), or (f) of this section, or 30 calendar days after 
the electronic notification of the denial of the appeal, specified in 
paragraph (e)(3)(iii) of this section, is sent to the responsible 
party.
    (vi) If the Director denies an appeal of a denied deadline 
specified in a granted extension request, the responsible party must 
submit clinical trial results information by the later of the deadline 
specified in the notification granting the extension request, specified 
in paragraph (e)(2)(i) of this section, or 30 calendar days after the 
electronic notification denying the appeal, specified in paragraph 
(e)(3)(iii) of this section, is sent to the responsible party.
    (f) Pediatric postmarket surveillance of a device product that is 
not a clinical trial. For each pediatric postmarket surveillance of a 
device product that is not a clinical trial as defined in this part, 
the responsible party must submit clinical trial results information as 
specified in Sec.  11.48(b) or section 402(j)(C)(3) of the Public 
Health Service Act (42 U.S.C. 282(j)(C)(3)), as applicable, not later 
than 30 calendar days after the date on which the final report of the 
approved pediatric postmarket surveillance of a device product, as 
specified in 21 CFR 822.38, is submitted to FDA.


Sec.  11.48  What constitutes clinical trial results information?

    (a) For each applicable clinical trial, other than a pediatric 
postmarket surveillance of a device product that is not a clinical 
trial, for which clinical trial results information must be submitted 
under Sec.  11.42, the responsible party must provide the following:
    (1) Participant flow. Information for completing a table 
documenting the progress of human subjects through a clinical trial, by 
arm, including the number who started and completed the clinical trial. 
This information must include the following elements:
    (i) Participant Flow Arm Information. A brief description of each 
arm used for describing the flow of human subjects through the clinical 
trial, including a descriptive title used to identify each arm;
    (ii) Pre-assignment Information. A description of significant 
events in the clinical trial that occur after enrollment and prior to 
assignment of human subjects to an arm, if any; and
    (iii) Participant Data. The number of human subjects that started 
and completed the clinical trial, by arm. If assignment is based on a 
unit other than participants, also include a description of the unit of 
assignment and the number of units that started and completed the 
clinical trial, by arm.
    (2) Demographic and baseline characteristics. Information for 
completing a table of demographic and baseline measures and data 
collected by arm or comparison group and for the entire population of 
human subjects who participated in the clinical trial. This information 
must include the following elements:
    (i) Baseline Characteristics Arm/Group Information. A brief 
description of each arm or comparison group used for describing the 
demographic and baseline characteristics of the human subjects in the 
clinical trial, including a descriptive title used to identify each arm 
or comparison group.
    (ii) Baseline Analysis Population Information--(A) Overall Number 
of Baseline Participants. The total number of human subjects for whom 
baseline characteristics were measured, by arm or comparison group and 
overall.
    (B) Overall Number of Units Analyzed. If the analysis is based on a 
unit other than participants, a description of the unit of analysis and 
the number of units for which baseline measures were measured and 
analyzed, by arm or comparison group and overall.
    (C) Analysis Population Description. If the Overall Number of 
Baseline Participants (or units) differs from the number of human 
subjects (or units) assigned to the arm or comparison group and 
overall, a brief description of the reason(s) for the difference.
    (iii) Baseline Measure Information. A description of each baseline 
or demographic characteristic measured in the clinical trial, including 
age, sex/gender, race, ethnicity (if collected under the protocol), and 
any other measure(s) that were assessed at baseline and are used in the 
analysis of the primary outcome measure(s) in accordance with Sec.  
11.48(a)(3). The description of each measure must include the following 
elements:
    (A) Name and description of the measure, including any categories 
that are used to submit Baseline Measure Data.
    (B) Measure Type and Measure of Dispersion: For each baseline 
measure submitted, an indication of the type of data to be submitted 
and the associated measure of dispersion.

[[Page 65149]]

