[Federal Register Volume 79, Number 225 (Friday, November 21, 2014)]
[Proposed Rules]
[Pages 69566-69680]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-26197]



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Vol. 79

Friday,

No. 225

November 21, 2014

Part II





Department of Health and Human Services





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42 CFR Part 11





Clinical Trials Registration and Results Submission; Proposed Rule

  Federal Register / Vol. 79 , No. 225 / Friday, November 21, 2014 / 
Proposed Rules  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

42 CFR Part 11

[Docket Number NIH-2011-0003]
RIN 0925-AA52


Clinical Trials Registration and Results Submission

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

ACTION: Notice of Proposed Rulemaking.

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SUMMARY: This Notice of Proposed Rulemaking proposes requirements for 
submitting registration and summary results information, including 
adverse event information, for specified clinical trials of drugs 
(including biological products) and devices and for pediatric 
postmarket surveillances of a device to ClinicalTrials.gov, the 
clinical trial registry and results data bank operated by the National 
Library of Medicine (NLM). This proposed 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 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. 
The proposed requirements would apply to the responsible party (meaning 
the sponsor or designated principal investigator) for certain clinical 
trials of drugs (including biological products) and devices that are 
regulated by the Food and Drug Administration (FDA) and for pediatric 
postmarket surveillances of a device that are ordered by FDA.

DATES: Comments are due on or before February 19, 2015.

ADDRESSES: Individuals and organizations interested in submitting 
comments, identified by RIN 0925-AA52 and Docket Number NIH-2011-0003, 
may do so by any of the following methods:
     Electronic Submissions: Use Federal eRulemaking Portal: 
http://www.regulations.gov. Follow the instructions for submitting 
comments. To ensure timelier processing of comments, NIH is no longer 
accepting comments submitted directly to it by email. The NIH 
encourages you to continue to submit electronic comments by using the 
Federal eRulemaking Portal: http://www.regulations.gov.
     Written Submissions: You may submit written submissions by 
Fax at 301-402-0169, or by Mail/Hand Delivery/Courier (For paper, disk, 
or CD-ROM submissions) to: Jerry Moore, NIH Regulations Officer, Office 
of Management Assessment, 6011 Executive Boulevard, Suite 601, MSC 
7669, Rockville, MD 20852-7669.
    Instructions: We welcome comments from the public on all issues set 
forth in this proposed rule, and on specific issues identified in the 
document. All submissions received must include the agency name, the 
Docket No., and Regulatory Information Number (RIN) for this 
rulemaking. All comments received at http://www.regulations.gov may be 
posted without change, including any personal information provided. The 
http://www.regulations.gov Web site is an ``anonymous access'' system, 
which means NIH will not know your identity or contact information 
unless you provide it in the body of your comment.
    You can assist us in considering your comment by referencing the 
number assigned to each key issue discussed in section III.C of this 
preamble or the number of the section of this proposed rule to which 
your comment relates.
    For access to background documents or comments received, go to 
http://www.regulations.gov and insert the docket number found in the 
brackets in the heading of this document into the ``Search'' box and 
follow the prompts.

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: Jerry Sheehan, Assistant Director for Policy 
Development, National Library of Medicine, National Institutes of 
Health, Department of Health and Human Services, telephone (301-496-
6221) (not a toll-free number), Fax (301-402-2586), or by email at 
[email protected].

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of This Regulatory Action

    This proposed 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 U.S.C. 282(j)), which were added by FDAAA to 
improve public access to information about certain clinical trials of 
FDA-regulated drugs, biological products, and devices and certain 
pediatric postmarket surveillances of a device. Under section 402(j) of 
the PHS Act, those responsible for specified clinical trials of 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 since 
September 27, 2008, and adverse events information since September 27, 
2009. Section 402(j) of the PHS Act requires the Secretary of Health 
and Human Services (HHS) to use rulemaking to expand the requirements 
for submission of summary results information, and authorizes the 
Secretary to use rulemaking to make other changes in the requirements 
for submission of registration and results information.
    This proposed 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. No patient-specific data are required 
to be submitted by this proposed rule or by the law this proposed rule 
is intended to implement.

Summary of the Major Provisions of the Regulatory Action

Applicable Clinical Trial
    This proposed rule specifies which clinical trials of FDA-regulated 
drugs, biological products, and devices and which pediatric postmarket 
surveillances of a device, are applicable clinical trials for which 
information must be submitted to ClinicalTrials.gov. This proposal 
specifies an approach for determining whether a particular clinical 
trial or study is an applicable clinical trial, based on descriptive 
information that would be submitted at the time of registration.

Responsible Party

    This proposed rule specifies that there must be one (and only one) 
responsible party for submitting information about an applicable 
clinical trial. The sponsor of an applicable clinical trial would be 
considered the responsible party, unless and until the sponsor 
designates a qualified principal investigator as the responsible party. 
This proposed rule specifies the approach for determining who would 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 
requirement to

[[Page 69567]]

submit information to ClinicalTrials.gov.

Registration

    This proposed rule specifies requirements for registering 
applicable clinical trials at ClinicalTrials.gov. It would require that 
the responsible party register an applicable clinical trial not later 
than 21 days after enrolling the first participant, and it specifies 
the data elements of clinical trial information that must be submitted 
at the time of registration. The proposed 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 data elements that are proposed 
under the Secretary's authority to modify the requirements for clinical 
trial information due at registration as long as such modifications 
improve, and do not reduce, the clinical trial information available to 
the public in ClinicalTrials.gov. We consider the proposed additional 
data elements necessary to enable the Agency 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 unambiguous. Some of these additional data elements were 
included in ClinicalTrials.gov before FDAAA was enacted.

Expanded Access Information

    Section 402(j) of the PHS Act requires the submission of 
information on how to obtain expanded access to investigational drugs 
used in applicable clinical trials, if the drugs are available through 
expanded access programs to patients who are not participating in 
relevant clinical trials. For an applicable clinical trial of a drug 
that is available under expanded access, this proposed rule would 
require the submission of a separate expanded access record containing 
details about how to obtain access to the investigational drug. If an 
expanded access record has already been submitted in conjunction with a 
different clinical trial of that same drug, the responsible party for 
the new clinical trial could link to the existing expanded access 
record rather than create a new one.

Results Submission

    This proposed rule implements the statutory requirement for the 
submission of summary results information for applicable clinical 
trials of drugs, biological products, and devices that are approved, 
licensed, or cleared by FDA. It also proposes to extend the requirement 
for results submission to applicable clinical trials of drugs, 
biological products, and devices that are not approved, licensed, or 
cleared by FDA. This proposed rule would require the submission of 
tables of data summarizing demographics and baseline characteristics of 
the enrolled participants and primary and secondary outcomes, including 
results of any scientifically appropriate statistical tests.
    In general, this proposed rule would require the submission of 
results not later than 1 year after the completion date of the clinical 
trial, which is defined as the date of final data collection for the 
primary outcome measure studied. Results submission could be delayed 
for up to 2 additional years with 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 for a new use of an approved, licensed, or cleared product that 
is being studied in the trial. This proposed rule also permits 
responsible parties to request extensions to the results submission 
deadlines for ``good cause''.

Adverse Events

    This proposed rule would require the responsible party to submit 
information summarizing the number and frequency of adverse events 
experienced by participants enrolled in a clinical trial, by arm and 
organ system. It would require submission of two tables of information: 
one summarizing all serious adverse events; and another summarizing 
other adverse events that occurred with a frequency of 5 percent or 
more in any arm of the clinical trial, regardless of whether such 
adverse events were anticipated or unanticipated.

Updates and Other Required Information

    This proposed rule would require that all submitted information 
must be updated at least annually if there are changes to report. More 
rapid updating would be 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 a clinical trial. This 
proposed rule also requires timely corrections to any errors discovered 
by the responsible party or the Agency during review of submissions.

Costs and Benefits

    Based on our cost estimates, this regulatory action 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., protocol information and clinical 
trial results). The benefits include greater public access to 
information about and evidence from applicable clinical trials (and 
other clinical trials) of FDA-regulated drugs, biological products, and 
devices, and greater clarity about what is required for those who are 
subject to the legal mandate to submit information to 
ClinicalTrials.gov.

Acronyms

AHRQ Agency for Healthcare Research and Quality
BLA Biologics License Application
CBER Center for Biologics Evaluation and Research, FDA
CDC Centers for Disease Control and Prevention
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
EMA European Medicines Agency
EU European Union
FAQ Frequently Asked Questions
FDA Food and Drug Administration
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
GCP Good Clinical Practices
HHS Department of Health and Human Services
ICH International Conference on Harmonisation of Technical 
Requirements of Pharmaceuticals for Human Use
ICMJE International Committee of Medical Journal Editors
ICTRP International Clinical Trials Registry Platform, WHO
IDE Investigational Device Exemption
IFPMA International Federation of Pharmaceutical Manufacturers and 
Associations
IND Investigational New Drug Application
IRB Institutional Review Board
IVD In Vitro Diagnostic
LPLV Last Patient Last Visit
MEDLINE[supreg] Medical Literature Analysis and Retrieval System 
Online
MedDRA Medical Dictionary for Regulatory Affairs
MeSH[supreg] Medical Subject Headings
MSSO Maintenance and Support Services Organization

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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
OMB Office of Management and Budget
OTC Over-the-Counter
PDF Portable Document Format
PhRMA Pharmaceutical Research and Manufacturers of America
PHS Public Health Service
PI Principal Investigator
PRS Protocol Registration System
R&D Research and Development
RFA Request for Applications
RIA Regulatory Impact Analysis
RIN Regulatory Information Number
SAP Statistical Analysis Plan
SNOMED CT[supreg] Systematized Nomenclature of Medicine--Clinical 
Terms[supreg]
SPIRIT Standard Protocol Items for Randomized Trials
U.S.C. United States Code
WHO World Health Organization
XML Extensible Markup Language

Table of Contents

I. Overview of Statutory Provisions
II. Background
    A. Clinical Trials Reporting Prior to Passage of FDAAA
    B. Implementation of Statutory Provisions Prior to Rulemaking
III. Overview of Proposed Rule
    A. Structure of Proposed Rule
    B. General Considerations in the Rulemaking
    C. Key Issues Considered in This Proposed Rule
    1. Elaboration of Statutory Definitions
    2. Modifications and Additions to the Elements of Clinical Trial 
Registration Information
    3. Posting of Registration Information for Applicable Device 
Clinical Trials
    4. Application of Rule to a Pediatric Postmarket Surveillance of 
a Device That Is Not a Clinical Trial
    5. Submission of Results Information for Applicable Clinical 
Trials of Unapproved, Unlicensed, or Uncleared Products
    6. Submission of Non-Technical and Technical Summaries of Trial 
Results
    7. Submission of the Full Protocol
    8. Increasing the Time Period for Submitting Results Information
    9. Retroactive Submission of Additional Results Information
    10. Standard Data Formats
    11. Additional Information to Improve Patient Understanding of 
Submitted Information
    12. Quality Control Procedures
    13. Updating Submitted Clinical Trial Information
    14. Statement To Accompany Certain Trials and Other Issues 
Related to Voluntary Submissions
    15. Adverse Event Information
    16. Privacy Considerations
    D. Effective Date/Compliance Date
    1. Effective Date
    2. Compliance Date
    3. Registration Information
    4. Results Information
    5. Voluntary Submissions
    6. Updates and Corrections to Clinical Trial Information
IV. Detailed Description of This Proposed Rule
    A. General Provisions--Subpart A
    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 form and manner must clinical trial information be 
submitted?--Sec.  11.8
    5. What definitions apply to this part?--Sec.  11.10
    B. Registration--Subpart B
    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 NIH post clinical trial registration information 
submitted under Sec.  11.28?--Sec.  11.35
    C. Results Submission--Subpart C
    1. Who must submit clinical trials results information?--Sec.  
11.40
    2. For which applicable clinical trials must clinical trial 
results information be submitted?--Sec.  11.42
    3. When must 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. When will NIH post submitted clinical trials results 
information?--Sec.  11.52
    6. Under what circumstances will the Secretary grant a waiver of 
the requirements of this subpart?--Sec.  11.54
    D. Additional Submissions of Clinical Trial Information--Subpart 
D
    1. What requirements apply to voluntary submission clinical 
trial information for clinical trials of FDA-regulated drugs and 
devices?--Sec.  11.60
    2. 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?--Sec.  
11.62
    3. When must information submitted to ClinicalTrials.gov be 
updated?--Sec.  11.64
    4. What are the requirements for corrections of clinical trial 
information?--Sec.  11.66
V. Response to Comments
VI. Regulatory Impact Statement
    A. The Proposed Rule
    B. Need for the Proposed Rule
    C. Benefits of the Proposed Rule
    D. Costs Associated With the Proposed Rule
    1. Registration of Applicable Clinical Trials
    2. Results Submission
    3. Delayed Submission of Results via Certification or Extension 
Request
    4. Triggered Submission of Clinical Trial Information Following 
a Voluntary Submission
    5. Expanded Access Records
    6. Non-Recurring Costs of Bringing Previously Submitted 
Registration Information Into Compliance With This Proposed Rule
    E. Alternatives to the Proposed Rule
    F. Regulatory Flexibility Act
    G. Unfunded Mandates Reform Act of 1995
    H. Federalism
VII. Paperwork Reduction Act of 1995
VIII. Congressional Review Act
IX. Legal Authority
X. References
XI. Codified

I. Overview of Statutory Provisions

    This proposed rule would establish procedures and requirements for 
registering and submitting results information, including adverse event 
information, for certain clinical trials of drugs (including biological 
products) and devices and pediatric postmarket surveillances of a 
device necessary to implement section 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 (referred to 
hereinafter as ``section 402(j) of the PHS Act'').
    Title VIII of FDAAA, enacted on September 27, 2007, amends the PHS 
Act by directing the Secretary of HHS, acting through the Director of 
the National Institutes of Health (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 directed to expand the data bank 
to include registration information for a broader set of clinical 
trials than were required to register under a previous law, the Food 
and Drug Administration Modernization Act of 1997 (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. 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.

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    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. 
Note that we use the term ``product'' hereinafter in this preamble to 
refer to either a drug (including a biological product), a device, or 
both, as each is defined in proposed Sec.  11.10.
    Second, for each applicable clinical trial subject to FDAAA, 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 
(PI) that limits the ability of the PI to discuss or publish the 
results of an applicable clinical trial after it is completed.
    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 submission as proposed in this 
rule 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 the regulation imposing those 
requirements. (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 submission provisions of section 
402(j)(3)(C) of the PHS Act. (See section 402(j)(3)(D)(v)(VI) of the 
PHS Act.).
    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 
Regulations.Gov: http://www.regulations.gov/search/Regs/home.html#docketDetail?R=NIH-2009-0002. We carefully reviewed the 
comments received in developing the proposed provisions that address 
the considerations enumerated in section 402(j)(3)(D) of the PHS Act. 
Many of the comments helped inform development of this proposed rule. 
For purposes of this rulemaking, we prepared a memorandum summarizing 
these comments and the issues commented upon [Ref. 1].
    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 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 default 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 
default provisions required by sections 402(j)(3)(I)(ii) and (iii) of 
the PHS Act took effect on September 27, 2009. 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 submission under section 
402(j)(3)(C) of the PHS Act.
    Furthermore, section 402(j)(4)(A) of the PHS Act directs that the 
data bank accept ``voluntary submissions'' of complete registration or 
complete

[[Page 69570]]

results information for certain clinical trials for which such 
information would not otherwise required to be submitted, provided that 
the responsible party complies with requirements that could involve 
submission of information on additional clinical trials.
    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. This preamble and 
proposed rule address this topic and serve as the required guidance.
    Section 402(j)(5) of the PHS Act specifies certain procedures and 
penalties related to non-compliance. Among other things, it directs NIH 
to post public notices of noncompliance in the data bank; requires 
report forms under certain HHS grants to include a certification that 
required registration and results submission under section 402(j) of 
the PHS Act are complete; prohibits HHS from funding responsible 
parties who do not fulfill their obligations 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 conforming amendments to the FD&C Act, which 
make failure to comply with specified requirements of section 402(j) of 
the PHS Act a prohibited act 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(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 Public Health Service 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.''

II. Background

    There is ongoing public interest in the transparency of information 
concerning clinical trials. The collection and public availability of 
information about clinical trials and their results is seen by many as 
an important public health issue. Advocates have argued that a central 
resource of clinical trial information is a potentially valuable tool 
to track the existence and progress of clinical trials and communicate 
their results, both positive and negative, as well as to provide 
potential participants with broad access to information about clinical 
trials seeking participants.

A. Clinical Trials Registration Prior to Passage of FDAAA

    Registration of a limited set of clinical trials has been required 
by U.S. law since the U.S. Congress mandated the establishment of a 
clinical trial registry in 1997. Section 113 of FDAMA amended the PHS 
Act to require HHS, acting through NIH and in coordination with FDA and 
the Centers for Disease Control and Prevention (CDC), to establish, 
maintain, and operate a data bank of information on clinical trials 
testing the effectiveness of drugs for serious or life-threatening 
diseases and conditions, whether federally or privately funded, that 
are conducted under an Investigational New Drug application (IND). The 
statute required the data bank to include a description of the purpose 
of each drug, participant eligibility criteria, the location of the 
clinical trial sites, and a point of contact for those seeking to 
enroll in the clinical trial. The FDAMA requirements, which were 
modified slightly in 2002 by the Best Pharmaceuticals for Children Act 
(Pub. L. 107-109, 115 STAT 1408, 1420-21), are currently codified at 42 
U.S.C. 282(i).
    NLM, a part of NIH, developed the registry, known as 
ClinicalTrials.gov, in response to this mandate 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. ClinicalTrials.gov 
is an Internet-based data bank that informs the public about the 
conditions and interventions being investigated in clinical trials, 
eligibility criteria, the location of trial sites, and contact 
information. It also provides links to additional public information 
about disorders and interventions relevant to the research described.
    While FDAMA required the registration of only certain clinical 
trials conducted under an IND, ClinicalTrials.gov accepts submissions 
of information about a broader range of clinical studies, in keeping 
with the long-standing authorities and responsibilities of HHS, the 
NIH, and the NLM. The PHS Act expressly directs the Secretary of HHS to 
``collect and make available through publications and other appropriate 
means, information as to, and the practical application of,'' research 
concerning the treatment ``of physical and mental diseases and 
impairments of man.'' (See 42 U.S.C. 241(a).) The NLM is expressly 
required to support ``the dissemination and exchange of scientific and 
other information important to the progress of medicine and to the 
public health'' (See 42 U.S.C. 286(a).) Consequently, since its 
creation, ClinicalTrials.gov has accepted registration information on 
different types of clinical trials, including trials of drugs for other 
than serious or life-threatening diseases or conditions, trials of 
medical devices, surgical procedures, and behavioral interventions, and 
has also accepted registration of information on other types of 
clinical studies, such as observational studies. Prior to passage of 
FDAAA, ClinicalTrials.gov contained information on more than 45,000 
clinical studies.
    The clinical trial data elements and descriptions used in 
ClinicalTrials.gov prior to FDAAA [Ref. 2] were developed following 
public notice and comment on two guidance documents: (1) A final 
guidance issued by FDA in 2002 describing the information to be 
submitted to the ClinicalTrials.gov registry pursuant to the 
registration requirement set forth in section 113 of FDAMA [Ref. 3] 
(See 67 FR 12022, Mar.18, 2002.); and (2) a draft guidance issued by 
FDA in January 2004 [Ref. 4] (See 69 FR 3923, Jan. 27, 2004.), 
proposing revisions to the final guidance issued in 2002 to include 
information on additional submissions required pursuant to the Best 
Pharmaceuticals for Children Act (Pub. L. 107-109, 115 STAT 1408, 1420-
21). This draft guidance was not finalized.
    Following establishment of ClinicalTrials.gov, the scientific 
community, general public, industry, and others engaged in high-
profile, public discussions about the need for increased access to 
information about clinical trials [Ref. 5]. For example, studies 
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. 6].
    The scientific and lay communities called for a range of new 
measures to improve access to and transparency of information about 
clinical trials, including broader mandatory registration and results 
submission. Incomplete access to information about clinical trials was 
seen by some to adversely affect investigators, journal editors, 
research funders, clinicians and participants. Proponents of more 
comprehensive registration of clinical trials in a publicly available 
data bank came from many quarters [Ref. 7, 8, 9]. For example, in 2004, 
the International Committee of Medical Journal Editors

[[Page 69571]]

(ICMJE) adopted a comprehensive trial registration policy aimed at 
increasing public access to trial information and preventing the 
selective publication of certain results. The updated 2007 ICMJE policy 
requires, as a condition for publication, registration of ``any 
research study that prospectively assigns human participants or groups 
of humans to one or more health-related interventions to evaluate the 
effects on health outcomes'' prior to the enrollment of the first 
participant [Ref. 10]. Industry groups also adopted registration 
policies. For example, in 2005, the International Federation of 
Pharmaceutical Manufacturers and Associations (IFPMA) stated that ``all 
clinical trials [sponsored by member companies], other than exploratory 
trials, should be submitted for listing in a free, publicly accessible 
clinical trial registry within 21 days of the initiation of patient 
enrollment . . .''[Ref. 11]. In a follow-up statement, IFPMA allowed 
for the delayed release of information in any of five fields that ``may 
be regarded as sensitive for competitive reasons by the sponsor'' [Ref. 
12]. Also in 2005, the World Health Organization (WHO) International 
Clinical Trial Registry Platform (ICTRP) Secretariat defined a 20-item 
minimum clinical trial registration dataset [Ref. 13]. The WHO minimum 
trial registration standard has been adopted broadly, including by the 
ICMJE, and does not allow withholding of the five fields considered 
``sensitive'' by IFPMA. The European Union has passed legislation 
requiring the public disclosure of registration and results information 
for certain clinical trials of drugs that are conducted in European 
Union countries, including trials of drugs for pediatric indications. 
The European Medicines Agency (EMA) is engaged in a public consultation 
to develop detailed technical specifications for the information to be 
submitted [Ref. 14, 15].
    Because ClinicalTrials.gov is compatible with and receptive to a 
variety of registration requirements, it may facilitate compliance with 
many laws and policies and attracts an extremely large and diverse 
group of data providers. Many trials are registered in 
ClinicalTrials.gov to satisfy the ICMJE policy, and the number of 
trials registered in ClinicalTrials.gov increased significantly after 
the announcement of the ICMJE policy [Ref. 16]. Clinical trial records 
in ClinicalTrials.gov account for more than 85 percent of trials in the 
registries searched by the WHO ICTRP Portal [Ref. 17]. We believe that 
the more comprehensive the data bank, the better suited it will be to 
serve public health goals, including those articulated in section 
402(j) of the PHS Act. As a result, we continue to encourage sponsors 
and other entities associated with studies not subject to section 
402(j) of the PHS Act to voluntarily register and submit the results of 
trials of all types of interventions and other types of clinical 
studies in ClinicalTrials.gov, bearing in mind that section 
402(j)(4)(A) of PHS Act may apply to such submissions.

B. Implementation of Statutory Provisions Prior to Rulemaking

    Due to the short statutory timelines for responsible parties to 
begin submitting registration and results information for applicable 
clinical trials under Title VIII of FDAAA, NIH proceeded to expand the 
ClinicalTrials.gov registry data bank immediately after enactment of 
FDAAA. The intent was to develop a data bank that would permit 
responsible parties to meet the statutory requirements to submit 
clinical trial information, even though regulations to clarify and 
expand those obligations had yet to be developed. In December 2007, NIH 
launched an expanded registry that could accommodate the submission of 
clinical trial registration information specified in section 402(j) of 
the PHS Act. It included all the registration data elements explicitly 
enumerated in section 402(j)(2)(A)(ii) of the PHS Act, as well as 
additional data elements that the Agency interpreted as necessary to 
meet other statutory requirements, maintain consistency with 
ClinicalTrials.gov data elements that were in place prior to FDAAA, and 
allow efficient operation of the data bank. Over time, the Agency 
posted information on the ClinicalTrials.gov Web site outlining its 
current thinking about the meaning of key terms defined in the statute, 
including ``applicable clinical trial'' and ``responsible party'' [Ref. 
18].
    In further expanding the data bank to accommodate the submission of 
results information specified in section 402(j)(3)(C) of the PHS Act, 
we commissioned a review of practices and standards used in existing 
results data banks [Ref. 19]; engaged in active dialogue with the 
clinical trial community, public and private sectors, including the 
patient community; and consulted with the NLM Board of Regents, which 
established a Working Group on Clinical Trials [Ref. 20] in late 2007 
and held meetings open to the public in 2008 [Ref. 21] and 2009 [Ref. 
22] that were announced in the Federal Register (73 FR 3473, Jan. 18, 
2008; 74 FR 3627, Jan 21, 2009). We held discussions with other 
standards development bodies that are active in areas related to trial 
information, such as the Clinical Data Interchange Standards Consortium 
(CDISC) and Health Level Seven (HL7). We also reviewed and considered 
various approaches to preparing summary reports on the results of 
clinical trials, including the ICH-E3 Clinical Study Report format 
[Ref. 23], which is used to guide the submission of drug trial results 
to regulatory agencies in the U.S., Europe, and Japan, and the CONSORT 
statements [Ref. 24], which are used to guide the publication of trial 
results in the peer-reviewed literature. We found that the ICH-E3 
format and CONSORT were designed to delineate the topics that should be 
included when preparing summary reports of trial results for their 
intended expert audiences (regulatory professionals and medical 
professionals, respectively). Both the ICH-E3 format and CONSORT 
recommend review and inclusion of information beyond that collected 
during an individual clinical trial. Neither addresses the 
communication of trial results to the general public, which is one of 
the intended audiences for data submitted to comply with section 402(j) 
of the PHS Act. We found no existing standards directly addressing the 
submission of summary results tables as required by Title VIII of 
FDAAA.
    As a result of these consultations and the review of existing 
approaches to results reporting, we decided to develop a results data 
entry system that would enable responsible parties to submit 
information in a structured manner. Structured data entry is necessary 
to enable the clinical trials data bank to accommodate the full range 
of study design and data types common or emerging in the clinical 
trials community, while simultaneously ensuring that all required data 
elements are provided; optimize the presentation of submitted data, 
including adverse event information, for various types of users, 
including those with less experience in interpreting information about 
the relative risks and benefits associated with particular 
interventions; and allow for efficient search capabilities, including 
searching by the data fields specified by the statute. Structured data 
entry requires a responsible party to submit data in pre-specified 
fields. As a result, a data bank can be created to manage all of the 
information from different trials at the level of the individual 
fields. This approach contrasts with the collection of heterogeneous, 
free-text documents

[[Page 69572]]