    (C) Unit of Measure. For each baseline measure for which data are 
collected, the unit of measure.
    (iv) Baseline Measure Data. The value(s) for each submitted 
baseline measure, by arm or comparison group and for the entire 
population of human subjects for whom baseline characteristics were 
measured.
    (v) Number of baseline participants (and units), by arm or 
comparison group and overall, if different from the Overall Number of 
Baseline Participants or Overall Number of Units Analyzed in Sec.  
11.48(a)(2)(ii)(A) and (B), respectively.
    (3) Outcomes and statistical analyses. Information for completing a 
table of data for each primary and secondary outcome measure by arm or 
comparison group, including the result(s) of scientifically appropriate 
statistical analyses that were performed on the outcome measure data, 
if any. This information must include the following elements:
    (i) Outcome Measure Arm/Group Information. A brief description of 
each arm or comparison group used for submitting an outcome measure for 
the clinical trial, including a descriptive title to identify each arm 
or comparison group.
    (ii) Analysis Population Information--(A) Number of Participants 
Analyzed. The number of human subjects for whom an outcome was measured 
and analyzed, by arm or comparison group.
    (B) Number of Units Analyzed. If the analysis is based on a unit 
other than participants, a description of the unit of analysis and the 
number of units for which an outcome was measured and analyzed, by arm 
or comparison group.
    (C) Analysis Population Description. If the Number of Participants 
Analyzed or Number of Units Analyzed differs from the number of human 
subjects or units assigned to the arm or comparison group, a brief 
description of the reason(s) for the difference.
    (iii) Outcome Measure Information. A description of each outcome 
measure, to include the following elements:
    (A) Name of the specific outcome measure, including the titles of 
any categories in which Outcome Measure Data in Sec.  11.48(a)(3)(iv) 
are aggregated.
    (B) Description of the metric used to characterize the specific 
outcome measure.
    (C) Time point(s) at which the measurement was assessed for the 
specific metric.
    (D) Outcome Measure Type. The type of outcome measure, whether 
primary, secondary, other pre-specified, or post-hoc.
    (E) Measure Type and Measure of Dispersion or Precision. For each 
outcome measure for which data are collected, the type of data 
submitted and the measure of dispersion or precision.
    (F) Unit of Measure. For each outcome measure for which data are 
collected, the unit of measure.
    (iv) Outcome Measure Data. The measurement value(s) for each 
outcome measure for which data are collected, by arm or comparison 
group and by category (if specified).
    (v) Statistical Analyses. Result(s) of scientifically appropriate 
tests of the statistical significance of the primary and secondary 
outcome measures, if any.
    (A) A statistical analysis is required to be submitted if it is:
    (1) Pre-specified in the protocol and/or statistical analysis plan 
and was performed on the outcome measure data,
    (2) Made public by the sponsor or responsible party prior to the 
date on which clinical trial results information is submitted for the 
primary outcome measures(s) studied in the clinical trial to which the 
statistical analysis applies, or
    (3) Conducted on a primary outcome measure in response to a request 
made by FDA prior to the date on which clinical trial results 
information is submitted for the primary outcome measure(s) studied in 
the clinical trial to which the statistical analysis applies.
    (B) Information for each statistical analysis specified in 
paragraph (a)(3)(v)(A) of this section must include the following 
elements:
    (1) Statistical Analysis Overview: Identification of the arms or 
comparison groups compared in the statistical analysis; the type of 
statistical test conducted; and, for a non-inferiority or equivalence 
test, a description of the analysis that includes, at minimum, the 
power calculation and non-inferiority or equivalence margin.
    (2) One of the following, as applicable:
    (i) Statistical Test of Hypothesis: The p-value and the procedure 
used for the statistical analysis; or
    (ii) Method of Estimation: The estimation parameter, estimated 
value, and confidence interval (if calculated).
    (4) Adverse event information. (i) Information to describe the 
methods for collecting adverse events during an applicable clinical 
trial:
    (A) Time Frame. The specific period of time over which adverse 
event information was collected and for which information is submitted 
in paragraph (a)(4)(iii) of this section.
    (B) Adverse Event Reporting Description. If the adverse event 
information collected in the clinical trial is collected based on a 
different definition of adverse event and/or serious adverse event than 
defined in this part, a brief description of how those definitions 
differ.
    (C) Collection Approach. The type of approach taken to collect 
adverse event information, whether systematic or non-systematic.
    (ii) Information for completing three tables summarizing 
anticipated and unanticipated adverse events collected during an 
applicable clinical trial:
    (A) Table of all serious adverse events grouped by organ system, 
with the number and frequency of each event by arm or comparison group;
    (B) Table of all adverse events, other than serious adverse events, 
that exceed a frequency of 5 percent within any arm of the clinical 
trial, grouped by organ system, with the number and frequency of each 
event by arm or comparison group; and
    (C) Table of all-cause mortality, with the number and frequency of 
deaths due to any cause by arm or comparison group.
    (iii) Information for each table specified in paragraph (a)(4)(ii) 
of this section must include the following elements, unless otherwise 
specified:
    (A) Adverse Event Arm/Group Information. A brief description of 
each arm or comparison group used for submitting adverse event 
information from the clinical trial, including a descriptive title used 
to identify each arm or comparison group.
    (B) Total Number Affected. The overall number of human subjects 
affected, by arm or comparison group, by:
    (1) Serious adverse event(s);
    (2) Adverse event(s) other than serious adverse events that exceed 
a frequency of 5 percent within any arm of the clinical trial; and
    (3) Deaths due to any cause.
    (C) Total Number at Risk. The overall number of human subjects 
included in the assessment, by arm or comparison group, for:
    (1) Serious adverse events;
    (2) Adverse event(s) other than serious adverse events that exceed 
a frequency of 5 percent within any arm of the clinical trial; or
    (3) Deaths due to any cause.
    (D) Adverse Event Information. For the two tables described in 
paragraphs (a)(4)(ii)(A) and (B) of this section, a description of each 
type of serious adverse event and other adverse event that is not a 
serious adverse event and exceeds a frequency of 5 percent within any 
arm of the clinical trial, consisting of the following attributes:

[[Page 65150]]

    (1) Descriptive term for the adverse event; and
    (2) Organ system associated with the adverse event.
    (E) Adverse Event Data. For the two tables described in paragraphs 
(a)(4)(ii)(A) and (B) of this section and for each adverse event listed 
in accordance with paragraph (a)(4)(iii)(D) of this section:
    (1) Number of human subjects affected by such adverse event.
    (2) Number of human subjects at risk for such adverse event.
    (5) Protocol and statistical analysis plan. A copy of the protocol 
and the statistical analysis plan (if not included in the protocol), 
including all amendments that have been approved by a human subjects 
protection review board (if applicable) before the time of submission 
under this subsection and that apply to all clinical trial Facility 
Locations. The responsible party must include the Official Title (as 
defined in Sec.  11.10(b)(2)), NCT number (as defined in Sec.  
11.10(a)) (if available), and date of the protocol and the statistical 
analysis plan on the cover page of each document. The responsible party 
may redact names, addresses, and other personally identifiable 
information, as well as any trade secret and/or confidential commercial 
information (as those terms are defined in the Freedom of Information 
Act (5 U.S.C. 552) and the Trade Secrets Act (18 U.S.C. 1905)) 
contained in the protocol or statistical analysis plan prior to 
submission, unless such information is otherwise required to be 
submitted under this part. The protocol and statistical analysis plan 
must be submitted in a common electronic document format specified at 
https://prsinfo.clinicaltrials.gov.
    (6) Administrative information--(i) Results Point of Contact. Point 
of contact for scientific information about the clinical trial results 
information, including the following:
    (A) Name or official title of the point of contact
    (B) Name of the affiliated organization, and
    (C) Telephone number and email address of the point of contact.
    (ii) Certain Agreements. An indication of whether the principal 
investigator is an employee of the sponsor and, if not, whether there 
exists any agreement (other than an agreement solely to comply with 
applicable provisions of law protecting the privacy of human subjects 
participating in the clinical trial) between the sponsor or its agent 
and the principal investigator that restricts in any manner the ability 
of the principal investigator, after the primary completion date of the 
clinical trial, to discuss the results of the clinical trial at a 
scientific meeting or any other public or private forum or to publish 
in a scientific or academic journal information concerning the results 
of the clinical trial
    (7) Additional clinical trial results information for applicable 
device clinical trials of unapproved or uncleared device products. (i) 
For an applicable device clinical trial of an unapproved or uncleared 
device product and for which clinical trial registration information 
has not been posted publicly on ClinicalTrials.gov by the Director in 
accordance with Sec.  11.35(b)(2)(i), the responsible party must 
provide the following data elements, as the data elements are defined 
in Sec.  11.10(b): Brief Title; Official Title; Brief Summary; Primary 
Purpose; Study Design; Study Type; Primary Disease or Condition Being 
Studied in the Trial, or the Focus of the Study; Intervention Name(s); 
Other Intervention Name(s); Intervention Description; Intervention 
Type; Device Product Not Approved or Cleared by U.S. FDA, if any 
studied intervention is a device product; Study Start Date; Primary 
Completion Date; Study Completion Date, Enrollment; Primary Outcome 
Measure Information; Secondary Outcome Measure Information; Eligibility 
Criteria; Sex/Gender; Age Limits; Accepts Healthy Volunteers; Overall 
Recruitment Status; Why Study Stopped; Name of the Sponsor; Responsible 
Party, by Official Title; Facility Name and Facility Location, for each 
participating facility in a clinical trial; Unique Protocol 
Identification Number; Secondary ID; Human Subjects Protection Review 
Board Status; and Record Verification Date.
    (ii) The responsible party shall submit all the results information 
specified in paragraph (a)(7)(i) and must submit an affirmation that 
any information previously submitted to ClinicalTrials.gov for the data 
elements listed in paragraph (a)(7)(i) of this section have been 
updated in accordance with Sec.  11.64(a) and are to be included as 
clinical trial results information.
    (b) Pediatric postmarket surveillance of a device product that is 
not a clinical trial. For each pediatric postmarket surveillance of a 
device product that is not a clinical trial, the responsible party must 
submit a copy of any final report that is submitted to FDA as specified 
in 21 CFR 822.38. The responsible party may redact names, addresses, 
and other personally identifiable information or commercial 
confidential information contained in the final report prior to 
submission to NIH, unless such information is otherwise required to be 
submitted under this part. The final report must be in a common 
electronic document format specified at https://prsinfo.clinicaltrials.gov.


Sec.  11.52  By when will the NIH Director post submitted clinical 
trial results information?

    Except for clinical trial results information submitted under 
section 402(j)(4)(A) of the PHS Act and Sec.  11.60, the Director will 
post publicly clinical trial results information on ClinicalTrials.gov 
not later than 30 calendar days after the date of submission.


Sec.  11.54  What are the procedures for requesting and obtaining a 
waiver of the requirements for clinical trial results information 
submission?

    (a) Waiver request. (1) A responsible party for an applicable 
clinical trial with a primary completion date on or after January 18, 
2017 may request a waiver from any applicable requirement(s) of this 
subpart C by submitting a waiver request in the format specified at 
https://prsinfo.clinicaltrials.gov/ to the Secretary or delegate prior 
to the deadline specified in Sec.  11.44(a) for submitting clinical 
trial results information.
    (2) The waiver request must contain:
    (i) The NCT number, Brief Title, and Name of the Sponsor of the 
applicable clinical trial for which the waiver is requested;
    (ii) The specific requirement(s) of this subpart C for which the 
waiver is requested; and
    (iii) A description of the extraordinary circumstances that the 
responsible party believes justify the waiver and an explanation of why 
granting the request would be consistent with the protection of public 
health or in the interest of national security.
    (3) The responsible party will not be required to comply with the 
specified requirements of this subpart for which a waiver is granted.
    (4) The responsible party must comply with any requirements of this 
subpart for which a waiver is not granted or must submit an appeal as 
set forth in paragraph (b) of this section. The deadline for submitting 
any required clinical trial results information will be the later of 
the original submission deadline or 30 calendar days after the 
notification of the denial is sent to the responsible party.
    (b) Appealing a denied waiver request. (1) A responsible party for 
an applicable clinical trial with a primary completion date on or after 
January 18,

[[Page 65151]]

2017 may appeal a denied waiver request by submitting an appeal to the 
Secretary or delegate in the format specified at https://prsinfo.clinicaltrials.gov/ not later than 30 calendar days after the 
date on which the electronic notification of the denial in paragraph 
(a)(4) of this section denying the request is sent to the responsible 
party.
    (2) The responsible party is not required to comply with any 
requirements of this subpart for which a waiver is granted upon appeal.
    (3) The responsible party must submit clinical trial results 
information to comply with any requirements of this subpart that are 
not waived upon appeal by the later of the original submission deadline 
or 30 calendar days after the notice of the denial upon appeal is sent 
to the responsible party.
    (c) If a waiver is granted under paragraph (a) or (b) of this 
section:
    (1) The Director will include a notation in the clinical trial 
record that specified elements of the requirements of this part have 
been waived.
    (2) The Secretary will notify, in writing, the appropriate 
committees of Congress and provide an explanation for why the waiver 
was granted, not later than 30 calendar days after any waiver is 
granted.
    (d) A responsible party for an applicable clinical trial with a 
primary completion date before January 18, 2017 may request a waiver 
from any applicable requirement(s) for clinical trial results 
information submission by submitting a waiver request, as specified in 
section 402(j)(3)(H) of the Public Health Service Act (42 U.S.C. 
282(j)(3)(H)).

Subpart D--Additional Submissions of Clinical Trial Information


Sec.  11.60  What requirements apply to the voluntary submission of 
clinical trial information for clinical trials of FDA-regulated drug 
products (including biological products) and device products?

    (a) If a responsible party voluntarily submits clinical trial 
information for a clinical trial described in paragraph (a)(1) of this 
section, the responsible party must meet the conditions specified in 
paragraph (a)(2) of this section.
    (1) The requirements of paragraph (a) of this section apply to a 
clinical trial that was initiated before January 18, 2017 and has a 
primary completion date before January 18, 2017, and that is either:
    (i) A clinical trial of an FDA-regulated drug product (including a 
biological product) or device product that is not an applicable 
clinical trial, or
    (ii) An applicable clinical trial that is not otherwise required to 
submit clinical trial registration information.
    (2) If the responsible party for a clinical trial described in 
paragraph (a)(1) of this section voluntarily submits clinical trial 
registration information and/or clinical trial results information, the 
responsible party must comply with the following requirements:
    (i) The responsible party must submit the information in paragraphs 
(b)(2)(i)(A), (B), or (C) of this section for the clinical trial being 
submitted voluntarily.
    (A) If the responsible party voluntarily registers a clinical 
trial, the responsible party must submit clinical trial registration 
information specified in section 402(j)(2)(A)(ii) of the Public Health 
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).
    (B) If the responsible party voluntarily submits clinical trial 
results information for a clinical trial for which the clinical trial 
registration information specified in section 402(j)(2)(A)(ii) of the 
Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) has not been 
submitted, the responsible party must submit the clinical trial results 
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the 
Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 
282(j)(3)(I)).
    (C) If the responsible party both voluntarily submits clinical 
trial registration information and voluntarily submits clinical trial 
results information, the responsible party must submit both clinical 
trial registration information specified in section 402(j)(2)(A)(ii) of 
the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) and clinical 
trial results information specified in sections 402(j)(3)(C) and 
402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) 
and 42 U.S.C. 282(j)(3)(I)).
    (ii) If, on or after September 27, 2007, a manufacturer submits an 
application or premarket notification to FDA for approval, licensure, 
or clearance of a drug product (including a biological product) or 
device product under sections 505, 510(k), 515, or 520(m) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C 355, 360(k), 360e, 
360j(m)) or section 351 of the Public Health Service Act (42 U.S.C. 
262) for the use studied in the clinical trial submitted under 
paragraph (a)(1) of this section, the responsible party specified in 
paragraph (a)(1) of this section must also submit the information 
specified in paragraph (a)(2)(iii) of this section by the deadline 
specified in paragraph (a)(2)(iv)(B) of this section for any applicable 
clinical trial that has not been submitted to ClinicalTrials.gov and 
that meets the following criteria:
    (A) The applicable clinical trial is required to be submitted to 
FDA under sections 505, 510(k), 515, or 520(m) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or 
section 351 of the Public Health Service Act (42 U.S.C. 262) in an 
application or premarket notification for approval, licensure, or 
clearance to market the drug product (including a biological product) 
or device product for the use studied in the clinical trial specified 
in paragraph (a)(1) of this section; and
    (B) The manufacturer of the drug product (including a biological 
product) or device product studied in the applicable clinical trial is 
also the responsible party for the clinical trial specified in 
paragraph (a)(1) of this section.
    (iii) Information to be submitted for clinical trials described in 
paragraph (a)(2)(ii) of this section:
    (A) If the clinical trial information voluntarily submitted for a 
clinical trial described in paragraph (a)(1) of this section consists 
only of the clinical trial registration information specified in 
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)), the information to be submitted in accordance with 
paragraph (a)(2)(ii) of this section must consist, at minimum, of the 
clinical trial registration information specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)).
    (B) If the clinical trial information voluntarily submitted for a 
clinical trial described by paragraph (a)(1) of this section consists 
of the clinical trial results information specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)), the information to be 
submitted in accordance with paragraph (a)(2)(ii) of this section must 
consist of the clinical trial results information specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
    (C) If the clinical trial information voluntarily submitted for a 
clinical trial described by paragraph (a)(1) of this section consists 
of both the clinical trial registration information specified in 
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) and the clinical trial results information specified 
in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service 
Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)), the 
information to be submitted in