(e.g., PDF documents). In the latter situation, NLM would be unable to 
make the displays consistent or create and populate a data bank that 
would support the search capabilities specified by section 402(j) of 
the PHS Act and needed to use the data bank. The development of a 
structured results data bank was consistent with the design of the 
existing ClinicalTrials.gov registry data bank, which launched more 
than seven years before the passage of FDAAA.
    In the spring of 2008, we announced in the Federal Register the 
beginning of an iterative process to advance development of a data bank 
to support the submission of the results information specified by 
section 402(j)(3)(C) of the PHS Act (73 FR 29525, May 21, 2008). Any 
user with a ClinicalTrials.gov account (i.e., an account for submitting 
registration information via the ClinicalTrials.gov Protocol 
Registration System, or PRS) was subsequently able to enter real or 
test data into the test system and view the resulting clinical trial 
records. Mechanisms for data entry and display and descriptions of 
individual data items were refined in response to comments from users 
of the test system, leading to the launch of an operational results 
submission system in September 2008. Further improvements to the system 
were made based on the experience of responsible parties submitting 
comments and from the Agency in reviewing results information submitted 
under section 402(j)(3)(C) of the PHS Act.
    The operational system for results information enables responsible 
parties to submit required information. Because section 402(j)(3)(C)(i) 
of the PHS Act calls for the information on demographic and baseline 
characteristics of the study sample to include information on ``the 
number of patients who dropped out of the clinical trial and the number 
of patients excluded from the analysis, if any,'' the operational 
system separates the collection of information about participant flow 
(i.e., the number of subjects who started the clinical trial, completed 
the clinical trial, and were excluded from the analysis or dropped out 
of the trial) from demographic and baseline data. Our review of a large 
number of clinical trials determined that the only demographic data 
consistently collected across all of these clinical trials were age and 
gender. The operational system therefore collects information about age 
and gender, facilitates submission of other commonly collected 
demographic data such as race or ethnicity, and allows definition and 
submission of other demographic data from the clinical trial. 
Responsible parties may define and submit information on baseline 
characteristics that are most relevant to the particular clinical 
trial.
    The operational results submission system that became available in 
September 2008 also supported the voluntary submission of information 
about serious adverse events and other frequent adverse events. 
Responsible parties were able to voluntarily submit information on 
serious and other adverse events in a manner largely consistent with 
the statutory default provisions in section 402(j)(3)(I)(iii)(I) and 
(II) of the PHS Act. Prior to implementing the capability to submit 
adverse event information, we found through our consultations and 
discussions that, although regulatory requirements and standards exist 
for the reporting of adverse events experienced by participants during 
a clinical trial, there is no standard approach for summarizing adverse 
event data from an entire clinical trial for purposes of inclusion in a 
public data bank. We viewed the process of enabling voluntary 
submission of summary adverse event information in the initial results 
submission system, prior to the statutory default provisions taking 
effect, as a means of determining whether the statutory default 
provisions would represent a feasible and ``best method'' of including 
adverse event information, consistent with section 402(j)(3)(I)(i) of 
the PHS Act. To help the Agency determine whether the 5 percent 
threshold specified in section 402(j)(3)(I)(iii)(II) of the PHS Act was 
an appropriate cap for information about frequent adverse events, we 
permitted data submitters to submit summary data on non-serious adverse 
events using a threshold other than 5 percent . They could choose any 
higher or a lower threshold.
    The Agency did not promulgate regulations implementing the best 
method for including adverse events within 18 months of the date of 
enactment of FDAAA due to the time needed to evaluate different 
strategies for submitting adverse event information. As a result, the 
statutory default provisions in section 402(j)(3)(I)(iii) of the PHS 
Act for submitting adverse events information were implemented in the 
data bank on September 27, 2009. Responsible parties submitting results 
information were required to submit ``a table of serious anticipated 
and unanticipated adverse events, grouped by organ system, with number 
and frequency of such event in each arm of the clinical trial'' and ``a 
table of anticipated and unanticipated adverse events that are not 
included in the [serious adverse event 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'' (See sections 402(j)(3)(I)(iii)(I) and (II) of the PHS 
Act.) While there is a requirement to submit non-serious adverse events 
with a frequency of 5 percent or more in any arm, responsible parties 
may submit data voluntarily on non-serious adverse events with a 
threshold of less than 5 percent. The system also accommodates the 
voluntary submission of information indicating the methodology used for 
assessing adverse events (systematic versus non-systematic) and the 
time period during which adverse event information was collected.
    We and the community of responsible parties have gained 
considerable experience with results submission, including adverse 
event information, since September 27, 2008, when results submission 
was required by section 402(j)(3)(C) of the PHS Act for certain 
applicable clinical trials. As of April 24, 2013, summary results for 
about 8,700 clinical trials had been submitted by responsible parties, 
processed by the Agency and made publicly available in the data bank. 
Based on this experience, we have refined the design of the data entry 
system, developed instructional materials to assist responsible parties 
in preparing data for submission, and refined procedures for processing 
submitted information. Responsible parties have improved their 
procedures for collecting and preparing data for submission to the data 
bank. We have drawn upon this considerable experience and the lessons 
learned in formulating this proposed rule.

III. Overview of Proposed Rule

A. Structure of proposed rule

    We propose to add a new Part 11 to Title 42 of the Code of Federal 
Regulations (CFR) to implement the statutory requirements set forth in 
section 402(j) of the PHS Act. This proposed rule is divided into four 
major subsections:
     Subpart A outlines the general provisions of this proposed 
rule. It specifies the purpose of the rulemaking, to whom this proposed 
rule applies, requirements for submission of truthful information, the 
form and manner of submitting information to the data bank at 
ClinicalTrials.gov, and definitions specific to this part.
     Subpart B specifies requirements for registering an 
applicable clinical

[[Page 69573]]

trial. It specifies who must register trials, which trials must be 
registered, when registration information must be submitted, where 
registration information must be submitted, what registration 
information must be submitted, and when submitted registration 
information will be posted.
     Subpart C specifies requirements for submission of results 
information, including adverse event information, for applicable 
clinical trials of drugs (including biological products) and devices 
that have been approved, licensed, or cleared by FDA and for applicable 
clinical trials of drugs (including biological products) and devices 
that have not been approved, licensed, or cleared by FDA. It specifies 
who must submit clinical trial results information; for which trials 
such information must be submitted; when such information is due, 
including provisions for delayed results submission and requesting 
extensions; where such information must be submitted; what clinical 
trial results information must be submitted; when such information will 
be posted; and the circumstances under which the NIH will grant a 
waiver of the results submission requirements.
     Subpart D specifies additional required submissions of 
information to the data bank, including the timing of updates and 
corrections to submitted information and mandatory submission of 
clinical trial information in the interest of public health for certain 
applicable clinical trials that otherwise would not be subject to the 
registration and results submission requirements of this part. It also 
specifies requirements affecting the voluntary submission of 
information about clinical trials for which the submission of 
registration and results information is not otherwise required under 
this part.
    Elements that are required to be considered in the rulemaking under 
section 402(j)(3)(D) of the PHS Act are addressed in the relevant 
subpart. For example, proposals related to results submission for 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products are contained in subpart C (Results Submission), while those 
related to the updating of submitted clinical trial information are 
contained in subpart D (Additional submissions of clinical trial 
information).

B. General considerations in the rulemaking

    As stated in section 402(j)(2)(A)(i) of the PHS Act, the data bank 
is intended ``to enhance patient enrollment and provide a mechanism to 
track subsequent progress of clinical trials.'' In addition to 
satisfying this obligation, we believe it is essential to continue to 
provide a comprehensive and robust data bank to encourage broad and 
widespread registration and submission of results of clinical trials 
and other types of clinical studies. Comprehensive registration and 
results submission for such studies is consistent with NLM's statutory 
obligations to disseminate information concerning research and to 
promote public health. It can provide information to potential research 
participants, reduce inadvertent and unnecessary duplication of 
clinical studies, help journal editors detect incomplete descriptions 
of the results of specific clinical trials, and allow analysis of the 
results of multiple clinical trials of the same or similar 
interventions, thus providing regulators, scientists, health 
professionals, and the public with more information regarding the 
potential benefits and harms of different interventions.
    We also believe it is essential for the data bank to serve a wide 
variety of users. While the public is the ultimate beneficiary of the 
data bank and the information contained in it, the overall public 
benefit will derive from access to and use of the data by different 
constituencies within the general public. We believe that clinical 
researchers, systematic reviewers, experts in evidence-based medicine, 
regulators, drug and device manufacturers, human subjects protection 
review boards (including institutional review boards (IRBs)), 
healthcare providers, disease and patient advocacy groups, students and 
educators, and patients and their family members may be able to use the 
available information to learn more about FDA-regulated products, to 
increase the efficiency of drug and device development processes, and 
to improve the design and conduct of clinical research studies, among 
other uses.
    Building a data bank that serves multiple users with varying 
degrees of expertise in analyzing and interpreting clinical trial data 
means that not all of the collected information will necessarily be 
easy for all users to interpret. Some members of the general public, 
for example, may have difficulty interpreting certain results 
information, including adverse event information, or putting it into 
context. To address such concerns, we currently provide and, consistent 
with sections 402(j)(3)(A)(ii)(I) and (II) of the PHS Act, intend to 
expand links to additional explanatory material, including general 
information about clinical trials; publicly available FDA, NIH, and 
systematic review information about the products being studied; NIH 
information about the conditions that are the focus of the clinical 
trial; peer-reviewed journal articles summarizing the results of 
clinical trials; and specified FDA information about the clinical 
trial. We intend to develop improved ways of displaying submitted 
clinical trial information and enabling users to search for it, as we 
continue to gain experience with the operational system and to consult 
with experts in risk communications and clinical trial research. We 
also expect to solicit public input on this topic using a variety of 
mechanisms.
    It is important to note that this proposed rule does not impose any 
requirements for the design or implementation of a clinical trial or 
for the collection of information during a clinical trial. This 
proposed rule specifies requirements for submitting information that 
describes a clinical trial as it was designed, conducted, and analyzed. 
The proposed data submission requirements are intended to accommodate 
current and emerging practices in design and implementation of clinical 
trials. We expect that the information required to be submitted to 
ClinicalTrials.gov will have been developed and collected prior to the 
time it must be submitted to the data bank and for reasons distinct 
from compliance with section 402(j) of the PHS Act and this proposed 
rule. In general, required information would have been included in 
standard clinical trial documentation (e.g., the protocol), collected 
during the course of the clinical trial (e.g., the types of adverse 
events specified in the protocol), or produced by the analysis that was 
specified in the protocol (e.g., outcome measures and statistical 
tests).

C. Key issues considered in this proposed rule

    In developing this proposed rule, we considered a number of issues 
associated with the implementation of the statutory requirements for 
registration under section 402(j)(2) of the PHS Act and results 
submission under section 402(j)(3)(C) of the PHS Act and with the 
expansion of the data bank via rulemaking, as specified in section 
402(j)(3)(D) of the PHS Act. We discuss these issues in this section of 
the preamble and reflect their implementation in the specific proposals 
described in section IV. We welcome comments on the Agency's proposals 
for addressing each of these topics in this proposed rule and 
additional information that might inform their implementation.

[[Page 69574]]

1. Elaboration of statutory definitions
    Section 402(j)(1)(A) of the PHS Act defines a number of terms that 
are essential to implementation of the statute and the development of 
this proposed rule. Among the most important are the terms applicable 
clinical trial and responsible party, which are key elements in 
defining the set of trials that are subject to the registration and 
results submission requirements of section 402(j) of the PHS Act and 
the individuals or entities that are responsible for submitting the 
required information, respectively.
    (a) Applicable clinical trial. Section 402(j)(1)(A)(i) of the PHS 
Act defines the term applicable clinical trial as either an applicable 
device clinical trial or an applicable drug clinical trial, both of 
which are defined in section 402(j)(1)(A) of the PHS Act. Section 
402(j)(1)(A)(ii) defines applicable device clinical trial as ``(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].'' Section 402(j)(1)(A)(iii) defines an applicable drug clinical 
trial as a ``controlled clinical investigation, other than a phase I 
clinical investigation, of a drug subject to section 505 of the [FD&C 
Act] or to section 351 of [the PHS Act,]'' where ``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.
    This proposed rule, in Sec.  11.10, adopts the statutory 
definitions of all three of these terms, replacing the phrase ``phase 
I'' in the definition of applicable drug clinical trial with the phrase 
``phase 1'' to be consistent with the numbering scheme used in FDA 
regulations at 21 CFR 312.21. Because of the significance of these 
terms in determining which clinical trials are subject to the 
provisions of this proposed part, we include in section IV.A.5 of this 
preamble an extensive elaboration of their meanings, interpreting each 
component part of the definitions in a way that is consistent with 
existing use of the stated terms in relevant FDA regulations, which may 
differ from current usage in some segments of the clinical research 
community. We also propose in Sec.  11.22(b) an approach for using a 
limited set of registration data elements to determine whether a 
particular study meets the definition of an applicable clinical trial. 
We believe there is significant advantage in having a simple mechanism 
for a responsible party to determine, based on a standard set of 
factors, whether a study meets the definition of an applicable clinical 
trial. Such a mechanism would reduce uncertainty among responsible 
parties about their data submission obligations under section 402(j) of 
the PHS Act and reduce their burden in making such a determination.
    A key consideration in the elaborations and the mechanism for 
determining whether a study meets the definition of an applicable 
clinical trial is defining what it means for an applicable drug 
clinical trial to be ``controlled'' or for an applicable device 
clinical trial to compare an intervention against a control. We explain 
our interpretation of these phrases in the preamble, and we include in 
Sec.  11.10 of this proposed rule a definition of the term ``control or 
controlled.'' Our proposed definition is consistent with the types of 
controls recognized by FDA in its regulations for clinical trials of 
drugs and devices (21 CFR 314.126(b)(2)(i)-(v) and 21 CFR 
860.7(f)(1)(iv)(a)-(d)) in that it includes both concurrent controls, 
as would be used in trials with multiple arms, and non-concurrent 
controls, as may be used in single-arm trials that are expressly 
designed to compare the effect of an intervention to an historical 
control or to baseline data, e.g., with participants serving as 
controls. It is broader than the FDA definitions of ``adequate and well 
controlled'' in 21 CFR 314.126(b) and ``well controlled'' in 21 CFR 
860.7(f) in that it does not imply a judgment about the adequacy or 
appropriateness of the control and the study design.
    Based on this definition, we would consider any clinical trial with 
multiple concurrent arms to be controlled for purposes of determining 
whether it is an applicable clinical trial subject to this proposed 
Part. We would also consider some single-arm clinical trials to be 
controlled. Such trials 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 we would consider 
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 without intervention, such as cancer).
    We propose in Sec.  11.28 that a responsible party who registers a 
single-arm trial indicate whether the trial protocol or statistical 
analysis plan specifies a control as defined in this part. While plans 
for analyzing collected data may change during the course of a study, 
we believe that the requirement that the control be specified in the 
protocol or statistical analysis plan will improve consistency in the 
interpretation of this requirement across trials. We considered 
requiring greater specification about the type of control, if any, used 
in the single-arm study, e.g., historical control (including subjects 
as their own control), but believe our proposed approach provides the 
information necessary for identifying applicable clinical trials while 
minimizing the burden on responsible parties. We propose in Sec.  
11.22(b) to use the information submitted by the responsible party to 
determine whether a trial meets the definition of an applicable 
clinical trial.
    We invite comments on our proposed approach for identifying single-
arm trials that would be considered controlled and on alternative ways 
to identify such trials. In particular, we invite 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 invite 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.
    (b) Responsible party. Section 402(j)(1)(A)(ix) defines the 
responsible party with respect to a clinical trial of a drug or device 
as: ``(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 . . . 
[of this part] for the submission of clinical trial information.'' We 
adopt this definition with minor, non-substantive

[[Page 69575]]

modifications in Sec.  11.10 of this proposed rule.
    Given the significance of the role that the responsible party plays 
in complying with section 402(j) of the PHS Act, we elaborate on the 
meaning and interpretation of this term in section IV.A.5 of this 
preamble. We have codified parts of the elaboration of the definition 
of responsible party in proposed Sec.  11.4(c), which specifies 
procedures for determining the responsible party. We have also included 
a definition of the term sponsor in proposed Sec.  11.10.
2. Modifications and Additions to the Elements of Clinical Trial 
Registration Information
    The clinical trial registration information required by section 
402(j)(2)(A)(ii) of the PHS Act includes 25 specific data elements 
grouped into 4 categories: Descriptive information, recruitment 
information, location and contact information, and administrative 
information. Additionally, section 402(j)(2)(A)(iii) of the PHS Act 
authorizes the Secretary, by regulation, to modify the statutory 
requirements for clinical trial registration information if a rationale 
is provided as to ``why such a modification improves and does not 
reduce'' such information. Proposed Sec.  11.28 lists the clinical 
trial information that we propose to require at the time of 
registration. The definitions of specific data elements are provided in 
proposed Sec.  11.10(b). For the most part, the proposed list of data 
items conforms to the list of items enumerated in section 
402(j)(2)(A)(ii) of the PHS Act, restating, and, in many instances, 
clarifying the statutory data items. However, this proposed rule 
includes certain modifications and additions to the data items listed 
in 402(j)(2)(A)(ii) of the PHS Act that we conclude improve the 
clinical trial information available to the public and implement the 
requirements of the statute. We do not believe that any of the proposed 
modifications and additions reduces the clinical trial information 
available to the public. As further explained in section IV.B.4 of this 
preamble, a number of the proposed modifications and additions to 
clinical trial registration information listed in section 
402(j)(2)(A)(ii) of the PHS Act are not new to some responsible parties 
and other users of the data bank who submitted information to 
ClinicalTrials.gov prior to FDAAA; many of the data elements are the 
same or similar to those collected in ClinicalTrials.gov prior to 
enactment of FDAAA.
    Our proposed modifications and additions to clinical trial 
registration information take the following general forms.
    (1) Structuring data entry for registration data elements to help 
the public use the data bank and compare entries, as required by 
section 402(j)(2)(B)(iv) of the PHS Act. We believe structured data 
entry for registration data elements helps satisfy the requirement at 
402(j)(2)(B)(iv) to ``ensure that the registry data bank is easily used 
by the public, and that entries are easily compared,'' because it will 
enable users to search the data bank using the criteria listed in 
section 402(j)(2)(B)(i) of the PHS Act and will prompt responsible 
parties to submit complete and accurate information. We therefore 
propose to require responsible parties to enter defined components of 
certain data elements, such as study design, outcome measure, and IND 
or IDE number. For example, in Sec.  11.10(b)(35), we propose to define 
the Food and Drug Administration IND or IDE number, a data element 
expressly required to be submitted at the time of registration by 
section 402(j)(2)(A)(ii)(IV)(cc) of the PHS Act (therein referred to as 
the ``IND/IDE protocol number'') to include the name of the FDA center 
that issued the IND or IDE (e.g., the Center for Drug Evaluation and 
Research (CDER), the Center for Biologics Evaluation and Research 
(CBER), or the Center for Devices and Radiological Health (CDRH)); the 
IND or IDE number; and any serial number that has been assigned by the 
sponsor to that filing. We believe these three components are necessary 
to provide complete information about IND/IDE number.
    (2) Additions to allow effective implementation of, or compliance 
with, other provisions of section 402(j) of the PHS Act. For example, 
this proposed rule in Sec.  11.28(a)(1)(xv) requires information about 
whether a product under study in a clinical trial is manufactured in 
the U.S. or one of its Territories because this information is 
necessary in some situations to determine whether or not a clinical 
trial meets the definition of an applicable clinical trial or would be 
considered a voluntary submission under section 402(j)(4)(A) of the PHS 
Act.
    (3) Additions to improve the quality and consistency of information 
available in the data bank and enabling users to better search for, 
retrieve, and understand it. For example, in Sec.  11.28(a)(1)(xi) of 
this proposed rule, we propose that responsible parties submit other 
current and former names for interventions studied in a clinical trial 
(if other such names exist) to help identify duplicative trial 
registrations and assist users in finding clinical trials for 
interventions that might be registered under different names (e.g., the 
name of the chemical compound, the brand name of an approved product, 
or an alias used during pre-marketing studies).
    (4) Addition to indicate the ethical and scientific review status 
of the clinical trials listed in the data bank. We believe that it is 
essential that patients and practitioners searching ClinicalTrials.gov 
for information about clinical trials retrieve information on whether a 
clinical trial registered in ClinicalTrials.gov is undergoing or has 
undergone review procedures with respect to ethical and scientific 
considerations. A small number of applicable clinical trials may not be 
required by applicable law, regulation, and/or institutional policy to 
seek approval from a human subjects protection review board (e.g., if a 
waiver has been provided, the clinical trial is determined to be exempt 
in accord with applicable law and regulation, or the clinical trial is 
not subject to laws, regulations, or institutional policies that 
require review by a human subjects protection review board). In such 
cases, the proposed rule would require responsible parties to indicate 
that human subjects protection review board approval is not required by 
applicable law, regulation, or institutional policy. We recognize that 
provision of information on human subjects review status cannot 
guarantee the quality of a clinical trial or the safety of human 
subjects who are enrolled in it. Nevertheless, we believe that 
requiring responsible parties to indicate whether a clinical trial 
registered in ClinicalTrials.gov is undergoing or has undergone review 
by a human subjects protection review board may provide some measure of 
assurance in most situations.
    We invite comments on our proposed modifications and additions to 
the data elements of clinical trial registration information, including 
the benefits and burdens associated with structuring certain 
registration data elements.
3. Posting of Registration Information for Applicable Device Clinical 
Trials
    Section 402(j)(2)(D) of the PHS Act establishes the timelines for 
posting clinical trial registration information submitted by 
responsible parties in the data bank. For applicable drug clinical 
trials, section 402(j)(2)(D)(i) of the PHS Act requires NIH to post 
publicly clinical trial registration information not later than 30 days 
after it has been

[[Page 69576]]

submitted. For applicable device clinical trials of devices that 
previously have been approved or cleared by FDA, section 
402(j)(2)(D)(ii)(II) of the PHS Act requires that clinical trial 
registration information be posted not later than 30 days after 
clinical trial results information is required to be posted by NIH. As 
discussed in detail in section IV.B.5(b) of this preamble, NIH has 
interpreted this provision as allowing NIH to post clinical trial 
registration information for applicable device clinical trials of these 
devices as soon as practicable. For applicable device clinical trials 
of devices that have not previously been approved or cleared, NIH 
intends that, consistent with section 402(j)(2)(D)(ii)(I) of the PHS 
Act, clinical trial registration information will be posted not earlier 
than the date on which FDA approves or clears the device and not later 
than 30 calendar days after the date of such approval or clearance.
    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 allowed by section 402(j) of the PHS Act and this rulemaking. 
For example, based on experience to date, we believe that some sponsors 
and principal investigators prefer to make their registration 
information publicly available in the data bank because this would be 
an easy way to meet the ICMJE policy [Ref. 10], which requires public 
registration in a data bank prior to enrollment of the first patient as 
a precondition for consideration for publication. Others prefer to make 
registration information available to the public to assist with or 
expand upon efforts to recruit potential human subjects for a trial. In 
other cases, responsible parties might wish to make some of the 
registration information available to demonstrate to others (e.g., a 
funding organization or the sponsor) that a clinical trial has, in 
fact, been registered as required by section 402(j) of the PHS Act and 
this proposed regulation.
    We considered, but do not propose, two potential mechanisms for 
addressing these situations: (1) Allowing a responsible party to give 
voluntarily the NIH permission to release clinical trial registration 
information for an applicable device clinical trial of a device that 
previously has not been approved or cleared for public posting in the 
data bank, and (2) allowing any individual or entity to whom the 
responsible party provides the NCT number for such a trial (i.e., the 
unique identifier that is assigned to a trial upon registration in the 
data bank) to access a very limited set of data sufficient to verify 
that the clinical trial of interest has been registered, but without 
revealing substantive information about the clinical trial, such as the 
focus of the clinical trial or the products involved. However, section 
402(j)(2)(D)(ii) 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 submitted in 
accordance with . . . [section 402(j)(2) of the PHS Act not be] posted 
publicly . . .'' before approval or clearance. Because neither of the 
mechanisms appears to be permissible under the statute, we have not 
proposed implementing either of these mechanisms in this rulemaking. We 
invite comments from the public on how, given the statutory language, 
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.
4. Application of Rule to a Pediatric Postmarket Surveillance of a 
Device That Is Not a Clinical Trial
    In section 801(c), FDAAA requires the Secretary of HHS to issue 
guidance on how section 402(j) of the PHS Act applies to a pediatric 
postmarket surveillance of a device that is not a clinical trial. 
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.'' This proposed rule 
in Sec.  11.10 defines ``pediatric postmarket surveillance of a 
device'' as ``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 or 
younger at the time of diagnosis or treatment. A pediatric postmarket 
surveillance of a device may be, but is not always, a clinical trial.''
    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: Its failure would be reasonably likely to have 
serious adverse health consequences; it is expected to have significant 
use in pediatric populations; it is intended to be implanted in the 
body for more than 1 year; or 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 [Ref. 25].
    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. Our proposed approach for applying the registration 
requirements to a pediatric postmarket surveillance of a device that is 
not a clinical trial is described in proposed Sec.  11.28(b). Our 
proposed approach for applying the results submission requirements to a 
pediatric postmarket surveillance of a device that is not a clinical 
trial is described in proposed Sec.  11.48(b). A pediatric postmarket 
surveillance of a device that is a clinical trial would be subject to 
the general requirements of this proposed rule, including the clinical 
trial registration and results submission requirements in proposed 
Sec. Sec.  11.28(a) and 11.48(a), respectively. Further elaboration of 
these proposals is contained in section IV.B of this preamble.
5. Submission of Results Information for Applicable Clinical Trials of 
Unapproved, Unlicensed, or Uncleared Products
    (a) General requirements and rationale. Section 402(j)(3)(D)(ii)(I) 
of the PHS Act requires the submission of results information for: (1) 
Each applicable drug clinical trial for a drug that is approved under 
section 505 of the FD&C Act or licensed under section 351 of the PHS 
Act; and (2) each applicable device clinical trial for a device that is 
cleared under section 510(k) of the FD&C Act or approved under section 
515 or 520(m) of the FD&C Act. By contrast, section 
402(j)(3)(D)(ii)(II) of the PHS Act requires that the Secretary 
establish, through regulation, whether or not results information must 
be submitted for applicable clinical trials of unapproved, unlicensed, 
or uncleared