[[Page 65152]]

accordance with paragraph (a)(2)(ii) of this section must consist of 
both the clinical trial registration information specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) and the clinical trial results information specified 
in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service 
Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
    (iv) Submission deadlines:
    (A) Secondary outcome measure(s) and adverse event information for 
voluntarily submitted clinical trials, under paragraph (a) of this 
section:
    (1) If data collection for secondary outcome measure(s) for a 
voluntarily submitted clinical trial under paragraph (a) of this 
section is not completed by the primary completion date of the 
voluntarily submitted clinical trial, clinical trial results 
information for the secondary outcome measure(s) required in section 
402(j)(3)(C) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C)) 
must be submitted by the later of the date that the clinical trial 
results information is voluntarily submitted for the primary outcome 
measure(s) or 1 year after the date on which the final subject was 
examined or received an intervention for the purposes of final 
collection of data for the secondary outcome(s), whether the clinical 
trial was concluded according to the pre-specified protocol or was 
terminated.
    (2) If data collection for adverse event information continues 
after the primary completion date of the voluntarily submitted clinical 
trial, any adverse event information collected after the primary 
completion date and subject to the submission requirements in section 
402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(I)) 
must be submitted by the later of the date that the clinical trial 
results information is voluntarily submitted for the primary outcome 
measure(s) or 1 year after the date of final collection of data for 
adverse event information, whether the clinical trial was concluded 
according to the pre-specified protocol or was terminated.
    (B) The clinical trial information specified in paragraph 
(a)(2)(iii) of this section must be submitted not later than the later 
of the date on which the application or premarket notification to FDA 
for approval, licensure, or clearance to market a drug product 
(including a biological product) or device product under section 351 of 
the Public Health Service Act (42 U.S.C. 262) or section 505, 510(k), 
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
355, 360(k), 360e, 360j(m)) for the use studied in the clinical trial 
specified under paragraph (a)(1) of this section is submitted to FDA or 
the date on which the clinical trial information specified in paragraph 
(a)(2)(i) of this section for the clinical trial specified under 
paragraph (a)(1) of this section is submitted to ClinicalTrials.gov.
    (b) If a responsible party voluntarily submits clinical trial 
information for a clinical trial described in paragraph (b)(1) of this 
section, the responsible party must meet the conditions specified in 
paragraph (b)(2) of this section.
    (1) The requirements of paragraph (b) of this section apply to a 
clinical trial that was initiated before January 18, 2017 and has a 
primary completion date on or after January 18, 2017, and that is 
either:
    (i) A clinical trial of an FDA-regulated drug product (including a 
biological product) or device product that is not an applicable 
clinical trial; or
    (ii) An applicable clinical trial that is not otherwise required to 
submit clinical trial registration information.
    (2) If the responsible party for a clinical trial described in 
paragraph (b)(1) of this section voluntarily submits clinical trial 
registration information and/or clinical trial results information, the 
responsible party must comply with the following requirements:
    (i) The responsible party must submit the information in paragraph 
(b)(2)(i)(A), (B), or (C) of this section for the clinical trial being 
submitted voluntarily.
    (A) If the responsible party voluntarily registers a clinical 
trial, the responsible party must submit clinical trial registration 
information specified in section 402(j)(2)(A)(ii) of the Public Health 
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).
    (B) If the responsible party voluntarily submits clinical trial 
results information for a clinical trial for which the clinical trial 
registration information specified in section 402(j)(2)(A)(ii) of the 
Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) has not been 
submitted, the responsible party must submit the data elements 
specified in Sec.  11.48, as well as the data elements listed below, as 
those data elements are defined in Sec.  11.10(b) and apply to the 
clinical trial and the intervention(s) studied: Brief Title; Official 
Title; Brief Summary; Primary Purpose; Study Design; Study Phase, for a 
clinical trial of a drug product (including a biological product); 
Study Type; Pediatric Postmarket Surveillance of a Device Product; 
Primary Disease or Condition Being Studied in the Trial, or the Focus 
of the Study; Intervention Name(s), for each intervention studied; 
Other Intervention Name(s), for each intervention studied; Intervention 
Description, for each intervention studied; Intervention Type, for each 
intervention studied; Device Product Not Approved or Cleared by U.S. 
FDA, if any studied intervention is a device product; Product 
Manufactured in and Exported from the U.S.; Studies a U.S. FDA-
regulated Device Product; Studies a U.S. FDA-regulated Drug Product; 
Study Start Date; Primary Completion Date; Study Completion Date; 
Enrollment; Eligibility Criteria; Sex/Gender; Age Limits; Accepts 
Healthy Volunteers; Overall Recruitment Status; Why Study Stopped; 
Availability of Expanded Access, if any studied intervention is an 
investigational drug product (including a biological product); Name of 
the Sponsor; Responsible Party, by Official Title; Facility 
Information, for each participating facility; Unique Protocol 
Identification Number; Secondary ID; U.S. Food and Drug Administration 
IND or IDE Number; Human Subjects Protection Review Board Status; 
Record Verification Date; and Responsible Party Contact Information.
    (C) If the responsible party both voluntarily submits clinical 
trial registration information and voluntarily submits clinical trial 
results information, the responsible party must submit both the 
clinical trial registration information specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) and the clinical trial results information specified 
in Sec.  11.48.
    (ii) If, on or after September 27, 2007, a manufacturer submits an 
application or premarket notification to FDA for approval, licensure, 
or clearance of a drug product (including a biological product) or 
device product under section 505, 510(k), 515, or 520(m) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or 
section 351 of the Public Health Service Act (42 U.S.C. 262) for the 
use studied in the clinical trial submitted under paragraph (b)(1) of 
this section, the responsible party specified in paragraph (b)(1) of 
this section must also submit the information specified in paragraph 
(b)(2)(iii) of this section by the deadline specified in paragraph 
(b)(2)(iv)(B) of this section for any applicable clinical trial that 
has not been submitted to ClinicalTrials.gov and that meets the 
following criteria:
    (A) The applicable clinical trial is required to be submitted to 
FDA under section 505, 510(k), 515, or 520(m) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e,

[[Page 65153]]

360j(m)) or section 351 of the Public Health Service Act (42 U.S.C. 
262) in an application or premarket notification for approval, 
licensure, or clearance to market the drug product (including a 
biological product) or device product for the use studied in the 
clinical trial specified in paragraph (b)(1) of this section; and
    (B) The manufacturer of the drug product (including a biological 
product) or device product studied in the applicable clinical trial is 
also the responsible party for the clinical trial specified in 
paragraph (b)(1) of this section.
    (iii) Information to be submitted for clinical trials described in 
paragraph (b)(2)(ii) of this section:
    (A) If the clinical trial information voluntarily submitted for a 
clinical trial described in paragraph (b)(1) of this section consists 
only of the clinical trial registration information specified in 
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)), the information to be submitted in accordance with 
paragraph (b)(2)(ii) of this section must consist, at minimum, of the 
clinical trial registration information specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)).
    (B) If the clinical trial information voluntarily submitted for a 
clinical trial described by paragraph (b)(1) of this section consists 
of the clinical trial results information specified in Sec.  
11.60(b)(2)(i)(B), the information to be submitted in accordance with 
paragraph (b)(2)(ii) of this section must consist of the clinical trial 
results information specified in Sec.  11.60(b)(2)(i)(B).
    (C) If the clinical trial information voluntarily submitted for a 
clinical trial described by paragraph (b)(1) of this section consists 
of both the clinical trial registration information specified in 
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) and the clinical trial results information specified 
in Sec.  11.48, the information to be submitted in accordance with 
paragraph (b)(2)(ii) of this section must consist of both the clinical 
trial registration information specified in section 402(j)(2)(A)(ii) of 
the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) and the 
clinical trial results information specified in Sec.  11.48.
    (iv) Submission deadlines:
    (A) Secondary outcome measure(s) and adverse event information for 
voluntarily submitted clinical trials, under paragraph (b) of this 
section:
    (1) If data collection for secondary outcome measure(s) for a 
voluntarily submitted clinical trial under paragraph (b) of this 
section is not completed by the primary completion date of the 
voluntarily submitted clinical trial, clinical trial results 
information for the secondary outcome measure(s) required in Sec.  
11.48(a)(3) must be submitted by the later of the date that the 
clinical trial results information is voluntarily submitted for the 
primary outcome measure(s) or 1 year after the date on which the final 
subject was examined or received an intervention for the purposes of 
final collection of data for the secondary outcome(s), whether the 
clinical trial was concluded according to the pre-specified protocol or 
was terminated.
    (2) If data collection for adverse event information continues 
after the primary completion date of the voluntarily submitted clinical 
trial, any adverse event information collected after the primary 
completion date and subject to the submission requirements in Sec.  
11.48(a)(4) must be submitted by the later of the date that the 
clinical trial results information is voluntarily submitted for the 
primary outcome measure(s) or 1 year after the date of final collection 
of data for adverse event information, whether the clinical trial was 
concluded according to the pre-specified protocol or was terminated.
    (B) The clinical trial information specified in paragraph 
(b)(2)(iii) of this section must be submitted not later than the later 
of the date on which the application or premarket notification to FDA 
for approval, licensure, or clearance to market a drug product 
(including a biological product) or device product under section 351 of 
the Public Health Service Act (42 U.S.C. 262) or section 505, 510(k), 
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
355, 360(k), 360e, 360j(m)) for the use studied in the clinical trial 
specified under paragraph (b)(1) of this section is submitted to FDA or 
the date on which the clinical trial information specified in paragraph 
(b)(2)(i) of this section for the clinical trial specified under 
paragraph (b)(1) of this section is submitted to ClinicalTrials.gov.
    (c) If a responsible party voluntarily submits clinical trial 
information for a clinical trial described in paragraph (c)(1) of this 
section, the responsible party must meet the conditions specified in 
paragraph (c)(2) of this section.
    (1) The requirements of paragraph (c) of this section apply to a 
clinical trial that was initiated on or after January 18, 2017 and has 
a primary completion date on or after January 18, 2017, and that is 
either:
    (i) A clinical trial of an FDA-regulated drug product (including a 
biological product) or device product that is not an applicable 
clinical trial; or
    (ii) An applicable clinical trial that is not otherwise required to 
submit clinical trial registration information.
    (2) If the responsible party for a clinical trial described in 
paragraph (c)(1) of this section voluntarily submits clinical trial 
registration information and/or clinical trial results information, the 
responsible party must comply with the following requirements:
    (i) The responsible party must submit the information in paragraph 
(c)(2)(i)(A), (B), or (C) of this section for the clinical trial being 
submitted voluntarily.
    (A) If the responsible party voluntarily registers a clinical 
trial, the responsible party must submit the clinical trial 
registration information specified in Sec.  11.28(a).
    (B) If the responsible party voluntarily submits clinical trial 
results information for a clinical trial for which the clinical trial 
registration information specified in Sec.  11.28(a) has not been 
submitted, the responsible party must submit the data elements 
specified in paragraph (b)(2)(i)(B) of this section.
    (C) If the responsible party both voluntarily submits clinical 
trial registration information and voluntarily submits clinical trial 
results information, the responsible party must submit both the 
clinical trial registration information specified in Sec.  11.28(a) and 
the clinical trial results information specified in Sec.  11.48.
    (ii) If, on or after September 27, 2007, a manufacturer submits an 
application or premarket notification to FDA for approval, licensure, 
or clearance of a drug product (including a biological product) or 
device product under section 505, 510(k), 515, or 520(m) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or 
section 351 of the Public Health Service Act (42 U.S.C. 262) for the 
use studied in the clinical trial submitted under paragraph (c)(1) of 
this section, the responsible party specified in paragraph (c)(1) of 
this section must also submit the information specified in paragraph 
(c)(2)(iii) of this section by the deadline specified in paragraph 
(c)(2)(iv)(B) of this section for any applicable clinical trial that 
has not been submitted to ClinicalTrials.gov and that meets the 
following criteria:
    (A) The applicable clinical trial is required to be submitted to 
FDA under section 505, 510(k), 515, or 520(m) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or 
section 351 of the Public Health Service Act (42 U.S.C. 262) in an