[[Page 69577]]

products, whether or not approval, licensure, or clearance was sought. 
If the Secretary requires, by regulation, the submission of results 
information for unapproved, unlicensed, or uncleared products, then 
section 402(j)(3)(D)(iv)(III) of the PHS Act authorizes the Secretary 
to determine, by regulation, ``the date by which such clinical trial 
information shall be required to be submitted,'' taking into account 
(a) the process under section 402(j)(3)(E)(iii) of the PHS Act for 
``delayed submission of results with certification'' when approval, 
licensure, or clearance is sought; and (b) whether there should be a 
delay of submission when approval, licensure, or clearance will not be 
sought.
    Pursuant to our authority under section 402(j)(3)(D)(ii)(II) of the 
PHS Act, we have decided to propose that results information be 
submitted for applicable clinical trials of drugs and devices that are 
not approved, licensed, or cleared by FDA, regardless of whether 
approval, licensure, or clearance is sought. In addition, pursuant to 
our authority under section 402(j)(3)(D)(iv)(III) of the PHS Act, we 
propose deadlines for submitting this results information that, as 
required by statute, take into account both the certification process 
under section 402(j)(3)(E)(iii) of the PHS Act for delayed submission 
of results when approval, licensure, or clearance is sought and whether 
there should be delayed submission of results when approval, licensure, 
or clearance will not be sought. As discussed in section III.D of this 
preamble, these proposals would apply to applicable clinical trials of 
unapproved, unlicensed, or uncleared products that reach their 
completion dates on or after the effective date of this rule, as well 
as certain applicable clinical trials of unapproved, unlicensed, or 
uncleared products that reach their completion dates prior to the 
effective date of the rule.
    We believe our proposal to require results submission for 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products is in furtherance of the express statutory purpose of the 
expanded data bank, 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.'' (See section 402(j)(3)(D)(i) of the PHS 
Act.) In developing our proposal, we considered a number of factors, 
many of which were raised at the Public Meeting [Ref. 1], notably the 
potential public health benefits of timely disclosure of results 
information for clinical trials of drugs that are not approved, 
biological products that are not licensed, and devices that are not 
approved or cleared; 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 submission requirements and 
policies (e.g., those of the EMA). Other considerations include the 
relative burden on the responsible party of submitting results for 
clinical trials of unapproved drugs, unlicensed biological products, 
and unapproved or uncleared devices, the date by which results must be 
submitted, and practical issues of implementation and compliance.
    The Agency finds compelling the arguments in support of a 
requirement to submit the results of applicable clinical trials of 
unapproved, unlicensed, or uncleared products. The availability of such 
information in ClinicalTrials.gov could have several potential public 
health benefits. Systematic disclosure of results of applicable 
clinical trials of unapproved, unlicensed, or uncleared products would 
mitigate the bias in information available to the public about studied 
medical products that stems from selective disclosure of clinical trial 
results [Ref. 26]. Currently, sponsors, researchers, and product 
manufacturers often voluntarily and selectively release to the public 
partial information about the results of specific studies, including 
those of unapproved, unlicensed, or uncleared products, via scientific 
publications and abstracts, press releases, and other announcements. 
Requiring the submission of results of applicable clinical trials of 
unapproved, unlicensed, or uncleared products in a systematic and 
standardized format would provide a more current and complete picture 
of results of clinical trials of FDA-regulated products, therefore 
reducing a potential source of bias.
    The public availability of results information about trials of 
unapproved, unlicensed, and uncleared drugs (including biological 
products) and devices would also help 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 unnecessary (e.g., because similar clinical 
trials have already been conducted but not published), or that are 
potentially harmful (e.g., because similar interventions have been 
shown to be harmful or ineffective in previous, unpublished clinical 
trials). It would also help potential human subjects make 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 would have access via 
ClinicalTrials.gov to information about other clinical trials of 
similar unapproved, uncleared, or unlicensed products that might help 
them in designing or considering the potential risks and benefits of 
participation in a clinical trial.
    In addition, submission of results of clinical trials of 
unapproved, unlicensed, or uncleared products would broaden the 
evidence base for systematic reviewers and others involved in assessing 
the benefits and harms of classes of drugs and devices. Many clinical 
trials compare unapproved, unlicensed, or uncleared drugs and/or 
devices with approved, licensed, or cleared drugs and/or devices, and 
the submission of results of such clinical trials could increase access 
to additional information about the marketed products for their 
approved, licensed, or cleared uses. In addition, many unapproved, 
unlicensed, or uncleared products are similar to products that are 
approved, licensed, or cleared and in the marketplace. This is 
particularly true of the unapproved, unlicensed, or uncleared versions 
of products that are studied in clinical trials that contribute to the 
evidence base for subsequent approval, licensure, or clearance of a 
different version of the product. Preliminary or alternative versions 
of a drug, for example, may differ from the approved or licensed 
version in dose, form, or inactive ingredients, even if they contain 
the same active ingredient(s). Results of clinical trials of unapproved 
products could therefore enhance the knowledge base for understanding 
classes of products.
    There is also a compelling ethical rationale for making available 
to the public the results from clinical trials that involve human 
subjects, regardless of the approval status of the product. Part of the 
agreement made with human subjects who agree to participate in clinical 
trials is that knowledge that is obtained in the clinical trial will be 
available for use in advancing biomedical science [Ref. 27].

[[Page 69578]]

Submission and subsequent posting of the results of applicable clinical 
trials of unapproved drugs, unlicensed biological products, and 
unapproved or uncleared devices to ClinicalTrials.gov that reach their 
completion dates on or after the effective date of a final rule would 
help to achieve that goal, especially for clinical trials for which 
results are never published in the scientific literature.
    We also are aware of ongoing regulatory efforts by the EMA to make 
results of clinical trials of drugs conducted within the EU available 
in a publicly accessible data bank, regardless of the approval status 
of the drug [Ref. 28, 29, 30]. Already, all clinical trials of drugs 
performed within the EU are registered in EMA's 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 
(https://www.clinicaltrialsregister.eu/). In June 2010, EMA issued for 
public comment the draft implementing technical guidance on the EudraCT 
results data bank. The technical guidance specifies summary results 
information that would be submitted to the data bank for public 
posting. 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 that document, EMA has 
worked with ClinicalTrials.gov staff to harmonize common data elements 
used by the two results data banks, which we view as a way of 
simplifying the process of submitting results to EudraCT and 
ClinicalTrials.gov, for those trial that are required to submit results 
to both data banks. Many clinical trials that would be subject to EMA 
regulations requiring the disclosure of clinical trial results would 
likely be applicable clinical trials subject to section 402(j) of the 
PHS Act. We believe that if clinical trial results information is 
available via another publicly accessible data bank (such as EudraCT), 
a number of the concerns that have been expressed about disclosure in 
ClinicalTrials.gov would no longer be applicable. The use of common 
data elements would promote harmonization of results information in 
EudraCT and ClinicalTrials.gov and simplify data submission for 
clinical trials that would be summarized in both databases.
    We recognize that the posting of results information about clinical 
trials of unapproved, unlicensed, and uncleared products presents 
special challenges. Such information would be accessible to care 
providers and their patients and would describe uses of products that 
are not approved, cleared, or licensed. Even for approved, cleared, or 
licensed uses the posted result information would contain information 
that is not included in approved labeling and that requires further 
interpretation for understanding potential risks and benefits. We 
believe that the results information from any individual clinical trial 
should be considered not on its own, but 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 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 
would indicate that the links were added by the NIH and not by the 
responsible party). As discussed further in section III.C.11, we would 
also 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, the limitations of the data presented, and cautions that the 
information should be used in conjunction with advice from healthcare 
professionals.
    We believe that all of these benefits can be best achieved by 
requiring the submission of results information for all applicable 
clinical trials involving unapproved, unlicensed, or uncleared 
products, regardless of whether FDA approval, licensure, or clearance 
is sought. Limiting results submission to those applicable clinical 
trials of unapproved, unlicensed, or uncleared products for which 
product development has been abandoned by industry would minimize 
industry concerns about disclosing potentially valuable information to 
competitors, but would do little to address concerns about bias in the 
disclosure of information. 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. Even if investigators and human 
subjects protection review boards have access to information from a 
clinical trial sponsor, they will not have access to the full range of 
unpublished results of other clinical trials that might be relevant to 
a clinical trial under consideration. We believe that concerns about 
commercial competitiveness resulting from disclosure of results 
information from clinical trials of products that are not approved, 
licensed, or cleared by the FDA can be mitigated by delaying the 
results submission deadline for applicable clinical trials of products 
that are still under development, as described later in this section. 
Indeed, disclosure of results information for clinical trials of 
products that are still under development could improve the efficiency 
of research and development (R&D) investments by reducing the 
likelihood that private companies, universities, and the U.S. 
Government will waste resources repeating studies of interventions that 
have already been conducted. In addition, limiting disclosure 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, as 
noted by some industry commenters, product development is often 
suspended for periods of time before being resumed when company 
priorities change or a developmental product is transferred to another 
company. Information about unapproved products still in product 
development pipelines might therefore remain undisclosed for long 
periods of time, depriving the public of the benefits that could result 
from disclosure even in situations where non-disclosure might provide 
little commercial advantage.
    We therefore propose, as authorized by section 402(j)(3)(D)(ii)(II) 
of the PHS Act and as specified in proposed Sec.  11.42(a), to require 
submission of clinical trial results information for applicable 
clinical trials that reach their completion dates on or after the 
effective date of the rule and that involve a drug, biological product, 
or device that is not approved, licensed, or cleared for any 
indication, regardless of whether the sponsor seeks approval, 
licensure, or clearance. We believe that requiring this information to 
be submitted is consistent with the statute's stated purpose in 
expanding 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.'' (See section 
402(j)(3)(D)(i) of the PHS Act).
    In considering the deadlines for submitting results information for 
applicable clinical trials of unapproved,

[[Page 69579]]

unlicensed, or uncleared products, as required by section 
402(j)(3)(D)(iv)(III) of the PHS Act, the Agency recognized a need to 
balance several considerations namely: Commercial interests in 
protecting information about products under development, public health 
benefits of timely access to results information, the burden associated 
with submission of results information, and administrative burden. We 
also considered the statutory requirements of section 
402(j)(3)(D)(iv)(III) of the PHS Act to take into account: (1) the 
certification process for delayed submission of results under section 
402(j)(3)(E)(iii) of the PHS Act ``when approval, licensure, or 
clearance is sought'' for a product studied in an applicable clinical 
trial; and (2) ``whether there should be a delay of submission when 
approval, licensure or clearance will not be sought.''
    As further described below, we propose to require results 
submission for applicable clinical trials involving unapproved, 
unlicensed, or uncleared products not later than 1 year after the 
completion date of the clinical trial, unless the responsible party 
submits a certification under section 402(j)(3)(E)(iii) of the PHS Act 
prior to that deadline indicating that initial approval, licensure, or 
clearance is being sought or may at a future date be sought.
    Delayed submission of results of applicable clinical trials 
involving products that are unapproved, unlicensed, or uncleared would 
be permitted only if the responsible party certifies under section 
402(j)(3)(E)(iv) of the PHS Act 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 an applicable clinical trial. 
For applicable clinical trials of unapproved, unlicensed, or uncleared 
products, results submission may be delayed only if section 
402(j)(3)(E)(iv) of the PHS Act applies. In determining whether section 
402(j)(3)(E)(iv) of the PHS Act applies to a particular applicable 
clinical trial, we took into consideration the fact that section 
402(j)(3)(D)(iv)(III)(aa) of the PHS Act indicates that the 
certification process under section 402(j)(3)(E)(iii) of the PHS Act 
applies ``when approval, licensure, or clearance is sought'' (emphasis 
added), whereas section 402(j)(3)(D)(iv)(III)(bb) of the PHS Act states 
that the Secretary shall determine, by regulation, ``whether there 
should be a delay of submission when approval, licensure, or clearance 
will not be sought'' (emphasis added). We consider these two provisions 
together to mean that delayed submission of results with certification 
is allowable if initial approval, licensure, or clearance is sought, 
meaning that the sponsor or manufacturer intends to continue with 
product development and thus either is seeking, or may at a future date 
seek, approval, licensure, or clearance. This proposed rule does not 
include a provision extending delayed submission when approval, 
licensure, or clearance will not be sought.
    Delayed submission of results would not be available to a 
responsible party who either meets the criteria in section 
402(j)(3)(E)(iv) of the PHS Act to certify but does not submit a 
certification prior to the deadline under the process set forth in 
section 402(j)(3)(E)(iii) of the PHS Act, or who does not meet the 
statutory criteria to submit a certification. In such instances, we 
propose that results be due not later than 1 year after the completion 
date, unless an extension for good cause is requested and granted under 
section 402(j)(3)(E)(vi) of the PHS Act. This deadline is consistent 
with the time frame in section 402(j)(3)(E)(i) of the PHS Act for 
submitting results information. Specifically with regard to applicable 
clinical trials of drugs (including, biological products) or devices 
for which approval, licensure, or clearance will not be sought, we 
interpret the phrase ``will not be sought'' to mean that the sponsor or 
manufacturer has no intention of developing a marketable product or 
otherwise has abandoned product development. For these trials, the 
Agency believes that the public benefits of disclosure of results 
information outweigh any private, commercial interests. We recognize 
that, in many cases, whether initial approval, licensure, or clearance 
is, or may at a future date be, sought is information that will be 
known only to the sponsor or manufacturer of the drug, biological 
product, or device 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. Accordingly, the Agency needs a way to verify that the sponsor 
or manufacturer is seeking, or may at a future date seek, initial 
approval, licensure, or clearance. Therefore, as a condition of 
delaying results submission for unapproved, unlicensed, or uncleared 
products, we propose in Sec.  11.44(c), to require the responsible 
party to certify that the sponsor or manufacturer intends to continue 
with product development and either is seeking, or may at a future date 
seek, approval, licensure, or clearance. See section 402(j)(3)(E)(iv) 
of the PHS Act. 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 proposed Sec.  11.44(c) criteria, as explained in this 
preamble. We recommend that if the sponsor has designated the PI as the 
responsible party under the process described under proposed Sec.  
11.4(c), the sponsor should be prepared to communicate with the 
responsible party to help ensure the accuracy of any certification that 
is made.
    If after submission of a certification that section 
402(j)(3)(E)(iv) of the PHS Act applies to a specific applicable 
clinical trial, the drug, biological product, or device studied in the 
applicable clinical trial becomes approved, licensed, or cleared for 
the indication studied in the applicable clinical trial, results 
information would be due 30 calendar days after approval, licensure, or 
clearance. If, after submission of a certification that section 
402(j)(3)(E)(iv) applies to the applicable clinical trial, initial 
approval is no longer being sought (i.e., product development is 
abandoned), we likewise do not believe that continued delays in results 
submission are warranted, and we recommend that the responsible party 
should submit results information as soon as practicable.
    Furthermore, we do not believe that a delay in submitting results 
for applicable clinical trials of unapproved, unlicensed, or uncleared 
products should be indefinite, enduring until a responsible party 
proactively asserts that product development has been abandoned or 
until the product is approved, licensed, or cleared. We therefore 
propose to limit the allowable delay period for results submission for 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products to 2 years after the submission of a certification for delayed 
results submission. The certification would have to be submitted prior 
to the date on which results information would otherwise be due (e.g., 
12 months after the completion date), and we would permit only one 
certification to be submitted for each clinical trial. Product 
development can extend over long periods of time and may even be 
suspended or remain inactive for significant periods of time, whether 
due to limited financing, changes in

[[Page 69580]]

corporate policy, revised strategic plans, or other reasons. While 
sponsors or manufacturers may find commercial advantage in protecting 
clinical trial results during this extended period, those advantages 
must be weighed against the disadvantages of denying access to results 
information to the research community, healthcare providers, and the 
public for an extended period.
    The proposed 2-year time limitation reflects a balance between the 
need to protect competitive advantage and the desire for public access 
to clinical trial results. Within this time frame, a sponsor or 
manufacturer would often make a decision about 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 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. The total delay in 
disclosure of results of up to 3 years after the completion date would 
provide sponsors with significant lead time in product development over 
potential competitors.
    (b) Additional results information for applicable clinical trials 
of unapproved or uncleared devices. Once clinical trial results 
information is submitted, section 402(j)(3)(G) of the PHS Act requires 
public posting of that information no later than 30 days after the date 
of submission (See proposed Sec.  11.52, which implements this 
statutory requirement). Thus, clinical trial results information for 
applicable clinical trials of both approved, licensed, and cleared, 
products and unapproved, unlicensed, and uncleared products will be 
publicly posted no later than 30 calendar days after submission. 
Section 402(j)(2)(D)(ii)(I) of the PHS Act requires the clinical trial 
information submitted upon registration of applicable device clinical 
trials of devices that have not previously been approved or cleared not 
be posted earlier than the date on which FDA approves or clears the 
device studied in the applicable clinical trial. (See section III.C.3. 
of this preamble.) Therefore the proposed timelines for submitting and 
publicly posting clinical trial results information in Sec. Sec.  11.44 
and 11.52 may result in the public availability of clinical trial 
results information for applicable device clinical trials for 
unapproved or uncleared devices before the information submitted during 
registration is posted for these same trials.
    We believe that posting clinical trial results information without 
the corresponding public availability of certain descriptive 
information that is the same type of information that is included as 
part of registration would fail to provide the necessary context for 
understanding clinical trial results information and would 
significantly limit access to and understanding of posted results data. 
This 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 would 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, e.g., 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. This 
type of information is not included as part of clinical trial results 
information under proposed Sec.  11.48(a) but is the same type of 
descriptive information submitted upon registration, e.g., Brief Title, 
Intervention Name, Study Start Date, Completion Date.
    Similarly, to enhance their understanding of the clinical trial 
results, researchers, healthcare providers, patients and other users of 
ClinicalTrials.gov need 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. They 
need to know whether the clinical trial is completed, if data are still 
being collected for other outcome measures, or if the clinical trial 
was terminated prematurely. They need to understand 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 did the outcome measures change during the course of the study). 
They also need information to assist them 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. They 
also need to know whether the clinical trial was reviewed for human 
subjects protection and who had authority over the conduct of the 
trial. In addition, they need to know 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 submitted results 
information, but is the same type of descriptive information provided 
during registration, e.g., Primary Purpose, Study Design, Primary 
Outcome Measure(s), Secondary Outcome Measure(s), Eligibility Criteria, 
Overall Recruitment Status, Oversight Authorities, Human Subjects 
Protection Review Board Status, Responsible Party, by Official Title, 
and Record Verification Date (See proposed Sec.  11.28(a).
    Section 402(j)(3)(D)(i) of the PHS Act states that the purpose of 
granting the Secretary rulemaking authority to expand the results 
information in the data bank is ``[t]o provide more complete results 
information and to enhance patient access to and understanding of the 
results of clinical trials.'' We believe it would be extremely 
challenging for the public to understand clinical trial results 
information without having access to certain descriptive information 
that is the same type of information submitted during trial 
registration. Thus, to ``enhance patient access to and understanding of 
the results,'' it is necessary for patients to have access to this 
descriptive information when clinical trial results information is 
posted, not only for applicable drug clinical trials of both approved 
and unapproved drugs (See section 402(j)(2)(D)(i) and section IV.B.5 of 
this preamble), but also for applicable device clinical trials of both 
approved or cleared devices and unapproved or uncleared devices.
    Section 402(j)(3)(D)(ii)(II) of the PHS Act grants the Secretary 
discretion in what can be required through rulemaking to be submitted 
as part of clinical trial results information for applicable device 
clinical trials of devices that have not been approved or cleared. 
Specifically, it allows the Secretary to require the submission of 
results information that is ``described in clause (iii).'' Clause 
(iii), or 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)]. . .[s]uch other categories as the Secretary 
determines appropriate'' (section 402(j)(3)(D)(iii)(IV) of the PHS 
Act). Thus, for applicable device clinical trials of unapproved or

[[Page 69581]]

uncleared devices, the Secretary can require, through rulemaking, 
submission of not only those results that are required under section 
402(j)(3)(C) of the PHS Act, but ``such other categories'' of 
information as the Secretary determines appropriate.
    To ``enhance patient access to and understanding of the results of 
the clinical trials'' as required by section 402(j)(3)(D)(i) of the PHS 
Act, we interpret ``such other categories'' of results information for 
applicable device clinical trials of unapproved or uncleared devices to 
include, among other things, certain descriptive information that is 
the same type of information that was required to be submitted under 
section 402(j)(2)(A)(ii) of the PHS Act. Accordingly, we propose under 
Sec.  11.48(a)(6) to require responsible parties to submit this 
descriptive information as part of clinical trial results information 
for applicable device clinical trials of unapproved or uncleared 
devices. Because this descriptive information would be defined as part 
of clinical trial results information, it would be posted no later than 
30 calendar days after it has been submitted, pursuant to section 
402(j)(3)(G) of the PHS Act. See proposed Sec.  11.48(a)(6) and section 
IV.C.4(g) of this preamble for a list of proposed required data 
elements.
    Requiring responsible parties for applicable device clinical trials 
of unapproved or uncleared devices to resubmit information they would 
have submitted previously to the data bank under proposed Sec.  
11.28(a), in order to comply with proposed Sec.  11.48(a)(6), would be 
inefficient and impose an unnecessary burden on responsible parties. It 
would also introduce the possibility that information provided at the 
time of results submission would be inconsistent with the information 
provided at the time of registration and require the Agency to perform 
a second quality review of information submitted at registration. To 
promote efficiency and lessen the burden on responsible parties, we 
propose to require these responsible parties to fulfill the proposed 
requirement under Sec.  11.48(a)(6) by affirming in the data bank when 
submitting clinical trial results information that they are submitting 
information that is already contained in the databank as part of their 
submission of clinical trial results information and that such 
information has been updated as specified in Sec.  11.64(c) and is to 
be included as clinical trial results information. Once this 
affirmation is made, the information listed in proposed Sec.  
11.48(a)(6) that had been previously submitted to the data bank, would 
automatically populate the results information data fields and be 
posted when results information is posted. This proposal would help us 
ensure that the clinical trial results information necessary ``to 
enhance patient access to and understanding of the results of clinical 
trials,'' consistent with section 402(j)(3)(D)(i) of the PHS Act is 
available to the public.
6. Submission of Non-Technical and Technical Summaries of Trial Results
    Section 402(j)(3)(D)(iii)(I) of the PHS Act specifies that the 
regulations shall require ``[a] summary of the clinical trial and its 
results that is written in non-technical, understandable language for 
patients, if the Secretary determines that such types of summary can be 
included without being misleading or promotional.'' Section 
402(j)(3)(D)(iii)(II) of the PHS Act specifies that the regulations 
shall require ``a summary of the clinical trial and its results that is 
technical in nature, if the Secretary determines that such types of 
summary can be included without being misleading or promotional.
    We interpret the provisions in sections 402(j)(3)(D)(iii)(I) and 
(II) of the PHS Act to mean that the proposed regulations are to 
require the submission of non-technical and technical narrative 
summaries if such summaries can be produced in such a way that they 
will not be misleading or promotional to potential users of the data 
bank. We believe it is necessary to demonstrate that narrative 
summaries of applicable clinical trials can be consistently produced in 
a way that will not be misleading or promotional.
    If non-technical or technical narrative summaries can 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. Such summaries 
might assist the public, clinicians, and researchers in understanding 
salient information about the characteristics of the participants in a 
specific applicable clinical trial and the benefits and harms 
experienced by those participants in that clinical trial. In fact, some 
users of ClinicalTrials.gov might find narrative summaries easier to 
understand than the summary results tables. Although summarized 
evidence from multiple clinical trials and observational studies, when 
available, would provide a more complete overall picture of a clinical 
trial's results, summaries of individual trials that are accurate and 
objective could also be useful, particularly for clinical trials that 
present the first evidence of benefits and harms for specific products 
or population groups, based on the experience of participants in that 
clinical trial.
    Another consideration is the optimum format for narrative, non-
technical summaries. For example, two existing widely-endorsed and used 
formats intended for reporting results of individual clinical trials 
for technical or expert audiences are the CONsolidated Standards for 
Reporting Trials (CONSORT) Statement [Ref. 31], a checklist of best 
practices for producing journal articles that report the results of 
clinical trials of any type of intervention; and the International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) topic E3--Structure and Content 
of Clinical Study Reports (ICH E3) [Ref. 23], a required format for 
summarizing results of individual clinical trials of drugs in 
submissions to FDA and to agencies that regulate the use of drugs in 
other countries. Both of these formats require narratives and data 
tables, including information that is already submitted to 
ClinicalTrials.gov to meet the registration and results submission 
requirements under section 402(j) of the PHS Act.
    The CONSORT Statement specifically addresses various ways in which 
reports of clinical trial results can be misleading and how to avoid 
these pitfalls, generally by providing additional types of information, 
such as limitations in trial design, participant populations, etc. The 
CONSORT Statement strongly recommends ``that at a minimum, authors 
should discuss the results of their trial in the context of existing 
evidence. This discussion should be as systematic as possible and not 
limited to studies that support the results of the current trial. 
Ideally, we recommend a systematic review and an indication of the 
potential limitation of the discussion if this cannot be completed'' 
[Ref. 31]. The ICH E3 format does not specifically address the 
potential for misleading narratives, but it does emphasize the need to 
address many specific topics whose omission might lead to a misleading 
summary, e.g., appropriateness of measurements, statistical analysis 
plans, determination of sample size, protocol deviations. The ICH E3 
guidance document also addresses the importance of context by stating 
that ``Clinical relevance and importance of the results should be also 
discussed in light of other existing data'' [Ref. 23].

[[Page 69582]]

    Another question to be addressed is whether a single, brief summary 
of an individual clinical trial can provide sufficient background or 
context to avoid being potentially misleading to a clinician or patient 
interested in the clinical significance of the results. Individual 
trials can contain a large number of primary and secondary outcome 
measures (more than 120 in some submissions to ClinicalTrials.gov), 
which would make it extremely difficult to prepare succinct summaries 
without presenting selective information about the outcome measures or 
adverse events, a process that can introduce bias into the summary. On 
the other hand, all of the data required in results reporting would be 
available alongside the technical and non-technical summaries, 
providing all data on outcome measures. In addition, we rely on 
publication of clinical trials results through scientific journals so 
scientists are accustomed to analyzing and reporting often complex data 
from their clinical trials. ClinicalTrials.gov links to publications 
where available to provide the user with additional information.
    In addition to reviewing the relevant literature, we consulted with 
the FDA Risk Communication Advisory Committee (meeting summary 
available at: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/RiskCommunicationAdvisoryCommittee/ucm116558.htm) and considered public comments from the public meeting 
held in April 2009 [Ref. 1]. We agree with those who commented that 
further research on this complex issue is warranted. Accordingly, NIH 
plans to undertake an evaluation to assess the value to the public of 
such summaries and whether they can be provided in a manner that is 
objective and not misleading. We are therefore deferring the decision 
about whether or not to require the submission of narrative summaries. 
We invite further public comment on methods that we might employ to 
help answer this question so that we can explore this issue more 
thoroughly before making a final determination.
    Consistent with section 402(j)(3)(A)(ii)(II), NIH will continue to 
provide links, where possible, from individual clinical trials listed 
in ClinicalTrials.gov to related peer-reviewed literature and other 
authoritative information related to the intervention(s) studied or the 
disease or condition addressed. To avoid potential confusion, such 
links are indicated to have been added by the Agency and not by the 
responsible party.
7. Submission of the Full Protocol
    Section 402(j)(3)(D)(iii)(III) of the PHS Act provides that the 
regulations shall require 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.'' This requirement could be 
satisfied in any of several ways: (1) Requiring 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 statistical analysis plan, 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 PDF.
    Evaluating the results of a clinical trial involves the careful 
study and appraisal of the clinical trial methodology, so that results 
can be interpreted and their significance assessed. It can require 
detailed information about the conduct of a clinical trial, including 
the methods of participant selection, randomization, and assignment to 
arms; methods of collecting baseline and clinical trial data; specific 
information about the interventions used in the clinical trial (e.g., 
other elements of care that were provided in addition to the specified 
interventions studied in the clinical trial); and assessment of adverse 
events. It can also require information on the statistical techniques 
used to analyze collected results information.
    We received comments on submission of protocols at the public 
meeting in April 2009 [Ref. 1]. At that time, commenters did not know 
what other registration and results information would be proposed in 
this NPRM for submission to ClinicalTrials.gov and could not take those 
requirements into account in their comments. Most comments addressed 
the question of whether or not to require submission of the full 
protocol and did not consider other approaches to meeting the statutory 
requirement in section 402(j)(3)(D)(iii)(III) of the PHS Act. Given the 
proposals for submission of additional registration and results 
information detailed in section IV of this preamble, we are not 
proposing to require submission of the full protocol or other 
``information on the protocol.''
    We invite public comment on whether the registration and results 
information that is proposed for submission in this NPRM is sufficient 
to meet the statutory requirement in section 402(j)(3)(D)(iii)(III) of 
the PHS Act to provide ``information on the protocol'' as may be 
necessary to help evaluate the results of the clinical trial or whether 
submission of additional information, including submission of the full 
protocol, should be required. Comments should address the relative 
benefits and burdens of preparing and submitting any additional 
information and should indicate how such information will help evaluate 
the results of the clinical trial. We will consider such input in 
formulating the final rule.
8. Increasing the Time Period for Submitting Results Information
    Section 402(j)(3)(D)(iv)(I) of the PHS Act requires that the 
Secretary determine, by regulation, whether the deadline for submission 
of clinical trial results information of 1 year after the completion 
date of the applicable clinical trial--the deadline established in 
section 402(j)(3)(E)(i) of the PHS Act, which does not apply when a 
certification for delay is submitted or a request for extension is 
granted--should be increased from 1 year to a period not to exceed 18 
months. The public comments on this matter helped inform our view [Ref. 
1]. We believe there is value in making results information for primary 
outcome measures available within 1 year of the completion date. We 
therefore have decided not to propose lengthening the deadline for 
submitting results information, but to propose specific mechanisms for 
accommodating extended data collection for secondary outcomes to 
avoiding the premature unblinding of trials.
    Proposed Sec.  11.44(a)(1) provides that clinical trial results 
must be submitted no later than 1 year after the completion date of the 
clinical trial, unless a certification for delay is submitted or a 
request for extension is granted. In accordance with the statutory 
definition in section 402(j)(1)(A)(v) of the PHS Act, the term 
``[c]ompletion date'' is defined in proposed Sec.  11.10--for a 
clinical trial--to mean ``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.''

[[Page 69583]]

    We interpret the phrase ``primary outcome'' to be synonymous with 
the phrase ``primary outcome measure.'' In the event that clinical 
trial results data for all pre-specified secondary outcome measures 
have not been collected by the completion date, proposed Sec.  
11.44(a)(2) provides a process for submitting ``partial results'' to 
the data bank. In particular, the responsible party will remain 
responsible for submitting results information for each remaining 
secondary outcome measure until the responsible party has submitted 
results data, including associated adverse event data, for all pre-
specified outcome measures. Such results information must be submitted 
no later than 1 year after the date on which the final subject was 
examined or received an intervention for purposes of final data 
collection for the secondary outcome measure at issue. In cases where 
results submission under our proposed schedule would necessitate 
unblinding a trial, and doing so would affect a pre-specified secondary 
outcome measure, responsible parties should submit a request for an 
extension of the deadline for good cause, which must contain the 
elements outlined in proposed Sec.  11.44(e). As discussed in greater 
detail in section IV.C.3(d) of this preamble, we believe that the need 
to preserve the scientific integrity of an applicable clinical trial 
for which data collection is ongoing would, in general, constitute good 
cause for an extension.
    Based on our experience with approximately 1,200 data providers who 
have submitted results data to ClinicalTrials.gov, 1 year after the 
completion date of a clinical trial appears to be a reasonable amount 
of time for electronic data submission. We are aware of other results 
submission requirements (e.g., in Germany and the European Union) that 
define completion date as last patient, last visit (LPLV), instead of 
the final data collection for primary outcome as defined in section 
402(j)(1)(A)(v) of the PHS Act. The European Union proposal would 
require results to be submitted within 6 months of the LPLV date of 
completion [Ref. 28].
    To inform our proposal, we reviewed in the summer of 2009 a set of 
230 randomly selected clinical trials registered in ClinicalTrials.gov. 
We found that about 80 percent of the clinical trials listed a single 
time frame for all pre-specified primary and secondary outcome 
measures. In other words, completion date as defined in section 
402(j)(1)(A)(v) of the PHS Act and LPLV are identical for most of the 
clinical trials.
    We recognize that many factors, such as rate of participant 
enrollment, may contribute to when final data are collected for the 
primary outcome measure. Thus, we propose that the responsible party: 
(1) As specified in Sec.  11.10(b)(17) provide a reasonable estimate of 
the completion date upon registering the clinical trial (the Agency 
interprets ``estimated completion date'' as used in section 
402(j)(3)(E)(i)(I) of the PHS Act to be synonymous with ``expected 
completion date'' as used in section 402(j)(2)(A)(ii)(I)(jj) of the PHS 
Act); and (2) update the information to indicate the actual completion 
date in accordance with the time frame established in Sec.  
11.64(b)(1)(viii). We note, if the estimated completion date of a 
clinical trial changes before or during the clinical trial, the 
responsible party would be required to update estimated completion date 
information consistent with Sec.  11.64.
    Updating the estimated completion date promptly to reflect the 
actual completion date is important because, as proposed, responsible 
parties would need to submit clinical trial results information not 
later than 1 year after the actual completion date (unless they submit 
a certification for delayed results submission or a request for a good-
cause extension is granted). Hence, as described in proposed Sec.  
11.64, we propose to require that responsible parties update the 
completion date in ClinicalTrials.gov not later than 30 calendar days 
after a change. As with other data elements at ClinicalTrials.gov, all 
changes to posted information are tracked publicly at the 
ClinicalTrials.gov archive.
9. Retroactive Submission of Additional Results Information
    Section 402(j)(3)(D)(iv)(II) of the PHS Act provides that the 
Secretary shall, by regulation, determine ``whether the clinical trial 
information described in [section 402(j)(3)(D)(iii) of the PHS Act] 
should be required to be submitted for an applicable clinical trial for 
which the clinical trial information described in [section 402(j)(3)(C) 
of the PHS Act] is submitted to the registry and results data bank 
before the effective date of the regulations.'' The clinical trial 
information described in section 402(j)(3)(D)(iii) of the PHS Act 
refers to: (1) technical and non-technical narrative summaries of the 
clinical trial, (2) the protocol or other information on the protocol 
to help evaluate the results of the trial, and (3) other categories of 
information as determined to be appropriate by the Secretary.
    As explained in sections III.C.6 and III.C.7 of this preamble, we 
do not propose in this rule a requirement for the submission of 
technical or nontechnical narrative summaries or for the submission of 
the full protocol (although we invite public comment on both topics). 
We propose to require submission of ``other categories of information'' 
in two situations: When a responsible party submits results for 
applicable clinical trial of a device that has not been cleared or 
approved (see section IV.C.4.f of this preamble); and when a 
responsible party submits results information voluntarily under section 
402(j)(4)(A) of the PHS Act. Neither of these situations would apply to 
clinical trials for which results information is submitted prior to the 
effective date of the rule because responsible parties would not be 
required prior to the effective date of the rule to submit results of 
applicable clinical trials of devices that are not approved or cleared; 
nor would they be subject to the voluntary submissions provisions in 
section 402(j)(4)(A) of the PHS Act. Therefore, we do not propose to 
require the submission of clinical trial information described in 
section 402(j)(3)(D)(iii) of the PHS Act for an applicable clinical 
trial for which the clinical trial results information is submitted to 
ClinicalTrials.gov before the effective date of the regulations. As 
described in section III.D of this preamble on Effective Date, we do, 
however, propose to require the responsible party for an applicable 
clinical trial that reaches its completion date prior to the effective 
date of the final rule to submit all of the results information 
specified in proposed Sec.  11.48 if the responsible party has not 
submitted results information prior to the effective date of the rule. 
Requiring the submission of this information would improve the 
uniformity and consistency of information available in the data bank 
for applicable clinical trials.
10. Standard Data Formats
    Section 402(j)(3)(D)(v)(I) of the PHS Act provides that regulations 
regarding the submission of expanded results information shall also 
establish ``a standard format for the submission of clinical trial 
information under [section 402(j)(3)(D)(v)(I) of the PHS Act] to the 
registry and results data bank.'' Proposed Sec.  11.48 of this proposed 
rule implements standard data formats for results information, 
including adverse event information, taking into consideration comments 
made at the public meeting [Ref. 1].
    As discussed in sections II.B and III.C.12 of this preamble, NLM is 
adopting a tabular, structured data entry

[[Page 69584]]

system to promote objective reporting, optimize data display, permit 
effective searching of ClinicalTrials.gov, and facilitate cross-trial 
comparisons. To the extent possible, our proposal for submitting 
adverse event information is consistent with ICH-E3 formats (see http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073113.pdf) and Body Organ System Class for grouping 
adverse events by organ system, as required by the statutory default 
provisions in section 402(j)(3)(I)(iii) of the PHS Act. We have 
developed a mechanism for uploading results data in an automated 
electronic fashion using eXtensible Markup Language (XML) files. We do 
not believe that uploads of data tables in other formats will allow for 
the comparability and consistency desired across trials and do not 
include such a mechanism in our proposal.
11. Additional Information to Improve Patient Understanding of 
Submitted Information
    Section 402(j)(3)(D)(v)(II) of the PHS Act requires that the 
regulations establish ``additional information on clinical trials and 
results that is written in nontechnical, understandable language for 
patients[.]'' We interpret this provision to mean, in part, that the 
regulations must specify additional expanded results information that 
responsible parties would be required to submit to ClinicalTrials.gov 
to assist patients in understanding and interpreting other submitted 
clinical trial information.
    As discussed elsewhere in this preamble (see sections III.C.2 and 
III.C.15) and in several sections of this proposed rule, we propose 
additional data elements or types of information that responsible 
parties must submit to enhance the interpretability of submitted 
information related to registration and results, including adverse 
events. In developing the proposed regulation, we took into account 
numerous suggestions that were made at the public meeting about 
resources that could be included in the data bank to assist patients in 
understanding and interpreting information in the data bank [Ref. 1].
    Although section 402(j)(3)(D)(v)(II) of the PHS Act does not 
require the Agency to develop and provide additional information in 
ClinicalTrials.gov to assist users in better understanding and 
interpreting the submitted clinical trial information, we have paid 
careful attention to comments about how the ClinicalTrials.gov Web site 
might be improved. ClinicalTrials.gov already contains site-level 
resources to assist patients and other users in obtaining and 
understanding information on clinical trials in the data bank, e.g., 
FAQs on understanding clinical trials, a glossary of clinical trial 
terms, and an introduction that describes the general purpose and 
content of the data bank and cautions that the information should be 
used in conjunction with advice from healthcare professionals. In 
addition, each clinical trial record contains links to definitions that 
explain to the public standard terms such as ``condition'' and 
``intervention;'' and, where it exists, to information at select 
consumer health Web sites that is relevant to the clinical trial. Such 
information includes: resources related to the conditions being 
studied, from MedlinePlus (http://www.nlm.nih.gov/medlineplus/) and the 
Genetics Home Reference (http://ghr.nlm.nih.gov/); resources related to 
the intervention(s) being investigated, from the NLM Drug Information 
Portal (http://druginfo.nlm.nih.gov/) and FDA's Web site (www.fda.gov); 
and publications related to the clinical trial, including freely 
available abstracts if available, from PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). As noted in section III.C.6 of this 
preamble, we intend to add links from clinical trial records to other 
sources of related, authoritative health information (e.g., information 
from government sources and/or peer reviewed publications). Such 
information will be labeled as being added by NLM.
12. Quality Control Procedures
    Section 402(j)(3)(D)(v)(III) of the PHS Act provides that the 
regulations shall also establish procedures for quality control ``with 
respect to completeness and content of clinical trial information,'' 
including using representative samples, in order ``to help ensure that 
data elements are not false or misleading and are non-promotional[.]'' 
In developing such procedures, the Agency is to consider the experience 
gained through the pilot quality control project, described in section 
402(j)(5)(C)(i) of the PHS Act. The pilot quality control project is 
``to determine the optimal method of verification to help ensure that 
the clinical trial information submitted under . . . [section 
402(j)(3)(C) of the PHS Act] is non-promotional and is not false or 
misleading in any particular . . .'' (See section 402(j)(5)(C)(i) of 
the PHS Act). Comments submitted to the docket and discussed at the 
public meeting also have been considered in developing the quality 
control procedures [Ref. 1].
    We note that Section 801(d)(2) of FDAAA includes a Rule of 
Construction, which states that the ``submission of clinical trial 
information, if submitted in compliance with [section 402(j) of the PHS 
Act], that relates to the use of a drug or device not included in the 
official labeling of the approved drug or device shall not be construed 
by the Secretary of Health and Human Services or in any administrative 
or judicial proceeding, as evidence of a new intended use of the drug 
or device that is different from the intended use of the drug or device 
set forth in the official labeling of the drug or device.'' Public Law 
110-85, section 801(d)(2) (emphasis added). Section 801(d)(2) further 
states that the availability of clinical trial information through the 
data bank, if submitted in compliance with such subsection, shall not 
be considered as labeling, adulteration, or misbranding of the drug or 
device under the FD&C Act.
    Consistent with many of the comments we received, we have designed 
the ClinicalTrials.gov results submission system to encourage objective 
reporting. As discussed in section III.C.10 of this preamble, the 
tabular, structured data entry system developed for ClinicalTrials.gov 
promotes objective reporting, optimizes the data display and permits 
effective searching of the data bank. In addition, as discussed in 
section III.C.6 of this preamble we have not included a proposed 
requirement to submit non-technical and technical narrative summaries 
of the results of a clinical trial. We intend to study this issue 
further and are inviting additional public comment on it. At present, 
procedures for quality control relate to the review of structured data 
that would be required to be submitted to ClinicalTrials.gov under this 
proposed rule.
    (a) Pilot Quality Control Project. As a preliminary step toward 
satisfying the required pilot quality control project under section 
402(j)(5)(C)(i) of the PHS Act, we conducted a quality control study 
that 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, conducted under 
contract by researchers at the Oregon Health Science University [Ref. 
32].
    The first part of the quality control study led to the development 
of detailed quality review criteria [Ref. 33, 34].

[[Page 69585]]

Since the launch of the ClinicalTrials.gov results data bank, each 
submission of results information has been reviewed for apparent 
validity, meaningful entries, logical and internal consistency, and 
formatting. We have tried to ensure that submitted results information 
is objective and contains no comments about conclusions, clinical 
implications, or comparisons with other studies or other data. Table 1 
lists common types of errors, deficiencies and inconsistencies with 
specific examples that were seen during this time period. Data 
submitters were notified of errors, deficiencies and/or inconsistencies 
found during this first part of the quality control study and asked to 
revise their submissions. During this period, clinical trial results 
information was not posted in ClinicalTrials.gov until the errors, 
deficiencies and/or inconsistencies identified by the quality review 
had been addressed by responsible parties. In some cases, corrected 
information was not provided until more than 30 days had passed from 
the initial submission.
    To assist responsible parties in avoiding such errors, deficiencies 
and inconsistencies, we developed and continue 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 results submission 
process, whether through data entry using Web-based forms or automated 
uploading of data files. We have developed and posted draft educational 
materials, such as tips on improving results submissions and ways to 
avoid common errors, deficiencies and inconsistencies observed in 
submissions to date. All such documents are available at http://prsinfo.clinicaltrials.gov/fdaaa.html. We will continue to provide 
support to responsible parties and, based on these interactions, 
develop new or updated materials in order to facilitate and streamline 
preparation of results data for submission to ClinicalTrials.gov and to 
help ensure that the submissions meet the quality review criteria.

    Table 1--Some Common Types of Errors, Deficiencies and Inconsistencies Identified in Results Submissions
----------------------------------------------------------------------------------------------------------------
        Data quality category                Description                Example                Explanation
----------------------------------------------------------------------------------------------------------------
Lack of apparent validity............  Data not plausible       Outcome measure          Measure of mean hours
                                        based on information     indicating a mean        per day can only have
                                        provided.                value of 263 hours per   values in the range of
                                                                 day of sleep.            0-24. Value of ``263''
                                                                                          is not valid.
Incomplete Information...............  Information              Outcome measure          Data are uninformative.
                                        insufficient to convey   description states       Unclear to what counts
                                        intended meaning.        ``clinical evaluation    of 100 and 96
                                                                 of adverse events,       participants refer.
                                                                 laboratory parameters    Outcome measure
                                                                 and imaging''; data      description not
                                                                 reported as 100 and 96   sufficiently
                                                                 participants, in each    descriptive to
                                                                 arm.                     understand specific
                                                                                          outcome.
Incomplete information...............  Information              Outcome measure          Data are uninformative
                                        insufficient to convey   assessed on a scale,     without an explanation
                                        intended meaning.        which is not             of what the scale is
                                                                 explained; data          assessing and the
                                                                 reported as mean         range and direction of
                                                                 values of 3.2 and 4.1    scores (e.g., whether
                                                                 in the two arms.         3.2 is better or worse
                                                                                          than 4.1 on a 5-point
                                                                                          scale).
Internal inconsistency...............  Data not consistent      Outcome measure title    A time-to-event measure
                                        with descriptive         is ``time to disease     requires a unit of
                                        information.             progression;'' data      time such as days or
                                                                 reported as 42 & 21      months.
                                                                 participants, in each
                                                                 arm.
Internal inconsistency...............  Data in one section are  Baseline                 If there is a third
                                        not consistent with      characteristics &        group, then Baseline
                                        data in another          participant flow         Characteristics and
                                        section.                 entered as 2-armed       Participant Flow
                                                                 study with a total of    modules must reflect
                                                                 400 participants;        this or group
                                                                 outcomes entered for 3   descriptions in
                                                                 arms with 600            Outcomes should
                                                                 participants.            explain their origin.
----------------------------------------------------------------------------------------------------------------

    These efforts have produced significant improvements in the quality 
of initial submissions of results information to ClinicalTrials.gov. 
Whereas in 2008 only 5 percent of submissions met the quality review 
criteria when first submitted, by 2012 approximately 36 percent of 
initial submissions met the quality review criteria. Improvements in 
the percentage of initial results submission that meet our quality 
review criteria may be a consequence of three factors: (1) greater 
familiarity among responsible parties and sponsors with the system and 
the associated rules, (2) better resource materials from 
ClinicalTrials.gov, and (3) growing awareness that the task of entering 
results requires involvement of personnel with a full understanding of 
the trial design and results. The number of responsible parties 
submitting data has increased each quarter.
    The second part of the quality control study compared the 
consistency of posted results information for phase 3 or 4 clinical 
trials of drugs that were completed prior to January 1, 2009 and had 
submitted results by November 17, 2010 with results information 
published in peer reviewed journals and documents made publicly 
available on the FDA Web site, such as medical reviews. A publication 
was identified for only 32 percent of the 342 trials that were sampled, 
and in 82 percent of the publication-trial pairs at least one 
discrepancy was found between the data submitted to ClinicalTrials.gov 
and the data contained in the peer-reviewed journal article. 
Discrepancies occurred in almost all fields analyzed, including number 
of arms, primary and secondary outcome measures (the name of the 
measure as well as the actual data), total enrollment, and number of 
serious adverse events. In cases where the publication addresses a 
subset of the data in the trial, the apparent discrepancies could be 
correct reflections of the clinical trial results for the population 
covered [Ref.38].
    The study results demonstrate that comparisons with publications 
cannot be used in real time to validate results submissions to 
ClinicalTrials.gov. For the great majority of clinical trials, no 
publications are available for comparison at the time results are 
submitted to the data bank. In addition, for clinical trials of 
products that have not been approved, licensed, or cleared, or for 
which a new indication is being

[[Page 69586]]

studied but has not yet been approved, licensed, or cleared, 
information about the clinical trial ordinarily is not available on 
FDA's Web site at the time results are submitted to ClinicalTrials.gov. 
Thus, we do not believe that comparisons with publications or FDA 
documents would provide a feasible or effective method of routinely 
screening submitted clinical trial records with results to help ensure 
that the clinical trial information is non-promotional and not false or 
misleading in any particular.
    As required by section 402(j)(5)(C)(i), we plan to continue 
conducting the pilot quality control project in coordination with the 
Commissioner of Food and Drugs until the effective date of this 
regulation to determine the optimal method of verification to help 
ensure that the clinical trial information submitted under section 
402(j)(3)(C) of the PHS Act is non-promotional and is not false or 
misleading in any particular. In addition, we will continue to use 
comparisons with random samples of publications or public FDA documents 
to identify problems and improve our procedures. In addition, if we 
become aware of a publication or FDA document that appears to contain 
information that is inconsistent with a submitted clinical trial 
record, we will consult with FDA on the appropriate next steps.
    (b) Proposed Quality Control Procedures. Based on the public 
comments we received, experience with the preliminary steps of the 
pilot quality control project, and consistent with current practice, we 
intend to continue a form of quality control at the time of clinical 
trial registration or submission of clinical trial results information 
that is similar to the procedures we have been using for the past 
several years. The quality control process will not affect the 
statutory deadlines for submitting or publicly posting submitted 
clinical trial information.
    Our quality control process cannot determine the veracity of the 
data submitted, and all entries in ClinicalTrials.gov will carry a 
disclaimer to that effect. Our quality control process is intended to 
help ensure that clinical trial information posted on 
ClinicalTrials.gov has face validity and is free from obvious errors. 
The identification of two or more data elements within a clinical trial 
record that are internally inconsistent is an effective method of 
identifying errors since, by logic, both pieces of data cannot be 
correct. By providing responsible parties with information as to which 
elements of submitted clinical trial information do not meet specified 
quality review criteria, we can better facilitate access by the public 
to information that is not obviously incomplete, incorrect, or 
inconsistent.
    Overall, our proposed quality control process for submission of 
clinical trial registration information or clinical trials results 
information will consist of two sequential components as follows: (1) 
an automated system-based check, followed by (2) a detailed, manual 
review. In the first component, the ClinicalTrials.gov system would 
alert 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 automated checks in order to assist 
submitters in detecting and minimizing errors, deficiencies, and 
inconsistencies in the information they are submitting.
    Once clinical trial information has passed the automated checks and 
been submitted, we would begin the second component of quality control: 
the detailed, manual review. We would review all data submissions that 
pass the automated system checks in order to identify, based on 
detailed quality review criteria, additional apparent errors, 
deficiencies, or inconsistencies that are not detected by the automated 
checks. If problems are identified in the detailed, manual review, we 
would send an electronic notification to the responsible party, 
indicating that the submission contains apparent errors, deficiencies 
and/or inconsistencies listing the errors, deficiencies and/or 
inconsistencies found, and requesting correction. Consistent with the 
proposal in Sec.  11.66 regarding correction of clinical trial 
information, responsible parties would be required to correct the 
errors, deficiencies and/or inconsistencies not later than 15 calendar 
days after being informed of them by the Agency or otherwise becoming 
aware of them (e.g., if they discover the errors, inconsistencies, and/
or deficiencies themselves), whichever is later. (See the discussion of 
the corrections provision in section IV.D.4 of this preamble).
    We expect to complete the quality control process and to receive 
submissions of corrected clinical trial information prior to the 
deadlines for posting such information publicly, as established by 
sections 402(j)(2)(D) and 402(j)(2)(G) of the PHS Act. We recognize 
that in some situations, the quality review process may not be 
completed prior to the statutory posting deadlines, and we will have to 
post submitted information that has not been corrected. Clinical trial 
information posted without having completed the quality control review 
and any necessary correction by the responsible party will include a 
statement indicating that it has not completed the quality control 
process. Users searching ClinicalTrials.gov will be able to elect to 
include or exclude clinical trial registrations or clinical trial 
results information that have not yet completed the quality control 
process proposed in this NPRM. When revised information correcting the 
noted errors has been submitted and the revised information has passed 
the quality control process, the statement that the clinical trial 
record has not completed the quality control process would be removed 
from the posted record. However, the information that was initially 
posted prior to completion of the quality control review would 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 believe additional precautions must be taken with clinical trial 
registration information that has not completed quality review. 
Clinical trial registration information may be used by patients and 
healthcare providers who are considering enrollment in a clinical 
trial. Although we will post information submitted when clinical trials 
are registered consistent with the time frames in section 402(j)(2)(D) 
of the PHS Act and with the statement described above, we will not 
assign an NCT number until information submitted has completed our 
quality control process. Thus, if the quality control process and any 
necessary data correction by the responsible party have not been 
completed within calendar 30 days after an applicable drug clinical 
trial has been registered, the information submitted will be posted 
without an NCT number. This approach is consistent with the practice 
that has been in effect since ClinicalTrials.gov was launched in 2000. 
This approach would 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 registration of 
the clinical trial has gone through the proposed two-stage quality 
control process. Use of NCT numbers is

[[Page 69587]]