[[Page 65154]]

application or premarket notification for approval, licensure, or 
clearance to market the drug product (including a biological product) 
or device product for the use studied in the clinical trial specified 
in paragraph (c)(1) of this section; and
    (B) The manufacturer of the drug product (including a biological 
product) or device product studied in the applicable clinical trial is 
also the responsible party for the clinical trial specified in 
paragraph (c)(1) of this section.
    (iii) Information to be submitted for clinical trials described in 
paragraph (c)(2)(ii) of this section:
    (A) If the clinical trial information voluntarily submitted for a 
clinical trial described in paragraph (c)(1) of this section consists 
only of the clinical trial registration information specified in Sec.  
11.28(a), the information to be submitted in accordance with paragraph 
(c)(2)(ii) of this section must consist, at minimum, of the clinical 
trial registration information specified in Sec.  11.28(a).
    (B) If the clinical trial information voluntarily submitted for a 
clinical trial described by paragraph (c)(1) of this section consists 
of the clinical trial results information specified in Sec.  
11.60(c)(2)(i)(B), the information to be submitted in accordance with 
paragraph (c)(2)(ii) of this section must consist of the clinical trial 
results information specified in Sec.  11.60(c)(2)(i)(B).
    (C) If the clinical trial information voluntarily submitted for a 
clinical trial described by paragraph (c)(1) of this section consists 
of both the clinical trial registration information specified in Sec.  
11.28(a) and the clinical trial results information specified in Sec.  
11.48, the information to be submitted in accordance with paragraph 
(c)(2)(ii) of this section must consist of both the clinical trial 
registration information specified in Sec.  11.28(a) and the clinical 
trial results information specified in Sec.  11.48.
    (iv) Submission deadlines:
    (A) Secondary outcome measure(s) and adverse event information for 
voluntarily-submitted clinical trials, under paragraph (c) of this 
section:
    (1) If data collection for secondary outcome measure(s) for a 
voluntarily submitted clinical trial under paragraph (c) of this 
section is not completed by the primary completion date of the 
voluntarily submitted clinical trial, clinical trial results 
information for the secondary outcome measure(s) required in Sec.  
11.48(a)(3) must be submitted by the later of the date that the 
clinical trial results information is voluntarily submitted for the 
primary outcome measure(s) or 1 year after the date on which the final 
subject was examined or received an intervention for the purposes of 
final collection of data for the secondary outcome(s), whether the 
clinical trial was concluded according to the pre-specified protocol or 
was terminated.
    (2) If data collection for adverse event information continues 
after the primary completion date of the voluntarily submitted clinical 
trial, any adverse event information collected after the primary 
completion date and subject to the submission requirements in Sec.  
11.48(a)(4) must be submitted by the later of the date that the 
clinical trial results information is voluntarily submitted for the 
primary outcome measure(s) or 1 year after the date of final collection 
of data for adverse events information, whether the clinical trial was 
concluded according to the pre-specified protocol or was terminated.
    (B) The clinical trial information specified in paragraph 
(c)(2)(iii) of this section must be submitted not later than the later 
of the date on which the application or premarket notification to FDA 
for approval, licensure, or clearance to market a drug product 
(including a biological product) or device product under section 351 of 
the Public Health Service Act (42 U.S.C. 262) or section 505, 510(k), 
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
355, 360(k), 360e, 360j(m)) for the use studied in the clinical trial 
specified under paragraph (c)(1) of this section is submitted to FDA or 
the date on which the clinical trial information specified in paragraph 
(c)(2)(i) of this section for the clinical trial specified under 
paragraph (c)(1) of this section is submitted to ClinicalTrials.gov.
    (v) All submissions of clinical trial information under paragraph 
(c) of this section are subject to the applicable update and 
corrections requirements specified in Sec.  11.64.
    (d) Statement to accompany applicable clinical trials submitted 
under paragraphs (a), (b), and (c) of this section. Each applicable 
clinical trial for which clinical trial information is submitted under 
paragraphs (a), (b), and (c) of this section and posted on 
ClinicalTrials.gov will include the statement ``This clinical trial 
information was submitted voluntarily under the applicable law and, 
therefore, certain submission deadlines may not apply. (That is, 
clinical trial information for this applicable clinical trial was 
submitted under section 402(j)(4)(A) of the Public Health Service Act 
and 42 CFR 11.60 and is not subject to the deadlines established by 
sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 
11.24 and 11.44.)''


Sec.  11.62  What requirements apply to applicable clinical trials for 
which submission of clinical trial information has been determined by 
the Director to be necessary to protect the public health?

    (a) A responsible party who receives notification that the Director 
has determined that posting of clinical trial information for an 
applicable clinical trial described in paragraph (b) of this section is 
necessary to protect the public health must submit clinical trial 
information as specified in paragraph (c) of this section.
    (b) An applicable clinical trial subject to this section must be 
either:
    (1) An applicable clinical trial of an approved, licensed, or 
cleared drug product (including a biological product) or device product 
that has a primary completion date on or after September 27, 1997; or
    (2) An applicable clinical trial that is subject to registration 
under Sec.  11.22(a) and studies a drug product (including a biological 
product) or device product that is unapproved, unlicensed, or 
uncleared, regardless of whether approval, licensure, or clearance was, 
is, or will be sought, and that is not otherwise subject to results 
information submission in accordance with the regulation.
    (c) Deadline for submission of clinical trial information:
    (1) General. Except as provided in paragraphs (c)(2) and (c)(3) of 
this section, a responsible party for an applicable clinical trial that 
is subject to this section must submit the clinical trial registration 
information specified in Sec.  11.28(a) and the clinical trial results 
information specified in Sec.  11.48(a) not later than 30 calendar days 
after the submission date specified in the notification described in 
paragraph (a) of this section.
    (2) Exception. If a responsible party submits a certification 
consistent with Sec.  11.44(b) or (c) not later than 30 calendar days 
after the submission date specified in the notification described in 
paragraph (a) of this section, the responsible party must submit the 
clinical trial results information specified in Sec.  11.48(a) not 
later than the deadline specified in Sec.  11.44(b) or (c), as 
applicable.
    (3) If a responsible party submitted clinical trial registration 
information describing the applicable clinical trial specified in the 
notification described in paragraph (a) of this section prior to the 
date on which the notification is sent to

[[Page 65155]]

the responsible party, the responsible party must update such clinical 
trial information to reflect changes, if any, in the applicable 
clinical trial not later than 30 calendar days after the submission 
date specified in the notification described in paragraph (a) of this 
section, irrespective of the deadline for updates specified in Sec.  
11.64.