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. 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 in a matter of days.
    Other elements of quality control are described in proposed Sec.  
11.66 and section IV.D.4 of this preamble. We recognize that clinical 
trial data elements that are submitted as free-text could be phrased in 
a manner that might be considered promotional or misleading. We solicit 
comment on ways in which the descriptions of the data elements in the 
proposed codified could be improved to help ensure that submitted 
clinical trial information is not promotional or misleading. We also 
seek comment on standards we could use for determining when clinical 
trial information should be considered to be promotional. Finally, we 
solicit comment regarding how the pilot quality control project may 
help ensure that the clinical trial information submitted under 
paragraph (j)(3)(C) is non-promotional and not false or misleading 
under paragraph (j)(5)(D).
    We note that compliance with our quality control process, including 
the requirements set forth in Sec.  11.66, does not necessarily 
constitute a legal defense to enforcement pursuant to section 301(jj) 
of the FD&C Act (21 U.S.C. 331) and 303(f) of the FD&C Act (21 U.S.C. 
333(f)).
13. Updating Submitted Clinical Trial Information
    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 
interpret the term ``clinical trial information'' to mean both 
information submitted when a clinical trial is registered 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 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. 
Our proposals take into consideration comments made at the public 
meeting [Ref. 1].
    Proposed Sec.  11.64(a)(1) provides that, in general, updates of 
clinical trial information must be provided every 12 months, unless 
there are no changes during the previous 12 months. Proposed Sec.  
11.64(a)(2) specifies that a responsible party must submit updates 
until the final clinical trial results information has been submitted 
for all primary and secondary outcome measures and all adverse events 
collected in accordance with the protocol. After all such results 
information has been submitted, a responsible party's obligation to 
update the record would end unless and until the responsible party 
becomes aware of errors in the submitted clinical trial information. In 
that case, the responsible party would need to submit corrected 
information as specified in proposed Sec.  11.66.
    Proposed Sec.  11.64(b) identifies several data elements that must 
be updated not later than 30 days after a change occurs (e.g., Overall 
Recruitment Status and Availability of Expanded Access), requires 
updates to U.S. FDA Approval, Licensure, or Clearance Status not later 
than 15 calendar days after the change occurred, and specifies 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. A responsible party would also be required to update the Record 
Verification Date any time the responsible party reviews the complete 
clinical trial record for accuracy, even if no other updates are 
submitted at that time. 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). Doing so will 
improve the accuracy of information that is used by ClinicalTrials.gov 
to automatically prepopulate some elements of results information. 
Further discussion of these update requirements appears in the 
description of proposed Sec.  11.64 in section IV of this preamble.
    As set forth in proposed Sec.  11.64(d)(2), all prior clinical 
trial information, including past updates of posted submissions, are 
tracked in the ClinicalTrials.gov archive, in which the full history of 
changes to clinical trial information for any clinical trial is 
accessible to the public. Note that, as discussed in section III.C.13 
of this preamble, the time frames for updating registration and results 
information do not apply to corrections of errors, corrections of 
falsified data, and other corrections of clinical trial information, 
which should be made in accordance with the time frames proposed in 
Sec.  11.66. (See section 402(j)(5)(D)(i) of the PHS Act.)
14. Statement To Accompany Certain Trials and Other Issues Related to 
Voluntary Submissions
    Section 402(j)(3)(D)(v)(V) of the PHS Act provides that the 
regulations shall also establish ``a statement to accompany the entry 
for an applicable clinical trial when the primary and secondary outcome 
measures for such clinical trial are submitted under paragraph (4)(A) 
[voluntary submissions] after the date specified for the submission of 
such information in paragraph (2)(C)[.]'' Some applicable clinical 
trials are not subject to mandatory registration or submission of 
results information because they were not initiated after, or ongoing 
as of, the dates established in section 402(j)(2)(C) of the PHS Act 
(i.e., 90 days after the date of enactment of FDAAA). They would be 
considered ``submitted under paragraph (4)(A)'' if the responsible 
party submits the information voluntarily to ClinicalTrials.gov or if 
the responsible party is required to submit the information under 
section 402(j)(4)(A) of the PHS Act because the applicable clinical 
trial is included in a marketing application or premarket notification 
submitted to FDA. Submitted information might consist of

[[Page 69588]]

registration information and/or results information. We interpret 
section 402(j)(3)(D)(v)(V) of the PHS Act to require a statement to be 
posted with the clinical trial registration and/or the results 
information for such applicable clinical trials because primary and 
secondary outcome measures are required at the time of both 
registration and submission of results information. See 
402(j)(2)(A)(ii)(ll) and (3)(C)(ii) of the PHS Act.
    We note that for applicable clinical trials subject to section 
402(j)(4)(A) of the PHS Act, it would be permissible for information 
about the primary and secondary outcome measures to be submitted after 
the deadline established for clinical trial registration under section 
402(j)(2)(C) of the PHS Act. We interpret section 402(j)(3)(D)(v)(V) of 
the PHS Act to require a statement that clarifies that the submission 
was not subject to the deadlines imposed by section 402(j) of the PHS 
Act for clinical trial registration and submission of results 
information. Such a statement would be valuable in demonstrating to 
users of ClinicalTrials.gov that the submitted information is not out-
of-compliance with the statutory deadlines for submitting information 
about the primary and secondary outcomes. Some commenters recommended 
specific language for the statement to accompany these voluntary 
submissions (Ref. 1).
    We propose in Sec.  11.60(b) that the following statement accompany 
each applicable clinical trial for which clinical trial information is 
submitted voluntarily to ClinicalTrials.gov under section 402(j)(4)(A) 
of the PHS Act or proposed Sec.  11.60(a): ``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.'' Proposed 
Sec.  11.60 provides that a responsible party may voluntarily submit 
complete clinical trial information for trials of FDA-regulated drugs 
or devices that are not applicable clinical trials, such as phase 1 
trials, but only if certain conditions are met. If a responsible party 
registers or submits clinical trial results information voluntarily for 
such a clinical trial, section 402(j)(4)(A) of the PHS Act requires 
that such information be complete, and that clinical trial information 
be submitted with respect to certain ``triggered'' applicable clinical 
trials. These requirements are discussed further in section IV.D.1 of 
this preamble.
15. Adverse Event Information
    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.'' Such regulations are to be 
issued not later than 18 months after the date of enactment of FDAAA 
(i.e., by March 27, 2009). Section 402(j)(3)(I)(ii) of the PHS Act 
specifies that if such 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), a set of default provisions in sections 402(j)(3)(I)(iii)(I) 
and (II) of the PHS Act (referred to hereinafter as ``the statutory 
default provisions'') take effect. The statutory default provisions 
require 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 
this proposed rule and in ClinicalTrials.gov, 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 event table in 
(2) as the ``other adverse events table.''
    The statutory default provisions set forth in sections 
402(j)(3)(I)(iii)(I) and (II) of the PHS Act became mandatory as of 
September 27, 2009. For a year prior to this date, responsible parties 
were able to submit adverse event data voluntarily and adjust the 
threshold for other adverse events to the level of their choice. Such 
an approach allowed us to test whether frequency thresholds other than 
5 percent were better suited to the submission of information about 
other adverse events and might constitute the ``best method'' for 
submitting information about other adverse events. Responsible parties 
were also able to submit comments on the way ClinicalTrials.gov 
collected adverse event information so that we could improve the design 
and implementation of the system. [See: Docket NIH-2009-0002]
    Our proposal for submitting adverse event information in Sec.  
11.48(a)(4) is based on the statutory default provisions in sections 
402(j)(3)(I)(iii)(I) and (II) of the PHS Act, with some modifications. 
We believe that the Secretary has authority to modify the statutory 
default provisions 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],'' and we believe that 
this clinical trial information is coextensive with 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 authority, under section 
402(j)(3)(D)(v)(VI) of the PHS Act, to modify the statutory default 
provisions for submission of adverse event information via regulation, 
provided that such modifications represent ``additions or modifications 
to the manner of reporting [adverse event information] . . .''
    We propose to maintain the requirement under the statutory default 
provisions in sections 402(j)(3)(I)(iii)(I) and (II) of the PHS Act to 
submit two tables of information summarizing anticipated and 
unanticipated adverse events that were collected in accordance with the 
protocol, i.e., one table for all serious adverse events and one table 
for other adverse events that exceed a frequency of 5 percent within 
any arm of the trial. We would continue to allow the submission of 
other adverse events with a frequency of less than 5 percent on a 
voluntary basis, as many data submitters have continued to do. 
Consistent with the statutory default provisions, our proposal would 
require submission of information on all such adverse events, not only 
those that are unanticipated or considered attributable to 
interventions studied in the clinical trial, to the extent that the 
collection of these data was specified in the protocol for the trial. 
By including information on adverse events, regardless of whether or 
not they were considered anticipated or attributed to the 
intervention(s) studied in the clinical trial, ClinicalTrials.gov would 
provide an

[[Page 69589]]

objective summary of the adverse events that were collected during the 
trial.
    We do not intend for our proposal to cause an investigator to 
collect adverse event information of a type or in a way that is not 
specified in the protocol. For clinical trials for which the protocol 
specifies collection of only a limited set of adverse events (e.g. 
unanticipated adverse reactions), we would require the responsible 
party to submit to ClinicalTrials.gov a summary of the information that 
was collected during the clinical trial about serious adverse events 
and other adverse events that exceed a frequency of 5 percent within 
any arm of the trial. In addition, as specified in proposed Sec.  
11.48(a)(4)(ii)(H), we would require the responsible party to describe 
how the types of adverse events collected in the clinical trial differ 
from the types of adverse events and serious adverse events defined in 
proposed Sec.  11.10. We believe this proposal would provide 
responsible parties with a convenient means of submitting required 
adverse event information without causing them to collect and submit 
information that is not specified in the protocol. It would also permit 
users of ClinicalTrials.gov to understand how submitted adverse event 
information differs in scope and kind from the adverse event 
information defined in this part.
    Implementing the statutory default provisions for adverse event 
information entails an interpretation of the requirement to submit 
information describing the ``number and frequency'' of adverse events. 
Sections 402(j)(3)(I)(iii)(II) and (III) of the PHS Act do not specify 
whether the number and frequency of adverse events refer to the number 
of participants who experience an adverse event and the frequency 
relative to the number of participants assessed for that adverse event 
(i.e., the number of participants who were ``at risk'' for experiencing 
that adverse event) or to the absolute number of adverse events or 
occurrences, independent of the number of participants involved. When 
an adverse event occurs only once in a participant, the two methods of 
summarizing adverse event data are equivalent (i.e., the number of 
participants experiencing an adverse event is equal to the number of 
events that occurred). However, when an adverse event occurs multiple 
times in a single participant, information about the number of adverse 
events without information about the number of affected participants 
could be confusing. For example, if the submitted information indicates 
that 20 headaches occurred in an arm with 100 participants, it would be 
unclear how many participants experienced headaches: the number could 
range from as many as 20 participants with one headache each to as few 
as one participant with 20 headaches.
    We interpret the statutory default provisions to require submission 
of information about the number of participants who experienced an 
adverse ``event'' and the total number of participants at risk for the 
adverse event. This interpretation is consistent with existing 
conventions for summarizing adverse event information (e.g., CONSORT 
Statement on Harms) and supports the important objective of summary 
results submission, which is to allow users to compare the number of 
participants who may have benefited from a particular intervention with 
the number who experienced adverse events during a trial. Consistent 
with requirements in effect at ClinicalTrials.gov since September 2009, 
we propose that responsible parties submit both the number of 
participants who experienced an adverse event and the total number of 
participants at risk for the adverse event. ClinicalTrials.gov provides 
features to simplify submission of the number at risk (e.g., when the 
number at risk is the same for all adverse events submitted) and would 
use this information in combination with the number of participants 
affected to compute the frequency automatically.
    We also believe there is value in making information available 
about the number of adverse events. Since September 2009, responsible 
parties have had the option of voluntarily submitting the total number 
of occurrences of each adverse event in addition to the number of 
participants affected. Many responsible parties have submitted this 
information voluntarily; nearly half of the results submitted in 2012 
for clinical trials that appear to meet the definition of applicable 
clinical trials included the total number of occurrences for adverse 
events. We will continue to provide a mechanism for responsible parties 
to voluntarily provide event level information for adverse events.
    We considered, but do not propose, requirements for responsible 
parties to provide the total number of occurrences of each serious 
adverse event and the number of such occurrences considered, as of a 
specific date, to be attributable to the intervention(s) under study. 
Participants in many clinical trials have serious conditions that cause 
adverse events; they are also subject to the accidents and other 
unpredictable health events that affect the general population. During 
the course of a clinical trial, participants may die or suffer other 
serious adverse events due to causes that are unrelated to the 
interventions they are receiving as part of the clinical trial. 
Evaluating whether a specific adverse event is likely to have been 
caused by an intervention studied in the clinical trial can be valuable 
while the clinical trial is ongoing and data are still being collected 
because it can lead to modifications in the clinical trial to better 
protect the human subjects. The value of attribution at the level of an 
individual adverse event is less certain after a clinical trial has 
completed and all clinical trial data have been collected. The 
determination of attribution is, by its nature, subjective, influenced 
by various biases, and can change over time within a given clinical 
trial. The ``gold standard'' for assessing possible causal 
relationships between an adverse event (or a series of adverse events) 
and an intervention after completion of a clinical trial is an 
empirical comparison of the adverse events that occurred in different 
arms of the clinical trial. Because adverse event information would be 
submitted to ClinicalTrials.gov after completion of a clinical trial 
(as long as three years after the completion date if the responsible 
party submits a certification for delayed results submission), we do 
not propose a requirement for including attribution information. We 
invite public comment on any aspect of this issue, as well as 
information about current practices for attribution of serious adverse 
events that might help us to refine proposed requirements for 
submission of adverse event information.
    To further assist users in understanding and interpreting submitted 
adverse event information, we propose to require the submission of 
additional information, based on our experience in operating 
ClinicalTrials.gov to-date. Some of this information is already 
collected on a voluntary basis in ClinicalTrials.gov, and some has been 
required since September 2009, but one data element is new.
    We propose to continue to require responsible parties to submit 
information about adverse events by organ class for each arm and for 
each table (serious adverse events and other adverse events), as 
required by the statutory default provisions in section 
402(j)(3)(I)(iii)(I) and (II) of the PHS Act. We propose to require 
responsible parties to use the organ system classes specified in the 
Medical Dictionary for Regulatory Affairs (MedDRA) (http://www.meddramsso.com/) to classify the specific adverse event terms 
(e.g., nausea) by organ system. Our

[[Page 69590]]

experience with voluntary and mandatory adverse events submission since 
September 2008 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 
between tables for a trial and across trials.
    We also propose to require responsible parties to submit the total 
number of participants affected by an adverse event at the organ system 
level. This information would be required for each arm of the clinical 
trial and for each adverse event table (serious adverse events and 
other adverse events). Section 402(j)(3)(I)(iii) of the PHS Act 
requires the listing of adverse events by organ system. We believe that 
one purpose of this provision is to enable comparisons across arms even 
when there are variations in the level of specificity or granularity of 
the data submitted. Unless the total number of participants with 
adverse events is provided at the level of the organ system, the 
serious adverse event and other adverse event tables will not be able 
to support such comparisons. For example, if one trial lists 5 
participants with ``rash'' under the ``Skin and subcutaneous tissue 
disorders'' organ system category and another lists 2 participants for 
each of three specific types of rashes under the same category, it is 
not possible to know which trial had more participants with adverse 
events affecting the skin, because certain participants in the second 
trial could have suffered more than one type of rash. Thus, in order to 
obtain an important benefit of listing adverse events by organ system, 
we believe that it is necessary to require responsible parties to 
submit the total number of participants affected by any adverse event 
within each organ system for which adverse event data were collected. 
For organ systems that do not have a submitted adverse event, 
ClinicalTrials.gov will automatically assume that the total number of 
participants affected by that organ system is 0 (zero) for serious 
adverse events, and less than the 5 percent threshold for other adverse 
events, which will reduce the burden of this proposed requirement.
    We also propose to continue to require responsible parties to 
submit information about the total number of participants affected by 
any adverse event for each arm in each table. As described earlier in 
this section, it is our view that this information permits better 
interpretation of the adverse event data by clearly presenting how many 
participants were affected by any adverse event in a given arm of the 
clinical trial.
    We also considered, but do not propose to require submission of 
several other types of information describing the collection of adverse 
events in a clinical trial. Responsible parties are currently able to 
submit some of this information voluntarily. We invite public comment 
on the potential benefit and burden of requiring that the following 
types of information be submitted to ClinicalTrials.gov. We will 
consider comments in preparing the final rule.
    Time frame: Time frame information would specify when during the 
clinical trial adverse event information was collected. Information on 
different types of adverse events may be collected during different 
time frames in a clinical trial. Some adverse events are recorded only 
during specific portions of the trial, while others may be recorded 
throughout the duration of the trial [Ref. 35, 36, 37]. Time frame 
information could assist users of ClinicalTrials.gov in interpreting 
correctly and comparing the relative occurrence of adverse events 
across different clinical trials. Submission of this information is 
currently optional. Responsible parties provided time frame information 
with more than half of the results information submitted in 2012 for 
probable applicable clinical trials.
    Collection approach: Collection approach information would indicate 
the type of approach taken to collect adverse event information, either 
``systematic assessment'' or ``non-systematic assessment.'' Systematic 
assessment involves 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. The approach 
used to assess adverse events affects comparability of information 
across clinical trials. For example, clinical trials using non-
systematic assessment typically will record fewer adverse events than 
those using systematic assessment [Ref. 37]. Therefore, knowledge of 
the type of approach used to identify adverse events may help users of 
ClinicalTrials.gov to interpret differences in the rates of adverse 
events in different clinical trials. Submission of assessment type 
information currently is optional in ClinicalTrials.gov. Responsible 
parties who choose to submit this information select from the set of 
descriptors available in ClinicalTrials.gov (either ``systematic 
assessment'' or ``non-systematic assessment''). To simplify data entry, 
responsible parties are able to indicate the assessment type for the 
adverse event table as a whole or by each adverse event in the table. 
Of results for probable applicable clinical trials submitted in 2012, 
76 percent included information about the approach to collecting some 
adverse events.
    All-cause mortality information: An all-cause mortality table would 
consolidate information about all participant deaths from any cause 
following assignment to an arm, by arm, for the clinical trial. 
Although information related to deaths may be part of other clinical 
trial results information, the total number of deaths that occurred 
during the clinical trial might not be readily apparent (e.g., 
submitted adverse event information might indicate a number of subjects 
who experienced a myocardial infarction, but would not necessarily 
indicate how many of the subjects died from the event). Submission of 
all-cause mortality information would be consistent with some clinical 
trial reporting guidelines [Ref. 23, 38], but it might need to be 
accompanied by additional explanatory information that would assist 
users in interpreting it correctly, e.g., to indicate that deaths may 
not have been associated with the interventions studied in the clinical 
trial.
    Standard vocabulary for adverse event terms. We also considered, 
but do not propose to require that adverse event terms be submitted 
according to a standard vocabulary. Although use of a single vocabulary 
might improve the comparability of adverse event data across trials 
represented in ClinicalTrials.gov, we do not believe it is reasonable 
to require responsible parties to submit adverse event data using a 
specific vocabulary. There is no agreed-upon standard adverse event 
vocabulary that is used in collecting and categorizing adverse event 
data for the full range of clinical trials. ClinicalTrials.gov 
currently allows responsible parties to indicate voluntarily any 
standardized vocabulary they have used when collecting adverse event 
data. Examination of the data voluntarily provided to date confirms 
that various versions of MedDRA are widely used by the pharmaceutical 
industry as the source of adverse event terms, but not by other 
entities (e.g., device manufacturers, non-industry organizations) that 
sponsor and conduct clinical trials. Other organizations use a variety 
of vocabularies, including SNOMED CT, which is an HHS-required standard 
for certification of electronic

[[Page 69591]]

health record products, or use no standard vocabulary at all. A 
requirement to submit adverse event data using a particular vocabulary 
would add significantly to the data submission burden for any 
responsible party who had used a different (or no) standard terminology 
in collecting adverse event data. In addition, requiring data collected 
under one terminology to be converted to a different terminology for 
submission to the data bank would carry unacceptable risks of data loss 
or misrepresentation. Such conversion is also a potentially much more 
difficult and time-consuming task than assigning high-level organ 
system classes to individual adverse event terms. As an alternative, we 
considered proposing that a single standard vocabulary be used to 
submit adverse event data for all clinical trials that are initiated 
after some date in the future (e.g., 2017). We rejected this approach 
because we do not think there is sufficient consensus on a standard 
vocabulary that is suitable for the full range of applicable clinical 
trials, and because ideally, data submission standards should follow 
data collection standards.
    We understand that adverse event data from individual clinical 
trials are inherently difficult to interpret or to compare with similar 
data from other trials of the same intervention. Many factors may 
contribute to differences in the adverse events data collected in 
different trials, including differences in patient populations, 
differences in the methods or duration of adverse events collection, or 
in the types of adverse events collected. In addition, adverse event 
information available in ClinicalTrials.gov for a clinical trial most 
likely will differ from the adverse event data included in published 
reports or FDA documents discussing the same clinical trial, which may 
contain information on only a subset of adverse events for specific 
trials or provide aggregated information from multiple clinical trials. 
To avoid confusion with adverse event information available from 
sources other than ClinicalTrials.gov and to assist ClinicalTrials.gov 
users with varying degrees of expertise in clinical trial design and 
data analysis in understanding the adverse event data contained in the 
data bank, we will include a prominent notice and explanation in 
ClinicalTrials.gov describing the types of adverse events that are 
listed in clinical trial records and how they might differ between 
clinical trials and from information available in other sources. In 
addition, we will consider steps such as (1) linking to and offering on 
the ClinicalTrials.gov site other resource materials describing issues 
that need to be considered when interpreting adverse event information 
(e.g., issues of attribution, participants at risk); (2) creating a 
default public display that highlights certain data (e.g., all serious 
adverse events and other adverse events with frequencies above a 
certain threshold, such as 20 percent); and (3) providing mechanisms to 
allow the user to customize the display (e.g., by adjusting the 
frequency threshold).
    We invite comments on all aspects of our proposed requirements for 
submission of adverse events information for clinical trials, 
including: (1) The benefit and burden of the proposed modifications to 
the statutory default provisions, including the number of participants 
affected by adverse events at the organ system level for both serious 
adverse events and other adverse events; (2) the potential benefit and 
burden of the additional information considered but not included in the 
proposal, such as the number of occurrences of each serious adverse 
event (in addition to the number of participants affected by a serious 
adverse event), the number of occurrences of each serious adverse event 
considered causally related to the intervention(s) studied, the time 
frame for collecting adverse events, the collection approach 
(systematic vs. non-systematic), and all-cause mortality information; 
(3) ways to reduce the data submission burden without reducing the 
value of the data submitted; and (4) approaches to increasing 
standardization in the vocabularies used in submitting adverse event 
information. We also invite and encourage the submission of any other 
information on current practices for collection, attribution, and 
summarization of adverse event data that might help us to refine the 
proposed requirements for submission of summary adverse event 
information.
16. Privacy Considerations
    We believe that, in general, the information submitted to 
ClinicalTrials.gov for the vast majority of applicable clinical trials 
subject to this proposed rule would pose no privacy concerns. 
Registration and results information submitted to ClinicalTrials.gov 
pursuant to this proposed rule would consist of summary level data only 
and would not contain personally identifiable information. It would 
consist of the same type of information that would be expected to be 
included in a journal article or other routine form of public 
scientific communication. In addition, participants would be aware that 
summary data would be posted at ClinicalTrials.gov. FDA regulations 
require that informed consent forms for applicable clinical trials of 
drugs and devices include a specific statement to inform potential 
participants that certain information about the clinical trial will be 
submitted to ClinicalTrials.gov, where it will be publicly posted [see 
21 CFR Sec.  50.25(c)].
    We also believe that in most cases it would not be possible to re-
identify individuals who participated in a clinical trial based on the 
data submitted to ClinicalTrials.gov. For clinical trials of common 
diseases, or that recruit large numbers of participants, and/or recruit 
participants from multiple locations, the summary information submitted 
to ClinicalTrials.gov would be unlikely to contain characteristics that 
would enable re-identification of study participants. Even the 
information submitted for small trials with limited numbers of sites 
and few study participants would, in general, provide no clear basis 
for re-identification.
    The risk of re-identification could be greater in particular types 
of clinical trials, such as small clinical trials that study treatments 
for rare diseases and have few recruitment sites or that recruit 
subjects from only small, well-defined populations. For some such 
clinical trials, we believe that a responsible party could submit 
required results information in a way that minimizes opportunities for 
re-identification. For example, if a trial of a rare disease recruits a 
participant of 90 years or more, the responsible party could consider 
submitting demographic information by grouping subjects into broader 
age categories or providing the mean age of all subjects in each arm of 
the trial, rather than breaking out the data for that one subject.
    In those situations in which a responsible party believes results 
information could not be submitted in a way that is consistent with 
this proposed rule without risk of re-identification, the responsible 
party could alternatively request a waiver of results submission 
requirements, as permitted by section 402(j)(3)(H) of the PHS Act and 
proposed in Sec.  11.54 of this rule. We believe such situations would 
be rare and such a waiver request would need to be evaluated on a case-
by-case basis.
    We invite public comment on other situations that might raise 
privacy concerns and on other approaches that we could propose to 
address them in a

[[Page 69592]]

way that is consistent with the requirements of section 402(j) of the 
PHS Act.