Sec.  11.64  When must clinical trial information submitted to 
ClinicalTrials.gov be updated or corrected?

    (a) Updates. (1) Clinical trial registration information:
    (i) The responsible party for an applicable clinical trial for 
which clinical trial registration information was required to be 
submitted if the clinical trial was initiated before January 18, 2017, 
must submit updates in accordance with the following:
    (A) In general, changes to the clinical trial registration 
information specified in section 402(j)(2)(A)(ii) of the Public Health 
Service Act (42 U.S.C. 282(j)(2)(A)(ii)) that was required at the time 
of submission must be updated not less than once every 12 months.
    (B) Overall Recruitment Status must be updated not later than 30 
calendar days after any change in overall recruitment status.
    (C) Primary Completion Date must be updated not later than 30 
calendar days after the clinical trial reaches its actual primary 
completion date.
    (ii) The responsible party for an applicable clinical trial, or for 
another clinical trial for which registration information was 
voluntarily submitted pursuant to Sec.  11.60(c), if the clinical trial 
was initiated on or after January 18, 2017, must submit updates in 
accordance with the following:
    (A) In general, changes to clinical trial registration information 
specified in Sec.  11.28 must be updated not less than once every 12 
months.
    (B) If the first human subject was not enrolled in the clinical 
trial at the time of registration, the Study Start Date data element 
must be updated not later than 30 calendar days after the first human 
subject is enrolled.
    (C) Intervention Name(s) must be updated to a non-proprietary name 
not later than 30 calendar days after a non-proprietary name is 
established for any intervention included in the Intervention Name(s) 
data element.
    (D) Availability of expanded access:
    (1) If expanded access to an investigational drug product 
(including a biological product) becomes available after an applicable 
clinical trial of that product has been registered, the responsible 
party, if both the manufacturer of the investigational drug product 
(including a biological product) and the sponsor of the applicable 
clinical trial, must, not later than 30 calendar days after expanded 
access becomes available, update the Availability of Expanded Access 
data element for that applicable clinical trial and, unless an expanded 
access record has already been created as required by Sec.  
11.28(a)(2)(ii)(H), submit the data elements in accordance with Sec.  
11.28(c) to create an expanded access record.
    (2) No later than 30 calendar days after the date on which the 
responsible party receives an NCT number for an expanded access record 
created as required by Sec.  11.28(a)(2)(ii)(H), the responsible party 
must update the Availability of Expanded Access data element by 
entering the NCT number in the clinical trial record for the applicable 
clinical trial.
    (E) Expanded access record:
    (1) Expanded Access Status, under Sec.  11.28(c)(2)(iv), must be 
updated not later than 30 calendar days after a change in the 
availability of expanded access to an investigational drug product 
(including a biological product) under section 561 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 360bbb).
    (2) Expanded Access Type, under Sec.  11.28(c)(1)(x), must be 
updated not later than 30 calendar days after a change in the type(s) 
of expanded access available for an investigational drug product 
(including a biological product) under section 561 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 360bbb).
    (F) Overall Recruitment Status must be updated not later than 30 
calendar days after any change in overall recruitment status. If, at 
any time, Overall Recruitment Status is changed to ``suspended,'' 
``terminated,'' or ``withdrawn,'' the responsible party must also 
submit the Why Study Stopped data element.
    (G) Individual Site Status must be updated not later than 30 
calendar days after a change in status for any individual site.
    (H) Human Subjects Protection Review Board Status must be updated 
not later than 30 calendar days after a change in status.
    (I) Primary Completion Date must be updated not later than 30 
calendar days after the clinical trial reaches its actual primary 
completion date. At the time, the date is changed to ``actual,'' and 
the Enrollment data element specifying the actual number of 
participants enrolled must be submitted.
    (J) Study Completion Date must be updated not later than 30 
calendar days after the clinical trial reaches its actual study 
completion date.
    (K) Responsible Party, by Official Title must be updated not later 
than 30 calendar days after a change in the responsible party or the 
official title of the responsible party.
    (L) Responsible Party Contact Information must be updated not later 
than 30 calendar days after a change in the responsible party or the 
contact information for the responsible party.
    (M) Device Product Not Approved or Cleared by U.S. FDA must be 
updated not later than 15 calendar days after a change in approval or 
clearance status has occurred.
    (N) Record Verification Date must be updated any time the 
responsible party reviews the complete set of submitted clinical trial 
information for accuracy and not less than every 12 months, even if no 
other updated information is submitted at that time.
    (O) If a protocol is amended in such a manner that changes are 
communicated to human subjects in the clinical trial, updates to any 
relevant clinical trial registration information data elements must be 
submitted not later than 30 calendar days after the protocol amendment 
is approved by a human subjects protection review board.
    (iii) In addition to the update requirements established in 
paragraphs (a)(1)(i) and (a)(1)(ii) of this section, clinical trial 
registration information must be updated at the time that clinical 
trial results information for that clinical trial is initially 
submitted.
    (A) If the clinical trial was initiated before January 18, 2017, a 
responsible party must submit updates to the clinical trial 
registration information described in Sec.  11.64(a)(1)(i).
    (B) If the clinical trial was initiated on or after January 18, 
2017, the responsible party must submit updates to the clinical trial 
registration information in accordance with Sec.  11.64(a)(1)(ii).
    (2) Clinical trial results information. The responsible party for 
an applicable clinical trial, or for another clinical trial for which 
results information was voluntarily submitted pursuant to Sec.  
11.60(b) or (c), where the clinical trial has a Primary Completion Date 
on or after January 18, 2017, must submit updates in accordance with 
the following:
    (i) In general, changes to required clinical trial results 
information, other than the protocol and statistical analysis plan 
specified in Sec.  11.48(a)(5) and certain agreements specified in 
Sec.  11.48(a)(6)(ii),must be updated not less than once every 12 
months.