D. Effective Date/Compliance Date

1. Effective Date
    We propose that the effective date of these regulations be 
established as 45 days after the date on which the final rule is 
published in the Federal Register. As of the effective date, the 
ClinicalTrials.gov system would be modified to be consistent with the 
final rule. As such, a responsible party that submits information into 
the data bank on or after the effective date must do so consistent with 
the final rule.
2. Compliance Date
    We propose that the compliance date for these regulations be 
established as 90 days after the effective date of the rule. We 
interpret this to mean that a responsible party would have until the 
compliance date of the rule to come into compliance with the 
requirements of this proposed Part. Accordingly, by the compliance date 
of the rule: (a) Responsible parties for all applicable clinical trials 
initiated on or after, or ongoing as of, the effective date would have 
to comply with the clinical trial registration information requirements 
of proposed subpart B; (b) responsible parties for all applicable 
clinical trials required to submit clinical trial results information 
by a date that is on or after the effective date of the rule (including 
such trials whose completion dates were prior to the effective date of 
the rule, but for which results are due on or after the effective date 
of the rule under section 402(j)(3)(E) of the PHS Act) would have to 
comply with the clinical trial results information requirements of 
proposed subpart C; (c) responsible parties that make voluntary 
submissions of clinical trial information on or after the effective 
date of the rule would have to comply with proposed Sec.  11.60 and any 
other applicable provisions of the final rule; and (d) responsible 
parties that submit clinical trial information to ClinicalTrials.gov, 
for both applicable clinical trials and clinical trials voluntarily 
submitted to the data bank under proposed Sec.  11.60, on or after the 
effective date of the rule, would be required to update such clinical 
trial information in accordance with the requirements of proposed Sec.  
11.64(c).
    Consistent with the foregoing, in instances in which submission of 
clinical trial registration or results information ordinarily would 
have been due between the effective date and the compliance date of the 
rule, the responsible party would have until the compliance date to 
submit the required clinical trial information. For example, if under 
this proposed part, clinical trial results information were due for an 
applicable clinical trial on a date that is 30 days after the effective 
date of the rule, the responsible party for that applicable clinical 
trial would have until the compliance date to submit such information. 
That said, because we propose to modify ClinicalTrials.gov consistent 
with the final rule as of the effective date of the rule, responsible 
parties seeking to come into compliance with the final rule after the 
effective date but prior to the compliance date would be able to do so.
    We recognize that there will be situations in which the 
determination of one submission deadline will be conditioned upon an 
earlier submission deadline. In such situations, the Agency would 
consider the deadline pursuant to section 402(j) of the PHS Act and the 
final rule, notwithstanding the compliance date, as the applicable date 
for purposes of determining a subsequent deadline. For example, 
responsible parties that submit a certification to delay results 
submission under section 402(j)(3)(E)(v) of the PHS Act or proposed 
Sec.  11.44(b)(1) must subsequently submit clinical trial results 
information no later than two years after the date of the 
certification. (See section 402(j)(3)(E)(v)(III) of the PHS Act and 
proposed Sec.  11.44(b)(2).) If the deadline for the certification to 
delay results submission falls between the effective date and 
compliance date of the rule, then the responsible party would have 
until the compliance date to submit the certification. However, the 
subsequent deadline--i.e., the date by which clinical trial results 
information is due--would remain 2 years after the certification would 
have been due absent the compliance date.
    We believe that the proposed 90-day delay between the effective 
date and the compliance date of the final rule would provide ample time 
for responsible parties of applicable clinical trials to come into 
compliance with the final rule. This proposed 90-day delay is the same 
number of days provided after the date of enactment of section 402(j) 
of the PHS Act for ongoing applicable clinical trials to submit 
registration information.
3. Registration Information
    Clinical trial registration information submitted on or after the 
effective date of the rule would need to comply with the clinical trial 
registration information requirements of proposed subpart B. 
Furthermore, if an applicable clinical trial is ongoing as of the 
effective date of the rule and clinical trial registration information 
for that trial had been submitted prior to the effective date of the 
rule, the responsible party would need to submit any revised or 
additional registration information necessary to comply with proposed 
Sec.  11.28 by the compliance date. This would help ensure that 
complete clinical trial registration information, as defined in this 
proposed rule, is available to the public for all ongoing applicable 
clinical trials subject to this proposed part. This also would ensure 
that certain information that was not previously required in order to 
register a clinical trial with ClinicalTrials.gov, but which is 
essential to the implementation of the proposed regulation, will be 
included in the data bank for all applicable clinical trials ongoing as 
of the effective date of the rule.
    By contrast, if an applicable clinical trial reached its completion 
date prior to the effective date of the rule, and thus would not be 
ongoing as of the effective date of the rule, the responsible party 
would not be required to submit the additional registration information 
that would be required by proposed Sec.  11.28. The responsible party 
would nevertheless be expected to have provided, at minimum, 
registration information containing all of the data elements specified 
in section 402(j)(2)(A)(ii) of the PHS Act, as they were available in 
ClinicalTrials.gov at the time of registration, namely, Brief Title, 
Brief Summary, Primary Purpose, Study Design, Study Phase (for an 
applicable drug clinical trial), Study Type, Primary Disease or 
Condition or Focus of the Study, Intervention Name, Intervention Type, 
Study Start Date, Completion Date (listed in ClinicalTrials.gov as 
``Study Completion Date''), Target Number of Subjects (listed in 
ClinicalTrials.gov as ``Enrollment''), Primary and Secondary Outcome 
Measures, Eligibility Criteria, Gender, Age Limits, Whether the Trial 
Accepts Healthy Volunteers (listed in ClinicalTrials.gov as ``Accepts 
Healthy Volunteers?''), Overall Recruitment Status, Individual Site 
Status, Availability of Expanded Access (for an applicable drug 
clinical trial) (listed in ClinicalTrials.gov as ``expanded access 
record''), Name of the Sponsor, Responsible Party by Official Title 
(listed in ClinicalTrials.gov as ``Responsible Party Information''), 
Facility Name and Facility Contact Information (either facility-
specific or central contact information), Unique Protocol 
Identification Number, Secondary ID, IND/IDE number (listed in 
ClinicalTrials.gov as ``IND/IDE Protocol''), and Record Verification

[[Page 69593]]

Date. We also would expect the responsible party to have updated these 
data elements as necessary, consistent with the section 402(j)(4)(C) of 
the PHS Act. For example, for each of the applicable clinical trials in 
this category, we would expect that the Completion Date data element 
would have been updated not later than 30 calendar days after the 
completion date of the clinical trial to reflect the ``actual'' 
completion date of the clinical trial. See section 402(j)(4)(C)(i)(IV) 
of the PHS Act.
    We recognize that the data elements listed in the previous 
paragraph do not provide sufficient information for the responsible 
party to demonstrate (or for the Agency to determine) in all cases 
whether a clinical trial that was registered in ClinicalTrials.gov 
prior to the effective date of the rule meets the definition of an 
applicable clinical trial and thus whether results information was 
required to be submitted. The need to determine whether a clinical 
trial is an applicable clinical trial, in all cases, is one of the 
reasons we have proposed in Sec.  11.28 to require the submission of 
several additional data elements as part of clinical trial registration 
information, e.g., Single Arm Controlled as part of Study Design (for 
single-armed studies); Product Manufactured in U.S.?; and U.S. FDA 
Approval, Clearance, or Licensure Status. Responsible parties may 
voluntarily submit such additional data elements for clinical trials 
that were registered and reached their completion dates before the 
effective date of this rule. Submission of this information will enable 
the clinical trial record to indicate whether or not the clinical trial 
is an applicable clinical trial subject to section 402(j) of the PHS 
Act.
4. Results Information
    We interpret the approval status of a product studied in an 
applicable clinical trial (i.e., either ``unapproved, unlicensed, or 
uncleared'' or ``approved, licensed, or cleared'') to be the approval 
status of the product on any given date. For example, if a drug being 
studied in an applicable clinical trial was unapproved as of the 
completion date, at that time, the applicable clinical trial would be 
of an unapproved product. However, if and when the study drug receives 
FDA approval (for any indication), the applicable clinical trial would 
be of an approved product as of the date of FDA approval.
    (a) Applicable clinical trials that reach their completion dates on 
or after the effective date of the rule. Responsible parties would be 
required to submit clinical trial results information specified in 
proposed subpart C for all applicable clinical trials that are required 
to be registered in ClinicalTrials.gov under section 402(j) of the PHS 
Act or this proposed rule that reach their completion dates on or after 
the effective date of the rule. This requirement would apply to 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products as well as approved, licensed, or cleared products.
    (b) Applicable clinical trials that reach their completion dates 
prior to the effective date of the rule--approved, licensed, or cleared 
products. In general, the responsible party for an applicable clinical 
trial of an approved, licensed, or cleared product that reaches its 
completion date prior to the effective date of the rule would not be 
required to submit the additional clinical trial results information 
required under proposed Sec.  11.48 if the responsible party has 
already submitted the clinical trial results information required under 
section 402(j)(3)(C) of the PHS Act. This reflects the Agency's 
decision, as further described in section III.C.9 of this preamble, not 
to exercise its authority under section 402(j)(3)(D)(iv)(II) of the PHS 
Act to require ``the clinical trial information described in [section 
402(j)(3)(D)(iii) of the PHS Act] . . . to be submitted for an 
applicable clinical trial for which the clinical trial information 
described in [section 402(j)(3)(C) of the PHS Act] is submitted to the 
registry and results data bank before the effective date of the 
regulations.'' We interpret the phrase ``is submitted'' to mean ``is 
required to be submitted,'' in order to make clear that this provision 
would also apply to those responsible parties who were required to 
submit results under section 402(j)(3)(C) of the PHS Act, but failed to 
do so.
    There are three scenarios in which we propose to require the 
responsible party for an applicable clinical trial of an approved, 
licensed, or cleared product that reaches its completion date prior to 
the effective date of the rule to submit the additional clinical trial 
results information under proposed Sec.  11.48:
    First, in certain cases, an applicable clinical trial may reach its 
completion date prior to the effective date of the rule, but the 
clinical trial results information is neither due nor submitted until 
after the effective date of the rule. For example, under section 
402(j)(3)(E)(i) of the PHS Act, clinical trial results information is 
due for an applicable clinical trial of an approved, licensed, or 
cleared product not later than 1 year after the completion date of the 
trial. Thus, if clinical trial results information is submitted after 
the effective date of the rule, consistent with this deadline, the 
responsible party would be required to submit the clinical trial 
results information required by proposed Sec.  11.48.
    Second, there may be situations consistent with proposed Sec.  
11.44(a)(2) in which an applicable clinical trial of an approved, 
licensed, or cleared product reaches its completion date prior to the 
effective date of the rule, has partial results information (i.e., 
primary outcome measures) submitted before the effective date of the 
rule, but has other partial results information (i.e., secondary 
outcome measures) that is neither due nor submitted until on or after 
the effective date of the rule. The Agency proposes to exercise its 
authority under section 402(j)(3)(D)(iv)(II) of the PHS Act in 
situations when partial results are due on or after the effective date 
of the rule to require the responsible party to submit clinical trial 
results information under proposed Sec.  11.48 for all outcome 
measures, including primary outcome measures submitted prior to the 
effective date of the rule. We make this proposal so that, for any such 
trial, the data bank ultimately will contain the same required data 
elements for both primary and secondary outcome measures.
    Third, as a result of modifications that would be made to the 
ClinicalTrials.gov data bank upon implementation of the final rule, the 
responsible party would be required to submit clinical trial results 
information as specified in proposed Sec.  11.48 for any applicable 
clinical trial of an approved, licensed, or cleared product for which 
results information was required to be submitted under section 
402(j)(3)(C) of the PHS Act prior to the effective date of the rule, 
but for which the responsible party failed to do so. Such responsible 
parties would be required to submit the clinical trial results 
information specified in Sec.  11.48, even though only the clinical 
trial results information specified in section 402(j)(3)(C) of the PHS 
Act would have been required had results information been submitted on 
time. Accordingly, we are electing to exercise our authority under 
section 402(j)(3)(D)(iv)(II) of the PHS Act to require such responsible 
parties of applicable clinical trials of approved, licensed, or cleared 
products to submit the additional results data elements specified in 
proposed Sec.  11.48. As discussed in section III.C.9 of this preamble, 
section 402(j)(3)(D)(iv)(II) of the PHS Act provides that the Secretary 
shall by regulation determine ``whether the clinical trial information 
described

[[Page 69594]]

in [section 402(j)(3)(D)(iii) of the PHS Act] should be required to be 
submitted for an applicable clinical trial for which the clinical trial 
information described in [section 402(j)(3)(C) of the PHS Act] is 
submitted to the registry and results data bank before the effective 
date of the regulations.'' We interpret the phrase ``is submitted'' to 
mean ``is required to be submitted,'' in order to make clear that this 
provision would also apply to those responsible parties who were 
required to submit results information under section 402(j)(3)(C) of 
the PHS Act, but failed to do so.
    (c) Results information for applicable clinical trials that reach 
their completion dates prior to the effective date of the rule--
unapproved, unlicensed, or uncleared products. With respect to 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products that reach their completion dates prior to the effective date 
of the final rule, whether clinical trial results information is 
required under this proposed rule would depend on whether the product 
under study gets approved, licensed, or cleared. If the drug or device 
under study in an applicable clinical trial that reached its completion 
date prior to the effective date of the rule is never approved, 
licensed, or cleared by FDA, then submission of results information 
would not be required. However, if the drug or device under study is 
subsequently approved, licensed, or cleared after the effective date of 
the rule, then, consistent with section 402(j)(3)(E)(iv) of the PHS 
Act, clinical trial results information required by proposed Sec.  
11.48 would be due by the earlier of 1 year after the completion date 
or 30 calendar days after the date of initial FDA approval, licensure 
or clearance. In addition, the clinical trial results information under 
Sec.  11.48 would be required if results were due and submitted after 
the effective date of this proposed rule.
5. Voluntary Submissions
    If on or after the effective date, a responsible party voluntarily 
submits clinical trial information for a clinical trial that is not an 
applicable clinical trial, or that is an applicable clinical trial but 
is not required to register in ClinicalTrials.gov under section 
402(j)(2)(C) of the PHS Act, the voluntary submissions provision of 
section 402(j)(4)(A) of the PHS Act and proposed Sec.  11.60 apply to 
that submission, regardless of the completion date of such trial.
6. Updates and Corrections to Clinical Trial Information
    With respect to clinical trial registration information or clinical 
trial results information that is due on or after the effective date of 
the rule, the Agency intends to require responsible parties to update 
such information, in accordance with proposed Sec.  11.64.
    With respect to clinical trial information that is due prior to the 
effective date of the rule, the Agency intends to continue requiring 
responsible parties to update such information in accordance with the 
requirements set forth in section 402(j)(4)(C) of the PHS Act. Because 
responsible parties that submitted clinical trial information to the 
data bank prior to the effective date of the final rule would have 
submitted only those data elements required under sections 402(j) of 
the PHS Act, which excludes any additional data elements required under 
the final rule, they would be required to update only that information 
that was required to be submitted prior to the effective date of the 
rule and only to the extent required under section 402(j)(4)(C) of the 
PHS Act.
    In the event that a clinical trial reaches its completion date 
prior to the effective date of the rule but clinical trial results 
information is due after the effective date of the rule, the 
responsible party would be required to update the clinical trial 
registration information in accordance with the requirements of section 
402(j)(4)(C) of the PHS Act, but it would be required to update the 
clinical trial results information submitted after the effective date 
in accordance with the requirements of proposed Sec.  11.64(c). As 
discussed earlier in this section, a responsible party of a clinical 
trial that is registered but ongoing as of the effective date of the 
rule would be required to submit registration information consistent 
with proposed Sec.  11.28 by the compliance date of the rule; 
consistent with this approach, responsible parties would be required to 
update the clinical trial registration information for such trials in 
accordance with the requirements of proposed Sec.  11.64(c).
    Notwithstanding the foregoing, if a responsible party becomes aware 
of previously submitted clinical trial information that contains errors 
that need to be corrected or that may have been falsified, the Agency 
proposes to require responsible parties to correct such previously 
submitted clinical trial information in accordance with proposed Sec.  
11.66(c), regardless of when such clinical trial information was 
submitted to data bank. We believe our proposed approaches outlined in 
this part balance the differing positions expressed in comments made at 
the public meeting. We invite public comment on the advantages and 
disadvantages of this proposed approach and on other approaches that 
might be considered by the Agency in establishing the effective date 
and the compliance date.

IV. Detailed Description of This Proposed Rule

    Proposed Subpart A, General Provisions, sets forth the purpose of 
the regulations; to whom the regulations apply; the form and manner for 
submission of clinical trial information; the requirement that the 
submission of information under this part be truthful and not false or 
misleading; and the definitions applicable to this part.
    Proposed Subpart B, Registration, sets forth the requirements 
related to clinical trial registration information. It delineates who 
must submit clinical trial registration information; which applicable 
clinical trials must be registered in ClinicalTrials.gov; when clinical 
trial registration information must be submitted; where clinical trial 
registration information must be submitted; what constitutes clinical 
trial registration information; and by when NIH will post submitted 
clinical trial registration information.
    Proposed Subpart C, Results Submission, addresses the submission of 
clinical trial results information. It delineates who must submit 
clinical trial results information for applicable clinical trials; 
which applicable clinical trials are subject to the results submission 
requirement; when the clinical trial results information must be 
submitted; where and in what format clinical trial results information 
must be submitted; what constitutes clinical trial results information; 
by when NIH will post submitted clinical trial results information; and 
under what circumstances a waiver of the regulations will be granted.
    Proposed Subpart D, Additional Submissions of Clinical Trial 
Information, sets forth the requirements and procedures for voluntary 
submissions of clinical trial information for clinical trials of FDA-
regulated drugs and devices, submissions required to protect the public 
health, and updates to previously-submitted clinical trial registration 
and results information.
    A detailed discussion of this proposed rule, its statutory basis, 
and the purpose of its provisions follows.

[[Page 69595]]

A. General Provisions--Subpart A

1. What is the purpose of this part--Sec.  11.2
    As set forth in proposed Sec.  11.2, the purpose of this part is to 
implement section 402(j) of the PHS 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 
specified clinical trials to the Director of NIH to be made publicly 
available through ClinicalTrials.gov, the Internet-accessible clinical 
trial registry and results data bank established by NLM at http://www.clinicaltrials.gov.
2. To whom does this part apply?--Sec.  11.4
    Proposed Sec.  11.4(a) specifies that this proposed rule applies to 
any person or entity that is considered to be the ``responsible party'' 
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. The responsible 
party would be either the sponsor of the clinical trial or a principal 
investigator who meets the criteria specified in proposed Sec.  
11.4(c)(2) and has been so designated by the sponsor. (See proposed 
Sec.  11.4(c).) Proposed Sec.  11.22 specifies which applicable 
clinical trials are required to submit registration information to 
ClinicalTrials.gov (i.e., applicable drug clinical trials and 
applicable device clinical trials that were initiated after September 
27, 2007, or that were initiated on or before September 27, 2007, and 
``ongoing'' (as such term is defined by this proposed rule) on December 
26, 2007, consistent with section 402(j)(2)(C) of the PHS Act. Proposed 
Sec.  11.60 specifies requirements for voluntary submissions of 
clinical trial information for applicable clinical trials that are not 
required to register under section 402(j) of the PHS Act (e.g., because 
they were completed prior to September 27, 2007), and for clinical 
trials that do not meet the definition of an applicable clinical trial. 
The voluntary submission of clinical trial registration or results 
information for such clinical trials, triggers a requirement to submit 
clinical trial registration or results information for certain other 
trials, as required by section 402(j)(4)(A) of the PHS Act. (See 
proposed Sec.  11.60(a)(2)(ii)).)
    In no case would this proposed rule apply to the sponsor or 
principal investigator or other individual or entity associated with a 
clinical trial of a health intervention that is not subject to FDA 
jurisdiction. Although section 402(j)(4)(A) of the PHS Act directs the 
NIH 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 this proposed 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 and thus this proposed rule as not applying to anyone who 
submits information to ClinicalTrials.gov for a study that is neither 
an interventional clinical trial nor a pediatric postmarket 
surveillance of a device as defined in this part (e.g., for a study 
that is an observational study), 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. Consistent with other statutory 
authorities of the NIH and long-standing practice, however, 
ClinicalTrials.gov may, and does, accept registration and results 
information on clinical studies and interventions that are not subject 
to the requirements of section 402(j) of the PHS Act and this proposed 
rule.
    Proposed Sec.  11.4(b) 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.'' Proposed Sec.  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 subpart B and updated in accordance with Sec.  
11.64(b)(1)(ix) and (x). We propose in Sec.  11.28(a)(4)(vii), to 
require submission of a data element entitled Responsible Party Contact 
Information that, as specified in proposed Sec.  11.10(b)(38) includes 
the name, official title, organizational affiliation, physical address 
(i.e., street address), mailing address, phone number, and email 
address of the responsible party. To minimize redundant data entry, we 
will provide a mechanism for the responsible party to indicate if the 
mailing address is the same as the physical address. In those cases in 
which the responsible party is an organization, as opposed to an 
individual, we would require the name and official title to correspond 
to a designated contact person for the organization. As described in 
section IV.B.4(a) of this preamble, if the responsible party is an 
individual, we intend to make the name of responsible party publicly 
available in the data bank, but we do not propose to make the other 
contact information publicly available (i.e., the physical address, 
mailing address, phone number, and email address). The other contact 
information will be used for internal administrative processes (e.g., 
for necessary communications). We note that the official title and 
organizational affiliation of the responsible party will also be made 
publicly available as part of the Responsible Party, By Official Title 
data element, which is required to be submitted to ClinicalTrials.gov 
at the time of registration. See section 402(j)(2)(A)(ii)(III)(bb) of 
the PHS Act.
    Proposed Sec.  11.4(c) outlines procedures for determining the 
responsible party for each applicable clinical trial or other clinical 
trial subject to this part. We believe that there must be one (and only 
one) responsible party for each applicable clinical trial or other 
clinical trial. Absent a responsible party, the objectives of 
registration and results submission cannot be met. Because the 
definition of responsible party under section 402(j) of the PHS Act 
specifies, first, that the sponsor will be the responsible party and, 
second, that the PI 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 proposed in this part, and assumes that such individual or 
entity is the responsible party, unless the PI has been designated the 
responsible party in accordance with the procedure established in 
proposed Sec.  11.4(c)(2). For a pediatric postmarket surveillance of a 
device that is not a clinical trial, the responsible party would be 
considered the entity whom FDA orders to conduct the pediatric 
postmarket surveillance of a device.
    Proposed Sec.  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 there can be only one sponsor. Without a defined 
sponsor, there cannot be a responsible party for a clinical trial 
because responsible party is defined as either the sponsor or the

[[Page 69596]]

principal investigator who has been so designated by the sponsor. The 
proposed definition of sponsor in Sec.  11.10(a), includes both a 
``sponsor'' and a ``sponsor-investigator'' as those terms are defined 
in 21 CFR 50.3. 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 proposed rule, if a clinical trial 
is being conducted under an IND or IDE, the IND/IDE holder would be 
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 would be 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 would be 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 would be 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 and this proposed 
part would be the sponsor.
    Proposed 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, as ``the principal 
investigator of such clinical trial if so designated by the sponsor, 
grantee, contractor, or awardee. . .'' In order to give practical 
effect to this provision, we believe that, for any given applicable 
clinical trial, only one entity--the sponsor--can designate the PI as 
the responsible party. We believe that 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 (e.g., in a situation in which there is no IND/
IDE holder, and the sponsor is considered the ``initiator'' of the 
trial). 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 PI (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 PI 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 [this proposed part] for the 
submission of clinical trial information.'' Accordingly, if the PI does 
not meet the specified conditions for serving as the responsible party, 
the sponsor cannot designate the PI as the responsible party, and the 
sponsor must remain the responsible party. In proposed Sec.  11.10(a) 
we define, for purposes of this part, the term principal investigator 
(PI) to mean ``the individual who is responsible for the 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 PI 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 mean ``the entire 
trial,'' and ``the data'' to mean ``all of the data'', including data 
collected at all sites of a multi-site trial.
    We wish to clarify our understanding of section 402(j)(3)(C)(iv) of 
the PHS Act, as it relates to whether a PI would be eligible to serve 
as the responsible party under this proposed part. Section 
402(j)(3)(C)(iv) of the PHS Act requires the responsible party to 
indicate, as an element of clinical trial results information, whether 
there exist ``certain agreements,'' which are described 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 
PI from serving as the responsible party. Rather, we view only those 
agreements that prevent the PI from performing the functions described 
in section 402(j)(1)(A)(ix)(II) of the PHS Act or from submitting 
clinical trial information or any updates to such information required 
by section 402(j) of the PHS Act and this proposed part as preventing 
the PI 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 PI as responsible party, and ensure that the PI has notice 
of the designation, we have proposed a process in Sec.  11.4(c)(2) for 
designating a PI, as follows: the sponsor shall provide notice of the 
designation to the PI and obtain acknowledgement of the PI's 
responsibilities under this proposed part. We intend to continue to 
provide mechanisms in the PRS for the sponsor and the PI to indicate 
the designation and the acknowledgement, respectively. The designation 
by the sponsor is currently reflected in ClinicalTrials.gov by having 
the PI submit clinical trial information via the sponsor's 
organizational account (the sponsor must provide an account for the PI 
within the sponsor's PRS organizational account). The acknowledgement 
is reflected by having the PI list his/her name as the responsible 
party and indicate that he/she was designated as responsible party by 
the sponsor. This approach has been implemented in ClinicalTrials.gov 
since 2011.
    If and when a designated principal investigator becomes unable to 
meet all of the requirements of a responsible party, proposed Sec.  
11.04(c)(3) outlines the mechanisms by which 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.
    We note that even if a sponsor designates a principal investigator 
as the responsible party for an applicable clinical trial registered 
under proposed Sec.  11.22, there may be times when the sponsor would 
need to provide the principal investigator with certain

[[Page 69597]]

information in order for the principal investigator to meet his or her 
obligations as responsible party under section 402(j) of the PHS Act 
and/or this proposed part. For example, the sponsor would likely have 
to provide the principal investigator with information to describe an 
expanded access program for which information is required to be 
submitted and updated pursuant to proposed Sec. Sec.  11.28(a)(2)(viii) 
and 11.64. In some cases, a principal investigator who is the 
responsible party would rely upon the sponsor to obtain information 
necessary to determine if the applicable clinical trial meets the 
criteria for delayed submission of results information under proposed 
Sec. Sec.  11.44(b) or (c). Although we would expect a principal 
investigator who is a responsible party to request such information 
from the sponsor, we also would expect a sponsor who has designated a 
principal investigator as the responsible party to provide such 
information. 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 
would not meet the criteria set forth in proposed 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 proposed Sec.  11.4(c)(2)(i), the principal investigator 
cannot be designated as a responsible party and the responsible party 
designation either would remain with or revert back to the sponsor.
3. What are the requirements for the submission of truthful 
information?--Sec.  11.6
    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, 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 under section 402(j)(5)(D) of the 
PHS Act. Other Federal laws also govern the veracity of information or 
claims 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) and 31 U.S.C. 
3802 (referencing civil and potential administrative liability of 
persons making certain false claims to the U.S. Government). Thus, we 
propose in Sec.  11.6(a) to require that ``[t]he clinical trial 
information submitted by a responsible party under this part shall not 
be false or misleading in any particular.'' In addition, proposed Sec.  
11.6(b) provides that ``[s]ubmission of false and/or misleading 
information would subject the responsible party to civil, criminal, 
and/or administrative liability under U.S. law.'' Specifically, all 
information submitted by a responsible party to ClinicalTrials.gov must 
be truthful, including information submitted voluntarily and other 
information that may not fall under the definition of clinical trial 
information, such as certifications for delayed submission and requests 
for good-cause extensions. Note, however, that this part does not 
require inclusion of information from any source other than the 
applicable clinical trial or other clinical trial that is the subject 
of the submission.
    To help ensure that responsible parties are aware of this 
requirement and to provide an opportunity for them to attest to the 
veracity of the information at the time of submission, we propose in 
Sec.  11.6(b) to require the responsible party, each time he or she 
submits clinical trial information or other information to 
ClinicalTrials.gov, to ``certify that, to the best of his or her 
knowledge, the information submitted is truthful and not misleading and 
that he or she is aware that the submission of false and/or misleading 
information would subject the responsible party to civil, criminal, 
and/or administrative liability under U.S. law.'' This requirement is 
similar to requirements to certify to the truthfulness of information 
about FDA-regulated products submitted to FDA, and we believe is an 
important component of efforts to help ensure that submitted 
information is not false or misleading, as required by section 
402(j)(5)(D) of the PHS Act, 18 U.S.C. 1001, and 31 U.S.C. 3802. We 
plan to implement this requirement in ClinicalTrials.gov by integrating 
a certification statement into the mechanism for submitting information 
electronically through the Protocol Registration System. The 
requirement of proposed Sec.  11.6 would be met by the responsible 
party making an attestation such as the following: ``I certify that the 
information I have submitted is, to the best of my knowledge, truthful 
and not misleading, and I am aware that the submission of false and/or 
misleading information would subject me to civil, criminal, and/or 
administrative liability under U.S. law.''
4. In what form and manner must clinical trial information be 
submitted?--Sec.  11.8
    Proposed Sec.  11.8 sets forth requirements for the form and manner 
of submitting clinical trial information to ClinicalTrials.gov. It 
specifies that information submitted under this proposed part must be 
submitted electronically to ClinicalTrials.gov in the form and manner 
specified at http://prsinfo.clinicaltrials.gov. No other form or manner 
of submission will be accepted. Proposed Sec. Sec.  11.10, 11.28 and 
11.48, specify the individual data elements of clinical trial 
information that must be submitted to ClinicalTrials.gov at the time of 
registration and results 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 specifies that 
the Study Design data element includes subelements of Interventional 
Study Model, Number of Arms, Arm Information, Allocation, Masking, and 
Single Arm Controlled).
    Sections IV.B.4 and IV.C.4 of this preamble describe the specific 
form and manner 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 the form of free-text; for other data elements and 
subelements, responsible parties would be required to select the best 
response from menus of options presented in ClinicalTrials.gov. Some 
menus would offer a fixed set of options without an ``other'' option; 
others would offer a prespecified set of options plus an ``other'' 
option. In most cases, responsible parties selecting the ``other'' 
option would be required to provide an additional free-text response to 
elaborate on their other selections. Some data elements without an 
``other'' option would 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 manner 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. 
They are routinely used to improve the quality and help ensure the 
completeness of data submitted to information systems. Their use can 
reduce typographical errors in data

[[Page 69598]]

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, consistent with the requirements of sections 
402(j)(2)(B)(iv) and (3)(D)(v)(I) of the PHS Act.
    In describing the registration and results information to be 
submitted to ClinicalTrials.gov, the preamble specifies whether 
information would be submitted as free text or as menu selections. For 
data elements with menu options, the preamble specifies the complete 
set of options proposed, including whether or not an ``other'' option 
would be offered. The choice of providing menu options versus free-text 
fields and the set of menu options offered for specific data elements 
and subelements are based on our experience in operating 
ClinicalTrials.gov and on comments received from users of 
ClinicalTrials.gov, including those who commented on the draft guidance 
documents that were issued in 2002 and 2004 [Ref. 3, 4] (see section 
II.A of the preamble) and the preliminary version of the results 
database and adverse event module that were available for testing 
beginning in the spring of 2008 (see section II.B. of this preamble).
    We anticipate that, from time to time, we might make minor changes 
to the specific form and manner in which responsible parties would 
submit individual data elements and subelements to ClinicalTrials.gov. 
Such changes would not require a responsible party to submit different 
or more clinical trial information than is specified in this proposed 
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 would provide prior notice and 
seek public comment on any proposed changes to the form and manner of 
submitting clinical trial information, and any changes would ultimately 
be reflected in the ClinicalTrials.gov data entry system at http://prsinfo.clinicaltrials.gov.
    We invite comment on the specific form and manner described in this 
proposed rule for submitting data elements and subelements of proposed 
clinical trial information, including comment 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 ``other'' options are needed for additional data 
elements. We also invite comment on the proposed approach described in 
this section for modifying the form and manner of submitting clinical 
trial information over time.
    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 a specified electronic format. 
Responsible parties submitting information on multiple clinical trials 
may upload information that is prepared as a batch submission. We 
expect this feature will be of interest to large entities (e.g., drug 
and device manufacturers) who might be the responsible party for 
multiple clinical trials. Additional information about submitting 
information to ClinicalTrials.gov is available at http://prsinfo.clinicaltrials.gov.
5. What definitions apply to this part?--Sec.  11.10
    Proposed Sec.  11.10 defines certain terms and data elements used 
in this proposed part. The terms defined in proposed Sec.  11.10(a) 
includes terms explicitly defined in section 402(j) of the PHS Act 
(e.g., ``applicable clinical trial'' and ``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 propose 
definitions to fit within the proposed framework for the expanded data 
bank and for 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 reference some terms defined under the PHS Act 
and the FD&C Act and implementing regulations, as necessary.
    In March 2009 the Agency provided an elaboration of its then-
current thinking about the definitions of the terms ``applicable 
clinical trial,'' ``applicable device clinical trial,'' ``applicable 
drug clinical trial,'' and ``responsible party'' in a document entitled 
``Elaboration of the Definitions of Responsible Party and Applicable 
Clinical Trial'' that was posted on the ClinicalTrials.gov Web site. 
The posted document invites comments on the elaborations, but no 
written comments were received by the Agency. We discuss below a number 
of the proposed definitions.
    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. 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 below in the 
definition of the term ``serious adverse event''). FDA regulations for 
IND safety reporting requirements that were issued on September 29, 
2010 (see 75 FR 59935, Sept. 29, 2010) 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 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.
    Because this proposed 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)), our proposed 
definition cannot be limited to adverse events that are anticipated, 
are likely to have been caused by the drug or device (or other type of 
intervention used in the clinical

[[Page 69599]]

trial), or that have a reasonable possibility of being related to the 
intervention under study. Instead, the proposed definition of adverse 
event must include all adverse events regardless of possible 
attribution and regardless of whether they were anticipated.
    The HHS Office for Human Research Protections (OHRP) has a 
definition of adverse event that covers drug, device, and other 
interventions and has the same scope of adverse events addressed by 
section 402(j) of the PHS Act, i.e., it includes both anticipated and 
unanticipated 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. 39]. The OHRP definition was adapted from the definition used by 
the International Conference on Harmonization (ICH) Guideline E6, Good 
Clinical Practice: Consolidated Guidance [Ref. 40], which was published 
by FDA as a guidance document in the Federal Register in 1997 (62 FR 
25692, May 9, 1997). 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.
    Our proposed definition of adverse event derives from the OHRP 
definition. We propose to define an adverse event 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 the 
subject's participation in the research.'' This interpretation helps 
improve consistency in the submission of adverse event information for 
applicable device clinical trials and applicable drug clinical trials. 
It is consistent with, although not identical to, the definition of 
adverse event included in FDA's IND regulations. We invite public 
comment on this proposed definition.
    Applicable clinical trial is the term used in section 
402(j)(1)(A)(i) of the PHS Act to designate the scope of clinical 
trials that may be subject to the requirements to submit clinical trial 
registration and results information as specified in this proposed 
part. Not all applicable clinical trials are subject to clinical trial 
registration and results submission requirements. For example, an 
applicable clinical trial that reached its completion date on or before 
September 27, 2007, is not subject to registration under section 402(j) 
of the PHS Act, nor is an applicable clinical trial that was ongoing as 
of September 27, 2007, and reached its completion date prior to 
December 26, 2007. This proposed rule adopts the definition of 
applicable clinical trial from section 402(j)(1)(A)(i) of the PHS Act, 
which relies on two other terms defined in that section of the PHS Act 
and this proposed rule, namely applicable device clinical trial and 
applicable drug clinical trial. In addition, in proposed Sec.  
11.22(b), we propose an approach for determining whether a clinical 
study or trial meets the definition of an applicable clinical trial.
    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. The term ``device'' is defined in 
section 402(j)(1)(A)(vi) as ``a device as defined in section 201(h) of 
the [FD&C] Act.'' We have adopted this definition of ``device'' in 
proposed Sec.  11.10. In addition, this proposed rule adopts, 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.''
    The first part of the definition in section 402(j)(1)(A)(ii)(I) 
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, 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. We 
interpret ``clinical study'' with respect to a device to mean an 
investigation in which a device is used in one or more human subjects. 
For purposes of 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 purposes only of the requirements 
under section 402(j) of the PHS Act and this proposed rule, the term 
``human subject'' does not include de-identified human specimens (see 
[Ref. 41]). 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 devices, ``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 devices do not 
specifically define the term ``clinical investigation,'' that term is 
defined in FDA regulations pertaining to clinical investigations of 
drugs and 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 device trials by defining a ``clinical study of a device'' 
as ``any experiment in which a device is administered, dispensed to, or 
used involving, one or more human subjects,'' defining an 
``experiment'' as ``any use of a device except for the use

[[Page 69600]]

of a marketed device 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 would include studies in which subjects are assigned to 
specific interventions according to a study protocol. Studies in which 
a device 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 purposes of this rulemaking. An example of studies that 
would not be considered clinical investigations include situations in 
which, after a device has been administered to a patient in the course 
of routine medical practice by a healthcare provider, a researcher not 
associated with the administration of the device reviews the records of 
the patients 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 ``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'' also may have non-concurrent (e.g., 
historical) control groups. An example of a retrospective study, and 
thus 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 is then studied.
    Third, we interpret ``of health outcomes.'' For purposes of the 
definition of applicable device clinical trial, a ``prospective 
clinical study of health outcomes'' is a clinical study in which the 
primary objective is to evaluate a defined clinical outcome directly 
related to human health. 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 proposed rule.
    (2) ``Comparing an intervention with a device against a control in 
human subjects.'' We interpret an ``intervention with a device'' to be 
one in which a device 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 purposes only of 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 of using the device such as, among other things, device 
regimens and procedures and use of prophylactic, diagnostic, or 
therapeutic agents.
    A clinical study is considered to ``compare an intervention with a 
device against a control in human subjects'' when it compares 
differences in the clinical outcomes, or diagnosis, between human 
subjects who received an intervention that included a device and human 
subjects who received other interventions, or no intervention (i.e., 
the control group). The intervention under study may be with a device 
that has never been cleared or approved or with a device that has been 
cleared or approved, regardless of whether the clearance or approval is 
for the indication 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 validated objective 
outcomes using objective performance criteria, by which we mean 
performance criteria based on broad sets of data from historical 
databases (e.g., literature or registries) that are generally 
recognized as acceptable values.
    Expanded access protocols under section 561 of the FD&C Act, under 
which investigational devices are made available to individuals under 
certain conditions, generally are not controlled clinical 
investigations and therefore generally are not applicable device 
clinical trials. In those instances in which use of an investigational 
device in an expanded access program is controlled and the program 
otherwise meets the definition of an applicable device clinical trial, 
the expanded access program would be considered an applicable clinical 
trial and would be registered as such. Similarly, continued access 
protocols, under which an investigational device continues to be made 
available after completion of a controlled trial while a marketing 
application is being prepared or reviewed, are, by definition, not 
controlled clinical investigations and, therefore, not applicable 
device clinical trials.
    (3) ``A device subject to section 510(k), 515, or 520(m)'' of the 
FD&C Act. 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 U.S.: (1) a finding of substantial 
equivalence under section 510(k) 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 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 an 
investigational device exemption (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.
    If a clinical study of a device (1) includes sites both within the 
U.S. (including any territory of the U.S.) and outside of the U.S., and 
(2) any of those sites is using (for purposes of the clinical study) a 
device 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 that is being conducted entirely outside of the U.S. (i.e., does 
not have any sites in the U.S. or in any territory of the U.S.) and is 
not conducted under an IDE may not be a clinical study of a device 
subject to section 510(k), 515, or 520(m) of the FD&C Act, and thus not 
an applicable device clinical trial, depending on where the device 
being used in the clinical study is manufactured. If the device is 
manufactured in the U.S. or any territory of the U.S., and is exported 
for study in another country (whether it is exported under section 
801(e) or section 802 of the FD&C Act), then the device is considered 
to be subject to section 510(k), 515, or 520(m) of the FD&C Act. If the 
device is manufactured outside of the U.S. or its territories, and the 
clinical study sites are all outside of the U.S. and/or its 
territories, then the device would not be considered to be 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

[[Page 69601]]

measure relates to feasibility and not to health outcomes.'' 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. Feasibility studies 
are sometimes referred to as phase 1 studies, pilot studies, prototype 
studies, or introductory trials. Feasibility studies are not considered 
applicable device clinical trials under this proposed part.
    The second part of the definition in section 402(j)(1)(A)(ii)(II) 
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 under 
section 522 of the FD&C Act, regardless of its design, is an applicable 
device clinical trial.
    Applicable drug clinical trial is the term used in section 402(j) 
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, if the trial is subject to the 
registration and results submission requirements under section 402(j) 
of the PHS Act. Section 402(j)(1)(A)(iii)(I) of the PHS Act provides 
the following detailed definition of the term applicable drug clinical 
trial: ``a controlled clinical investigation, other than a phase I 
clinical investigation, of a drug subject to section 505 of the Federal 
Food, Drug, and Cosmetic Act or to section 351 of th[e] [PHS] Act.'' 
Sections 402(j)(1)(A)(iii)(II) and (III) of the PHS Act further clarify 
that 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 propose to 
adopt the statutory definition of this term, replacing ``phase I'' with 
``phase 1,'' to be consistent with the numbering scheme used in FDA 
regulations (21 CFR 312.21). We provide additional elaboration of the 
interpretation of applicable clinical trial below.
    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 
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 to be 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) First, with regard to a ``drug subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or section 351 of th[e] [Public 
Health Service] Act,'' proposed Sec.  11.10 adopts the definition of 
the term ``drug'' in section 402(j)(1)(A)(vii) of the PHS Act as 
follows: ``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.'' In 
keeping with the requirements of the FD&C Act and section 351 of the 
PHS Act, a drug 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 new drug application 
(NDA) or licensed biologics license application (BLA), or if an 
approved NDA or licensed BLA would be required in order for that drug 
or biological product to be legally marketed. A non-prescription drug 
that is or could be marketed under an existing over-the-counter (OTC) 
drug monograph (See 21 CFR 330-358) is not considered ``subject to 
section 505 of the [FD&C] Act.''
    A drug or a biological product that is subject to section 505 of 
the FD&C Act or to 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 investigational new drug 
application (IND) is in effect. Drugs (including biological products) 
that are being studied under an IND are considered ``subject to section 
505'' both because (in most situations) the drug 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. However, whether a drug 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 
that clinical investigation. Therefore, a drug (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 or biological product is ``IND exempt'' 
(i.e., does not require an IND because that clinical investigation 
falls within 21 CFR 312.2(b)). Hence, provided it meets all other 
criteria of the definition, a clinical investigation of a drug 
(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 (including a biological product) that is not 
otherwise subject to section 505 or to 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 (including a biological 
product) (1) includes sites both within the U.S. (including any 
territory of the U.S.) and outside of the U.S., and (2) any of those 
sites is using (for purposes of the clinical investigation) a drug 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 (including a biological product) that 
is being conducted entirely outside of the U.S. (i.e., does not have 
any sites in the U.S. or in any territory of the U.S.) may or may not 
be a clinical investigation of a drug or biological product subject to 
section 505 of the FD&C Act or section 351 of the PHS Act, and thus not 
an applicable drug clinical trial, depending on where the drug 
(including biological product) being used in the clinical investigation 
is manufactured. If the drug (including a biological product) is 
manufactured in the U.S. or any territory of the U.S., 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 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 (including a 
biological

[[Page 69602]]

product) is manufactured outside of the U.S. or its territories, the 
clinical investigation sites are all outside of the U.S., and the 
clinical investigation is not being conducted under an IND, the drug 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.
    (2) Second, with regard to ``clinical investigation,'' section 
402(j)(1)(A)(iii)(II) of the PHS Act provides that ``clinical 
investigation'' has the meaning given that term in 21 CFR 312.3, which 
defines ``[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 ``clinical investigation'' of a drug includes 
studies in which human subjects are assigned to specific interventions 
according to a protocol. However, a situation in which a drug is 
administered or provided to a patient as part of routine medical care 
and not under a study or protocol would not be considered a ``clinical 
investigation'' for purposes of this rulemaking. Examples of studies 
that might fall under this description include situations in which, 
after a drug has been administered to a patient in the course of 
routine medical practice by a healthcare provider, a researcher not 
associated with the administration of the drug reviews the records of 
the patients 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 in the 
course of his or her routine medical practice would not be considered a 
``clinical investigation'' under this definition. Because these 
activities would not be considered ``clinical investigations'' under 21 
CFR 312.3, they would not be considered applicable drug clinical trials 
under section 402(j) of the PHS Act and this proposed part. 
Accordingly, in the approach described below in Sec.  11.22(b)(2), we 
consider an ``interventional'' study (or investigation) of a drug to be 
an applicable drug clinical trial.
    (3) Third, 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 drug effect. The purpose of the control 
is to distinguish the effect of a drug from other influences, such as 
the spontaneous change in the course of the diseases, placebo effect, 
or biased observation. The control will provide data about 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: (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).)
    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 purposes of submitting an abbreviated new 
drug application under 21 U.S.C. 355(j) or a new drug application as 
described in 21 U.S.C. 355(b)(2)) is considered to be a controlled 
clinical investigation. In this case, the control generally would be 
the previously approved drug product. However, as discussed below, 
bioequivalent or comparative bioanalysis studies that fall within the 
scope of studies described in 21 CFR 320.24(b)(1), (2), and (3) share 
many of the characteristics of a phase 1 study and would be considered 
phase 1 trials (and thus not applicable clinical trials) in this 
proposed rule.
    Similar to expanded access to investigational devices, as discussed 
above in the definition of applicable device clinical trial, the use of 
an investigational drug in an expanded access program under section 561 
of the FD&C Act is generally not ``controlled,'' and generally does not 
meet the definition of a ``controlled clinical investigation.'' In 
those instances in which use of an investigational drug in an expanded 
access program is controlled and the program otherwise meets the 
definition of an applicable drug clinical trial, the expanded access 
program would be considered an applicable clinical trial.
    (4) Fourth, 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 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.'' Studies that are phase 1 studies 
under 21 CFR 312.21 are not applicable drug clinical trials. Studies 
that are phase 1/phase 2 studies are not considered phase 1 studies and 
may be applicable drug clinical trial 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 purposes of submitting an 
abbreviated new drug application under 21 U.S.C. 355(j) or a new drug 
application 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 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, and to 
develop the data that will support beginning phase 2 studies, 21 CFR 
312.21(a) does not limit phase 1 trials to that situation. 
Bioequivalence or comparative bioavailability studies that fall within 
the scope of the studies described in 21 CFR 320.24(b)(1), (2), and (3) 
share many of the characteristics of phase 1 clinical investigations as 
described in 21 CFR 312.21(a), and therefore will be considered to be 
phase 1 trials for purposes of section 402(j) of the PHS Act. However, 
bioequivalence or comparative bioavailability trials that fall within 
the scope of 21 CFR 320.24(b)(4) do not share the characteristics of 
phase 1 trials as

[[Page 69603]]

described in 21 CFR 312.21(a), and thus would not be considered to be 
phase 1 trials for purposes of section 402(j) of this proposed part.
    In addition, for purposes of implementing this proposed rule, we 
propose 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 device; a 
biological product and device; a drug and biological product; or a 
drug, biological product, and 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 
drug in proposed Sec.  11.10 includes a biological product, a 
combination product under this proposed rule would always consist, in 
part, of a drug. For this reason, we propose to treat clinical trials 
of combination products that meet the definition in 21 CFR 3.2(e) as 
applicable drug clinical trials, for purposes of implementing this 
proposed rule, so long as the clinical trial of the combination product 
is a controlled clinical investigation, other than a phase 1 clinical 
investigation (as described in above), and the combination product is 
subject to sections 505 of the FD&C Act and/or section 351 of the PHS 
Act (as described above) and/or section 510(k), 515, or 520(m) of the 
FD&C Act (as described in the definition of an applicable device 
clinical trial). Such clinical trials of combination products would 
therefore be subject to the registration and results submission 
requirements, including requirements for posting clinical trial 
information, for applicable drug clinical trials as described in this 
proposed part. We believe this approach will provide clarity to 
responsible parties conducting clinical trials of combination products.
    Approved drug is defined to mean ``a drug that is approved for any 
indication under section 505 of the FD&C Act or a biological product 
licensed for any indication under section 351 of the PHS Act.''
    Approved or cleared device. 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 submission and public 
posting of clinical trial information. Accordingly, we believe that it 
is helpful to define the term ``approved or cleared device.'' 
Specifically, we want to clarify that our definition of approved or 
cleared device refers 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. Consistent with the reference in section 
402(j)(2)(D)(ii) of the PHS Act to approval or clearance of a device 
under the designated sections of the FD&C Act, we propose to define an 
approved or cleared device as ``a device that is cleared under section 
510(k) of the FD&C Act or approved under section 515 or 520(m) of the 
FD&C Act for any indication.''
    Arm is defined 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.''
    Clinical trial is defined 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.'' The proposed definition 
explicitly includes ``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. We have 
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 is 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.
    Further, in terms of defining the scope of a clinical trial, we 
recognize that it is sometimes difficult to determine the boundaries of 
a single clinical trial when there are two or more closely related 
clinical trials. In general, a clinical trial has an explicit group of 
human subjects who are assigned to interventions based on a protocol. 
The data from these human subjects are assessed and analyzed based on a 
protocol. However, when two different clinical trials share the same 
protocol, but the groups of human subjects are different and the 
outcomes will be analyzed separately, then they 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 of the study 
sites. 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 that requires a separate consent process, it would be considered a 
separate clinical trial.
    Clinical trial information is the term defined in section 402(j) of 
the PHS Act to designate those data elements that the responsible party 
is required to submit to ClinicalTrials.gov when registering or 
submitting results information for a clinical trial, as described in 
Sec. Sec.  11.28 and 11.48 of this proposed rule, respectively. 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. Paragraph (2) refers to 
registration requirements and paragraph (3) refers to results 
submission requirements. Section 402(j)(3)(I)(v) of the PHS Act also 
expressly provides that adverse event information included in the data 
bank pursuant to the paragraph (3)(I) ``is deemed to be clinical trial 
information included in such data bank pursuant to subparagraph (C).'' 
Therefore, for purposes of this proposed 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 under 
this part.''
    Clinical trial registration information is defined to mean ``the 
data elements that the responsible party is required to submit to 
ClinicalTrials.gov under Sec.  11.28.'' The full set of data elements 
under Sec.  11.28 must be submitted in order to register under proposed 
subpart B.
    Clinical trial results information is defined 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).'' The full set of data elements under Sec.  11.48 
must be submitted when providing results

[[Page 69604]]

information under proposed subpart C. Clinical trial results 
information includes the adverse event information set forth in 
proposed Sec.  11.48(a)(4). We include adverse event information as 
part of clinical trial results information 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].'' As discussed in greater detail in 
section IV.D.1 of this preamble, if, under proposed Sec.  11.60, a 
responsible party seeks to submit clinical trial results information 
voluntarily for a clinical trial for which clinical trial registration 
information specified in Sec.  11.28(a) is not submitted, clinical 
trial results information is defined to include the data elements in 
proposed Sec.  11.48(a) and the data elements set forth in proposed 
Sec.  11.60(a)(2)(i)(B).
    Comparison group is defined in this proposed rule 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.'' 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, results data are 
often analyzed by intervention (e.g., results for human subjects when 
receiving intervention X versus results for human subjects when taking 
intervention Y), rather than by arm. When submitting results 
information to ClinicalTrials.gov under proposed Sec.  11.48, we 
believe responsible parties should submit the data in the same way in 
which it was analyzed, whether by arm (as defined above) or by 
comparison group. We do expect that the set of comparison groups for a 
particular trial would account for all of the participants in the 
analysis.
    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.'' 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 to 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)&(II) of the PHS Act 
(unless the deadline is delayed or extended using one of the mechanisms 
described in proposed Sec.  11.44). For purposes of this proposed rule, 
we interpret ``expected completion date'' to be synonymous with 
``estimated completion date.''
    This proposed rule adopts the statutory definition of completion 
date with respect to applicable clinical trials that are clinical 
trials with one modification. If a clinical trial has multiple primary 
outcome measures, each with a different date on which the final human 
subject is examined or receives an intervention for purposes of final 
data collection, the ``completion date'' refers to the date upon which 
data collection is completed for all of the primary outcomes. While 
this approach may delay somewhat the submission and public availability 
of clinical trial results information for the earliest primary 
outcomes, we expect any such delays to be minimal. Most clinical trials 
registered at 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, the proposed 
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 submission deadline in such a situation under proposed 
Sec.  11.44(e), the proposed definition should reduce the number of 
good-cause extension requests that responsible parties might be 
expected to file. Submission of results data 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 data from the clinical trial, rather than 
data for only some of the primary outcomes. Thus, for purposes of this 
proposed rule, completion date means ``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.''
    We note 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 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'' or LPLV) 
and is also collected by ClinicalTrials.gov. To improve concordance 
with section 402(j) of the PHS Act and to be consistent with our 
proposed definition, ClinicalTrials.gov will begin to use the term 
completion date once the final regulations take effect. We will include 
a notice in ClinicalTrials.gov to alert responsible parties to this 
change in data element name.
    For a pediatric postmarket surveillance of a device that is not a 
clinical trial, completion date means ``the date on which the final 
report summarizing the results of the pediatric postmarket surveillance 
is submitted to FDA.'' (See proposed Sec.  11.10.)
    Control or 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. For purposes of this proposed 
rule, the term ``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 
baseline data), as reflected in the pre-specified primary or secondary 
outcome measures.'' This is consistent with 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)). FDA has also adopted as 
guidance the International Conference on Harmonization E10: Choice of 
Control Group and Related Issues in Clinical Trials (ICH E10), which 
describes considerations to be

[[Page 69605]]

used in choosing a control group. 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).
    Our proposed definition of controlled is consistent with the types 
of controls recognized by FDA and the ICH E10 guidance, but is 
potentially broader in that it does not require that the study be 
``adequate,'' i.e., that the control allows a valid comparison of the 
two treatments. It is consistent in that it explicitly recognizes both 
concurrent and non-concurrent controls. We recognize that this 
interpretation may differ from common use of the term ``controlled'' by 
some researchers, who may consider only studies with concurrent 
controls to be ``controlled,'' but we believe it is important to 
maintain consistency with the approach of the FDA and ICH E10 and to 
include non-concurrent controls. Our definition of controlled is 
broader than that of ``well-controlled'' used by FDA and ICH E10 
because FDA regulations and the ICH E10 guidance describe the more 
limited circumstances in which use of a non-concurrent control 
constitutes a ``well-controlled'' clinical trial, i.e., one that might 
serve to support marketing. Although FDA regulations state that 
historical controls are usually reserved for special circumstances, 
such as studies of a disease with ``high and predictable mortality'' 
(e.g., certain malignancies) or in which the effect of the drug is 
``self-evident'' (e.g., anesthesia, cardioversion), our proposed 
definition of controlled would include all studies using an historical 
control, regardless of whether the study is of a disease with a ``high 
and predictable mortality'' or in which the effect of the drug is self-
evident. Our proposed definition would encompass all studies and 
investigations with a placebo concurrent control, dose-comparison 
concurrent control, no treatment concurrent control, active treatment 
concurrent control, and historical control, but it would 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. Hence it would cover all trials that are controlled, 
using concurrent or non-concurrent controls, regardless of whether they 
would be considered ``well-controlled.''
    Under our proposed definition, any clinical trial with two or more 
arms would be considered controlled because it would involve the 
comparison of data collected concurrently from different arms of the 
study. Some single-arm trials that meet the other components of the 
definition of an applicable clinical trial, e.g., not phase 1 or a 
feasibility study, could also meet this definition of controlled. These 
include the single-arm trials of FDA-regulated products that have as a 
stated objective in their protocol to evaluate a response rate to an 
intervention, to measure effectiveness of an intervention at specific 
endpoints, and/or to compare the effect of an intervention against an 
identified baseline. Thus, single-arm clinical trials that explicitly 
identify primary or secondary outcomes in the protocol that involve 
comparisons to historical data (including baseline data) would be 
considered controlled.
    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. For purposes of this 
proposed rule, the term ``enrolled'' means ``a human subject's 
agreement to participate in a clinical trial, as indicated by the 
signing of the informed consent document(s).'' (See proposed Sec.  
11.10.)
    Human subjects protection review board is defined in Sec.  11.10 of 
this proposed rule 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 
propose to include this definition to clarify the scope of the review 
boards for which Human Subjects Protection Review Board Status must be 
submitted under proposed Sec.  11.28 (see section IV.B.4(a)(4) of this 
preamble). For clinical trials conducted in the U.S. or under an IND or 
IDE, the term human subjects protection review board would mean an 
institutional review board, as defined in the cited regulations issued 
by the FDA and OHRP within HHS. For clinical trials conducted outside 
the United States or otherwise outside the scope of the regulations for 
institutional review boards, the term would refer 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'' at 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 50]
    Interventional is defined in this proposed 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.'' We 
propose to define this term to distinguish interventional studies from 
observational studies, as those terms are used in the clinical research 
community. Observational studies include those in which a patient 
receives an intervention as part of routine medical care, and a 
researcher studies the effect of the intervention. They also include 
retrospective reviews of patient medical records or relevant 
literature, as may occur in a pediatric postmarket surveillance of a 
device. Interventional studies are those in which a researcher assigns 
subjects to specific interventions (or to no intervention) according to 
a study protocol for purposes of the investigation. For purposes of 
this part, we use the term ``clinical trial'' to refer to 
interventional studies to the exclusion of observational studies. (See 
the proposed 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 proposed Sec.  11.28 and defined in Sec.  11.10. 
Responsible parties must indicate whether a study being registered is 
``interventional'' or