[[Page 65156]]

    (ii) For applicable device clinical trials of unapproved or 
uncleared device products, the responsible party must update the 
following data elements, as defined in Sec.  11.10(b), in accordance 
with the following:
    (A) Intervention Name(s) must be updated to a non-proprietary name 
not later than 30 calendar days after a non-proprietary name is 
established for any intervention included in the Intervention Name(s) 
data element.
    (B) Primary Completion Date must be updated not later than 30 
calendar days after the clinical trial reaches its actual primary 
completion date. At the time the date is changed to ``actual,'' the 
Enrollment data element specifying the actual number of participants 
enrolled must be submitted.
    (C) Study Completion Date must be updated not later than 30 
calendar days after the clinical trial reaches its actual study 
completion date.
    (D) Overall Recruitment Status must be updated not later than 30 
calendar days after any change in overall recruitment status. If, at 
any time, Overall Recruitment Status is changed to ``suspended,'' 
``terminated,'' or ``withdrawn,'' the responsible party must also 
submit the Why Study Stopped data element.
    (E) Record Verification Date must be updated any time the 
responsible party reviews the complete set of submitted clinical trial 
information for accuracy and not less than every 12 months, even if no 
other updated information is submitted at that time.
    (3) A responsible party's obligation to submit updates as specified 
in this section ends on the date on which all required clinical trial 
results information has been submitted as specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 
U.S.C. 282(j)(3)(C)) and 42 U.S.C. 282(j)(3)(I)) or as specified in 
Sec.  11.48, as applicable, and corrections have been made or addressed 
in response to any electronic notice received under Sec.  11.64(b)(1). 
If no clinical trial results information is required to be submitted, a 
responsible party's obligation to submit updates to clinical trial 
registration information ends on the date on which all required 
clinical trial registration information has been submitted as specified 
in section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii) or Sec.  11.28, as applicable, and corrections have 
been made or addressed in response to any electronic notice received 
under Sec.  11.64(b)(1).
    (4) Public availability of updates. (i) Updates to clinical trial 
registration information and clinical trial results information will be 
posted in accordance with Sec.  11.35 and Sec.  11.52, respectively.
    (ii) The Director will retain prior clinical trial registration 
information and clinical trial results information and make it publicly 
available in accordance with Sec.  11.35 and Sec.  11.52, respectively, 
through ClinicalTrials.gov so that updates do not result in the removal 
of any information from the original submission or any preceding 
update.
    (b) Corrections--(1) Quality control. After clinical trial 
registration information has been submitted as specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) or Sec.  11.28, as applicable, or clinical trial 
results information has been submitted as specified in sections 
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or Sec.  11.48, as 
applicable, including the updates specified in paragraph (a) of this 
section, the Director may provide electronic notification to the 
responsible party of apparent errors, deficiencies, and/or 
inconsistencies in the submitted information identified during 
procedures for quality control review established by the Director, as 
specified at https://prsinfo.clinicaltrials.gov. The responsible party 
must correct or address all apparent errors, deficiencies, and/or 
inconsistencies identified in the notification not later than 15 
calendar days for clinical trial registration information, or 25 
calendar days for clinical trial results information, after the date of 
the electronic notification sent to the responsible party.
    (2) Other corrections. (i) A responsible party who becomes aware of 
errors, other than those specified in paragraph (b)(1) of this section, 
in any clinical trial information submitted under this part shall have 
not more than 15 calendar days for clinical trial registration 
information, or 25 calendar days for clinical trial results 
information, to correct or address such errors.
    (ii) A responsible party's obligation to correct or address errors 
as specified in paragraph (b)(2) of this section ends on the date on 
which all required clinical trial results information has been 
submitted as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the 
Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 
282(j)(3)(I)) or Sec.  11.48, as applicable, and corrections have been 
made or addressed in response to any electronic notice received under 
Sec.  11.64(b)(1). If no clinical trial results information is required 
to be submitted, a responsible party's obligation to correct or address 
errors ends on the date on which all required clinical trial 
registration information has been submitted as specified in section 
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 
282(j)(2)(A)(ii)) or Sec.  11.28, as applicable, and corrections have 
been made or addressed in response to any electronic notice received 
under Sec.  11.64(b)(1).
    (3) Compliance with the quality control review process, including 
the requirements of this section, does not constitute a legal defense 
to enforcement pursuant to section 301(jj) of the Federal Food, Drug 
and Cosmetic Act (21 U.S.C. 331(jj)), section 303(f)(3) of the Federal 
Food, Drug and Cosmetic Act (21 U.S.C. 333(f)(3)), or any other Federal 
law.

Subpart E--Potential Legal Consequences of Non-compliance


Sec.  11.66  What are potential legal consequences of not complying 
with the requirements of this part?

    (a) Civil or criminal judicial actions. Failure to comply with the 
requirements of this part, issued under section 402(j) of the Public 
Health Service Act (42 U.S.C. 282(j)), is a prohibited act under one or 
more provisions of section 301(jj) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 331(jj)):
    (1) Failure to submit the certification required by section 
402(j)(5)(B) of the Public Health Service (42 U.S.C. 282(j)(5)(B)) that 
all applicable requirements of section 402(j) have been met, or 
knowingly submitting a false certification under section 402(j)(5)(B), 
is a prohibited act under section 301(jj)(1) of the Federal Food, Drug, 
and Cosmetic Act.
    (2) Failure to submit clinical trial information required under 
section 402(j) of the Public Health Service Act is a prohibited act 
under section 301(jj)(2) of the Federal Food, Drug, and Cosmetic Act.
    (3) Submission of clinical trial information under section 402(j) 
that is false or misleading in any particular is a prohibited act under 
section 301(jj)(3) of the Federal Food, Drug, and Cosmetic Act.
    (b) Civil monetary penalty actions. Any person who violates section 
301(jj) of the Federal Food, Drug, and Cosmetic Act is subject to civil 
monetary penalties under section 303(f)(3) of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 333(f)(3)).
    (c) Grant funding actions. Under section 402(j)(5)(A) of the Public 
Health Service Act (42 U.S.C. 282(j)(5)(A)), if an applicable clinical 
trial is funded in whole or part by the Department of Health and Human 
Services, any required grant or progress report forms

[[Page 65157]]

must include a certification that the responsible party has made all 
required registration and results submissions. If it is not verified 
that the required registration and results clinical trial information 
for each applicable clinical trial for which a grantee is the 
responsible party has been submitted, any remaining funding for a grant 
or funding for a future grant to such grantee will not be released. If 
the head of an HHS agency verifies that a grantee has not submitted 
such required clinical trial information, the agency head will provide 
notice to the grantee of the non-compliance and allow the grantee 30 
days to correct the non-compliance and submit the required clinical 
trial information.

    Dated: September 8, 2016.
Francis S. Collins,
Director, National Institutes of Health.
    Approved: Dated: September 9, 2016.
Sylvia Mathews Burwell,
Secretary.
[FR Doc. 2016-22129 Filed 9-16-16; 11:15 am]
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