[[Page 69606]]

``observational,'' or is an expanded access program that does not meet 
the definition of an applicable clinical trial. 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 proposed definitions of applicable 
device clinical trial and applicable drug clinical trial). A study 
should be designated interventional if it meets the proposed definition 
even if the medical products being studied are being used in a manner 
considered to be the standard of care. A study that is designated 
``observational'' can be an applicable clinical trial only if it is a 
pediatric postmarket surveillance of a device as defined in this part. 
(See the proposed definition of pediatric postmarket surveillance of a 
device).
    NCT number is the term used in this proposed part to refer to the 
term ``National Clinical Trial number[,]'' which is used in section 
402(j)(2)(B)(i)(VIII) of the PHS Act. Since its launch in 2000, 
ClinicalTrials.gov has assigned each submitted clinical trial record a 
unique identifier once the information has completed quality review 
procedures. While the identifier originally was called a National 
Clinical Trial number, that nomenclature was soon changed to ``NCT 
number'' in recognition of the fact that ClinicalTrials.gov also 
receives clinical trial information about trials being conducted in 
countries other than the United States. We propose to maintain the term 
``NCT number'' in this part. 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 their 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. 10]. For trials registered in ClinicalTrials.gov, 
this unique identifier is the NCT number. When published in journal 
articles, NCT numbers are also included in MEDLINE records and are 
searchable through PubMed [Ref. 42]. For purposes of this proposed 
rule, 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.'' The 
NCT number is assigned to clinical trials and expanded access records 
once registration information has been submitted to the Director and 
the Director's quality control process has been completed, with the 
exception that if a responsible party voluntarily submits only clinical 
trial results information under Sec.  11.60(a)(2)(i)(B), the NCT number 
is assigned once complete clinical trial results information has been 
submitted to the Director and the Director's quality control process 
has been completed.
    Ongoing is defined in this proposed rule in Sec.  11.10 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.'' This 
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. 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, we 
define 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.''
    Outcome measure is defined in this proposed rule 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.'' 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. In this proposed part, outcome measure 
refers to measurements taken on those human subjects who are enrolled 
in the clinical trial of interest. 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 comparator can be explained in 
detail. Clinical trial information submitted for a clinical trial of 
interest would not describe 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 below.
    Pediatric postmarket surveillance of a device is a term used in 
section 402(j)(1)(A)(ii)(II) of the PHS Act to describe a type of 
applicable device clinical trial. The term ``[a]pplicable device 
clinical trial'' includes ``a pediatric postmarket surveillance as 
required under . . . [section 522 of the FD&C Act].'' Pursuant to 
section 522, 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). Thus, for purposes of this proposed rule, the term 
pediatric postmarket surveillance of a device is defined 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. A pediatric postmarket surveillance of 
a device may be, but is not always, a clinical trial.'' (See proposed 
Sec.  11.10.)
    Primary outcome measure(s) 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 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) also expressly is required as a clinical 
trial results information data element by section 402(j)(3)(C)(ii) of 
the PHS Act. We believe this 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

[[Page 69607]]

of clinical trial results information. We propose to define primary 
outcome measure 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 . . .'' (See proposed Sec.  
11.10.) We note that for the purpose of this proposed rule, ``primary 
outcome'' has the same meaning as ``primary outcome measure.'' (See 
proposed Sec.  11.10.) See also the discussion in part IV of this 
preamble regarding primary outcome measure as a clinical trial 
registration information data element in proposed Sec.  
11.28(a)(1)(xix) and as a clinical trial results information data 
element in proposed Sec.  11.48(a)(3).
    Principal Investigator (PI) is a term used in the definition of 
responsible party in section 402(j)(1)(A)(ix) of the PHS Act. For 
purposes of this proposed rule, principal investigator means ``the 
individual who is responsible for the scientific and technical 
direction of the study.'' (See proposed Sec.  11.10.) This proposed 
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 have modified 
that definition to remove references to ``applicant organization'' and 
``project or program supported by the grant'' that are specific to NIH-
funded grants and would not necessarily apply to applicable clinical 
trials that are funded by industry or other non-governmental 
organizations. We use 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 have also modified the definition in order to indicate 
that it 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. 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 PI 
unless he or she also has overall responsibility for the clinical trial 
at all sites at which it is being conducted. This interpretation is 
consistent with the requirement in section 402(j)(1)(A)(ix) of the PHS 
Act that a principal investigator may be 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 proposed part.
    We note that the PI of a grant awarded by a Federal Government 
agency that funds a clinical trial may not necessarily be the PI for 
that clinical trial for purposes of this proposed rulemaking. For 
example, the PI on a federal grant who has responsibility for only one 
site of a multi-site clinical trial (See, e.g., 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 proposed part in order to meet the definition of 
responsible party. Accordingly, the PI on such a grant would not be 
considered to be the responsible party for purposes of registering and 
submitting clinical trial results information under section 402(j) of 
the PHS Act and this proposed part.
    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. For purposes of this proposed rule, 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.'' This proposed definition is derived from 
ICH E6(R1): Good Clinical Practice: Consolidated Guideline [Ref. 40], 
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 statistical analysis plan.
    Responsible party is the term used in section 402(j) of the PHS Act 
in order 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 and for submitting clinical trial 
information to ClinicalTrials.gov. Consistent with the definition 
provided in section 402(j)(1)(A)(ix) of the PHS Act, this proposed rule 
defines the term ``responsible party'' 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.'' Proposed 
procedures for determining which individual or entity meets the 
definition of responsible party are specified in Sec.  11.4(c) and 
described in section IV.A.2 of this preamble.
    Secondary outcome measure(s) 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) also is expressly required as a clinical trial 
results information data element by section 402(j)(3)(C)(ii) of the PHS 
Act. 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. Our proposed definition of ``secondary outcome measure'' 
means ``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. A clinical trial may have more than one secondary 
outcome measure.'' This definition is consistent with the WHO Trial 
Registration standard and ICMJE registration policies

[[Page 69608]]

[Ref. 10, 13]. We note that for the purpose of this proposed rule, 
``secondary outcome'' has the same meaning as ``secondary outcome 
measure.''
    The specification in proposed Sec.  11.10 that a secondary outcome 
measure is ``specifically planned to be analyzed as part of the 
clinical trial'' is intended to help responsible parties differentiate 
between secondary outcome measures and tertiary or other lesser outcome 
measures that are more exploratory in nature. We consider secondary 
outcome measures to be those outcome measures (other than the primary 
outcome measures) that are not considered exploratory and for which 
there is a specific analysis plan. In general, the analysis plan would 
be specified in the protocol or statistical analysis plan, but 
protocols do not always contain detailed information about statistical 
analysis, and statistical analysis plans may not be complete at the 
time a trial is registered. Hence, the plan to analyze the secondary 
outcome measure may be expressed only in other formal trial 
documentation (e.g., a grant application, contract, or published 
journal article). We view outcomes measures that are not part of an 
analysis plan or are indicated to be exploratory as tertiary or lower 
level outcome measures that do not need to be submitted to 
ClinicalTrials.gov, but for which information may be submitted 
voluntarily. See discussion in sections IV.B.4 and IV.C.4 of this 
preamble, respectively, regarding secondary outcome measure(s) as a 
clinical trial information data element to be submitted at the time of 
registration following proposed Sec.  11.28(a)(1)(xx) and at the time 
of results submission, following proposed Sec.  11.48(a)(3).
    Serious adverse event is a term used but not defined in section 
402(j)(3)(I) of the PHS Act. 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. In 
defining the term ``serious adverse event'' in its IND Safety Reporting 
regulations at 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 
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.'' 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, because it is 
restricted to unanticipated effects, we do not consider this definition 
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. Although we are relying on an FDA drug regulation, we emphasize 
that ``serious adverse event,'' as defined for purposes of this 
proposed rulemaking, applies to both drugs and devices.
    Therefore, for purposes of this rulemaking, we draw upon the FDA 
definition of ``serious adverse event'' in 21 CFR 312.32(a), because it 
more fully characterizes the criteria for ``other serious problems'' as 
well as ``any life-threatening problem'' or ``[d]eath.'' Our proposed 
rule defines serious adverse event 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.'' 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 (DSM V). By referring to adverse events (and 
thus the definition of that term in this proposed part), our proposed 
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 proposed definition of adverse event, our 
proposed definition of serious adverse event encompasses both 
anticipated and unanticipated effects regardless of attribution or 
association with the intervention.
    Sponsor is a term used in section 402(j) of the PHS Act to define 
responsible party. 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. There are two types of sponsors defined in 
21 CFR 50.3, both of which meet the definition of sponsor for purposes 
of this proposed rule. The first type is a ``sponsor,'' which is 
defined 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 is a 
``sponsor-investigator,'' which is defined as ``an individual who both

[[Page 69609]]

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.'' We believe that the definition of sponsor used in this 
proposed rule, must encompass both a sponsor and a sponsor-investigator 
because both terms are relevant in determining who initiates the 
clinical trial. Hence, we propose to define sponsor as ``either a 
`sponsor' or `sponsor-investigator', as each is defined 21 CFR 50.3 or 
any successor regulation.'' Procedures for determining which individual 
or entity would be considered the sponsor of a applicable clinical 
trial or other clinical trial subject to this part are specified in 
proposed 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 will be considered to be the responsible party of an 
applicable clinical trial or other clinical trial, unless and until 
that responsibility is delegated to the PI, consistent with the 
requirements of section 402(j)(1)(A)(ix) of the PHS and this proposed 
part.
    Proposed Sec.  11.10(b) defines certain data elements that are part 
of the clinical trial information that must be submitted to 
ClinicalTrials.gov under this proposed part.

B. Registration--Subpart B

    Proposed subpart B sets forth the requirements for registration. It 
identifies who must submit clinical trial registration information; 
which applicable clinical trials must be registered in 
ClinicalTrials.gov; when clinical trial registration information must 
be submitted; where clinical trial registration information must be 
submitted; what constitutes clinical trial registration information; 
and by when NIH will post submitted clinical trial registration 
information.
1. Who must submit clinical trial registration information?--Sec.  
11.20
    Proposed Sec.  11.20 requires that ``[t]he responsible party for an 
applicable clinical trial specified in Sec.  11.22 must register the 
applicable clinical trial [. . .] .'' 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].''
2. Which applicable clinical trials must be registered?--Sec.  11.22
    (a) General specification. Proposed Sec. Sec.  11.22(a)(1) and (2) 
specify which applicable clinical trials must be registered with 
ClinicalTrials.gov. They 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 [. . .] 
.'' This is consistent with section 402(j)(2)(C) of the PHS Act. We 
note that under section 402(j)(2)(C)(iii) of the PHS Act, in the case 
of an applicable clinical trial for a non-serious or non-life-
threatening disease or condition that was ongoing as of September 27, 
2007, clinical trial registration information was not required to be 
submitted until September 27, 2008. However, this distinction is no 
longer relevant because any such trial already should have been 
registered in the data bank.
    We note that this proposal differs from guidance that the Agency 
originally provided regarding its interpretation of section 
402(j)(2)(C) of the PHS Act. The original interpretation may have 
resulted in some responsible parties registering applicable clinical 
trials that we no longer believe are subject to the registration 
requirement of section 402(j)(2)(C) of the PHS Act and this proposed 
part (i.e., applicable clinical trials for non-serious or non-life-
threatening diseases or conditions that were ongoing as of September 
27, 2007, but not as of December 26, 2007). We believe that our 
revised, proposed interpretation more accurately implements the text of 
section 402(j)(2)(C) of the PHS Act. This revised interpretation was 
announced to the public in October 2009 through the NIH Guide [Ref. 
43], the ClinicalTrials.gov Listserv [Ref. 44], and ClinicalTrials.gov. 
Although there is no legal requirement for responsible parties to keep 
clinical trial information for such previously-registered applicable 
clinical trials in ClinicalTrials.gov, we anticipate that many 
responsible parties will want to continue to make clinical trial 
information for such applicable clinical trials available to the public 
through the data bank. We do not intend to remove these clinical trial 
records from ClinicalTrials.gov, but we note that the clinical trial 
information for such clinical trials would be considered voluntary 
submissions of clinical trial information under section 402(j)(4)(A) of 
the PHS Act and would be subject to all of the requirements applicable 
to voluntarily-submitted clinical trial information under section 
402(j)(4)(A) of the PHS Act, including but not limited to the 
requirements that such information be truthful and not misleading in 
accordance with proposed Sec.  11.6 and updated in accordance with 
proposed Sec.  11.64. The Agency recognizes that some responsible 
parties for applicable clinical trials described in this paragraph may 
not want to be subject to the requirements that apply to clinical trial 
information submitted under 402(j)(4)(A) of the PHS Act or proposed 
Sec.  11.60. To address this situation, any responsible party who 
wishes to remove an active clinical trial record from 
ClinicalTrials.gov for such an applicable clinical trial must submit an 
electronic request to the Agency at [email protected] to have 
the record removed from the data bank. We note that if the Agency 
removes a clinical trial record from ClinicalTrials.gov as a result of 
such a request, the clinical trial record would continue to be 
available to the public in the ClinicalTrials.gov archives; however, 
the responsible party for such an applicable clinical trial would not 
be subject to the requirements of section 402(j) of the PHS Act or this 
proposed part. For example, clinical trial results information is not 
required to be submitted for these clinical trials.
    Proposed Sec.  11.22(a)(3) provides clarification for determining 
the date on which an applicable clinical trial is initiated. This date 
is important for determining if an applicable clinical trial is 
required to register in ClinicalTrials.gov, because, as described 
above, the registration requirements of section 402(j) of the PHS Act 
and this proposed part apply only to applicable clinical trials 
initiated after September 27, 2007, and to applicable clinical trials 
that were initiated prior to September 27, 2007 and ongoing on December 
26, 2007. However, section 402(j) of the PHS Act does not define how to 
determine when an applicable clinical trial is ``initiated.'' We 
considered several possibilities for determining the date of 
initiation, including our longstanding practice for ClinicalTrials.gov 
which was to consider the date of initiation to be the date that an 
applicable clinical trial is open to recruitment. In order to be 
consistent with the definitions of ``ongoing'' and ``enrolled'' and 
these proposed regulations, we propose instead that for any applicable 
clinical trial, other than a pediatric postmarket surveillance of a 
device that is not a clinical trial, the date of initiation means the 
date on which the first human subject is enrolled in the clinical

[[Page 69610]]

trial. For any pediatric postmarket surveillance of a device that is 
not a clinical trial, we propose that the date of initiation be the 
date on which FDA approves the plan for conducting the surveillance. 
This date will be well-documented in correspondence with FDA and 
represents the first date on which the pediatric postmarket 
surveillance of a device could be started in accordance with an 
approved plan.
    (b) Determination of applicable clinical trial. Proposed Sec.  
11.22(b) sets forth an approach for determining whether or not a 
clinical trial or study meets the definition of an applicable clinical 
trial. By relying on certain aspects of the detailed discussions in 
section IV.A.5 regarding the definitions of applicable device clinical 
trial and applicable drug clinical trial, this approach outlines 
specific data elements that would be submitted as part of the 
registration process. For clinical trials and studies that are 
registered with ClinicalTrials.gov, it would provide a simple mechanism 
for determining whether or not the clinical trial or study is an 
applicable clinical trial that is subject to section 402(j) of the PHS 
Act and this part, and we could indicate such status in 
ClinicalTrials.gov. The order in which the data elements are considered 
would not influence the outcome: A clinical trial for which the 
submitted information meets the criteria specified below would be 
considered an applicable clinical trial.
    Other than situations where a clinical trial that is not an 
applicable clinical trial is registered voluntarily (see proposed Sec.  
11.60), there is no requirement under section 402(j) of the PHS Act or 
this proposed part for a responsible party to submit clinical trial 
registration information to ClinicalTrials.gov for a clinical trial or 
study that does not meet the definition of an applicable clinical 
trial. Algorithms following the approach outlined here could be 
developed to allow potential registrants to determine a priori whether 
their clinical trial or study meets the definition of an applicable 
clinical trial, without having to go through the registration process. 
To this end, we would make such algorithms accessible on 
ClinicalTrials.gov outside of the registration system.
    The proposed approach of using specified data elements to determine 
whether a clinical trial or study meets the definition of an applicable 
clinical trial is intended to amend and replace the approach currently 
implemented in ClinicalTrials.gov, which asks potential registrants to 
indicate whether their trial is an applicable clinical trial. We 
believe our proposed approach accurately reflects the proposed 
definitions of the terms applicable device clinical trial and 
applicable drug clinical trial. We invite public comment on this 
proposed approach and on whether there are any types of clinical trials 
or studies which might be errantly classified as applicable clinical 
trials that do not in fact meet the definitions of applicable device 
clinical trial or applicable drug clinical trial, or, conversely, any 
types of clinical trials or studies that do in fact meet the 
definitions of applicable device clinical trial or applicable drug 
clinical trial that might fail to be classified as applicable clinical 
trials.
    Consistent with the elaboration provided in section IV.A.5 of this 
preamble for the proposed definition of applicable device clinical 
trial, under proposed Sec.  11.22(b)(1), a study would meet the 
definition of an applicable device clinical trial if (1) it is a 
Pediatric Postmarket Surveillance of a Device required by FDA under 
section 522 of the FD&C Act (regardless of whether the pediatric 
postmarket surveillance is a clinical trial), (2) it meets all of the 
following criteria for the submitted data elements: (a) The Study Type 
is interventional; (b) the Primary Purpose selected is other than 
feasibility; (c) either the Number of Arms is two or more, or the 
Number of Arms is one and Single Arm Controlled is selected; (d) the 
Intervention Type selected is something other than a combination 
product; (e) the clinical trial Studies an FDA-regulated Device; and 
(f) 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 the U.S. or one of its 
territories and is exported for study in another country, or the 
clinical trial has a U.S. Food and Drug Administration IDE Number.
    Taking a similar approach for applicable drug clinical trials, and 
consistent with the elaboration provided in section IV.A.5 of this 
preamble for the proposed definition of applicable drug clinical trial, 
proposed Sec.  11.22(b)(2) states that a clinical trial meets the 
definition of an applicable drug clinical trial if it meets all of the 
following criteria for the submitted data elements: (1) The Study Type 
is interventional; (2) the Study Phase is other than phase 1; (3) 
either the Number of Arms is two or more, or the Number of Arms is one 
and Single Arm Controlled is selected; (4) the clinical trial Studies 
an FDA-regulated Drug; and (5) one or more of the following applies: At 
least one Facility Location is within the U.S. or one of its 
territories, the drug under investigation is a Product Manufactured in 
the U.S. and is exported for study in another country, or the clinical 
trial has a U.S. Food and Drug Administration IND Number.
    With respect to Study Phase, we do not consider a phase 1/phase 2 
study to be a phase 1 study; therefore, a clinical trial that is 
indicated to be phase 1/phase 2 would be considered an applicable drug 
clinical trial if it meets the other conditions listed in (1) through 
(5) above and would be required to register at ClinicalTrials.gov if it 
also meets the conditions specified in proposed Sec.  11.22(a). If a 
clinical trial is registered as phase 1/phase 2, and 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 submission specified in 
subpart C. However, submitted registration information would continue 
to be posted in ClinicalTrials.gov.
    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 an FDA-regulated drug in 
one arm and studies an FDA-regulated device in another arm and compares 
outcomes of the two arms would meet both definitions. If the device 
studied in such an applicable clinical trial is not approved or cleared 
by FDA for any use and is not a component of a combination product, it 
would be treated as an applicable device clinical trial in that we 
would not post clinical trial registration information for that 
clinical trial prior to the date of approval or clearance of the 
device, consistent with proposed Sec.  11.35(b)(2). We consider this 
situation to differ from that of an applicable clinical trial in which 
a studied device is part of a combination product. As explained in the 
discussion of the definition of an applicable drug clinical trial in 
section IV.A.5 of this preamble, any applicable clinical trial that 
studies a combination product would be treated as an applicable drug 
clinical trial under this proposed rule.

[[Page 69611]]

3. When must clinical trial registration information be submitted?--
Sec.  11.24
    Proposed Sec.  11.24 specifies the deadlines by which a responsible 
party must submit clinical trial registration information to register 
an applicable clinical trial in ClinicalTrials.gov. Consistent with 
section 402(j)(2)(C) of the PHS Act, proposed Sec.  11.24(a) requires 
that clinical trial registration information be submitted on the later 
of December 26, 2007, or 21 calendar days after the first human subject 
is enrolled in the clinical trial. However, section 402(j)(2)(C)(iii) 
of the PHS Act provides an exception to this deadline. For any 
applicable clinical trial that was not for a serious or life-
threatening disease or condition (e.g., was not for indications such as 
acquired immunodeficiency syndrome (AIDS), all other stages of human 
immunodeficiency virus (HIV), Alzheimer disease, cancer, or heart 
failure; See [Ref. 4]), was initiated on or before September 27, 2007, 
and was still ongoing on December 26, 2007, the responsible party must 
submit clinical trial registration information by the later of 
September 27, 2008, or 21 calendar days after the first human subject 
is enrolled in the clinical trial. This proposed rule mirrors this 
standard in Sec.  11.24(b)(1).
    With regard to registering a pediatric postmarket surveillance of a 
device that is not a clinical trial, the submission deadlines described 
above may not be applicable because such surveillances may not entail 
formal recruitment of human subjects. We propose in Sec.  11.24(b)(2), 
therefore, that registrations of pediatric postmarket surveillances of 
a device that are not clinical trials be submitted ``not later than 
December 26, 2007, or 21 calendar days after FDA approves the 
postmarket surveillance plan, whichever date is later.'' This provides 
a clear deadline for submission of clinical trial registration 
information, and the 21-day period is consistent with the requirement 
in section 402(j)(2)(C)(ii) of the PHS Act that clinical trials be 
registered 21 days after enrollment of the first human subject.
4. What constitutes clinical trial registration information?--Sec.  
11.28
    Proposed Sec.  11.28 identifies 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 conform to the 
items enumerated in section 402(j)(2)(A)(ii) of the PHS Act. In many 
instances, the Agency, through this proposed rulemaking has 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 have also taken into 
consideration the WHO trial registration standards and have sought to 
maintain consistency with the clinical trial registration requirements 
of the ICMJE [Ref. 13, 10].
    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 consider 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 believe, in general, that maintaining 
consistency with the pre-existing data elements for ClinicalTrials.gov 
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, 
but also we believe that maintaining consistency will minimize 
confusion for those who submitted registration information previously 
to ClinicalTrials.gov prior to enactment of section 402(j) of the PHS 
Act. It will also 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. It will serve the 
public by facilitating cross-comparison of entries made before and 
after enactment of section 402(j) of the PHS Act. It also will ensure 
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 would 
improve and not reduce the clinical trial information submitted to 
ClinicalTrials.gov.
    As further discussed in section III.C.2 of this preamble, in 
developing our proposed set of data elements for clinical trial 
registration information, we have 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., 
proposing to add data elements to indicate whether a product under 
study in a clinical trial in manufactured in the U.S. and whether a 
study is a pediatric postmarket surveillance of a device, 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., proposing to add Other Intervention 
Name(s) and Intervention Description to help users identify and 
differentiate among similar interventions studied in registered 
clinical trials; or
    (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., proposing to 
add Human Subjects Protection Review Board Status to indicate to 
potential human subjects and other users whether an applicable clinical 
trial has received needed

[[Page 69612]]

approvals or is not subject to such requirements.
    (a) Registration data elements for applicable clinical trials other 
than pediatric postmarket surveillances of a device that are not 
clinical trials. Proposed Sec.  11.28(a) specifies 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. A pediatric postmarket surveillance of a device that does not 
take the form of a clinical trial would be registered by submitting the 
clinical trial information specified in Sec.  11.28(b). The clinical 
trial registration information data elements in Sec.  11.28(a) 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 proposes via this rule are 
listed in the categories in which they best fit. The clinical trial 
registration information data elements, grouped by category, are as 
follows.
(1) Descriptive Information
    Brief Title. 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 does not 
define the term, other than to indicate that the title is ``intended 
for the lay public.'' We interpret 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. Prior to FDAAA, those submitting 
information to the ClinicalTrials.gov registry pursuant to FDAMA, were 
requested to include a ``brief title'' of the trial [Ref. 2]. This term 
was defined to mean a ``protocol title intended for the lay public'' 
[Ref. 2]. This definition of ``brief title'' also is consistent with 
``public title'' (data item #9) of the WHO Trial Registration standard 
and ICMJE registration policies [Ref. 13, 10].
    Based on our experience to date with ClinicalTrials.gov, we 
recognize 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 believe 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 might see referenced in 
other media (e.g., news reports, journal articles). As such, we 
consider an acronym used to identify a clinical trial to be part of the 
brief title. Therefore, in proposed Sec.  11.10(b)(1), Brief Title is 
described 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.'' Although we do not specify 
what type of information must be conveyed by the Brief Title, we 
believe that a Brief Title intended for the lay public should include, 
where possible, information on the participants, condition being 
evaluated, and intervention(s) studied.
    Official Title. Using the authority in section 402(j)(2)(A)(iii) of 
the PHS Act we propose to require a responsible party to submit an 
``official title'' as part of clinical trial information when 
registering an applicable clinical trial at ClinicalTrials.gov. In 
proposed Sec.  11.10(b)(2), we define Official Title as: ``The title of 
the clinical trial, corresponding to the title of the protocol.'' We 
believe 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 
in ClinicalTrials.gov with information about the clinical trial that is 
contained in other sources, such as scientific publications, regulatory 
submissions, and media reports, which often use the official title of 
the study protocol. Those who learn about a clinical trial from one of 
these other sources could more easily search for the trial in 
ClinicalTrials.gov using the Official Title. Prior to passage of FDAAA, 
those submitting information to ClinicalTrials.gov were able to submit 
an ``official title'' as an optional data element, defined to mean 
``Official name of the protocol provided by the study principal 
investigator or sponsor'' [Ref. 2]. This submission of an official 
title is also consistent with the WHO Trial Registration standard and 
ICMJE registration policies, which require the submission of a 
``scientific title'' (data item #10) [Ref. 13, 10].
    Brief Summary. 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.'' Prior to FDAAA, those submitting information to the 
ClinicalTrials.gov registry pursuant to FDAMA were requested to include 
a ``brief summary'' of the clinical trial [Ref. 4]. This term was 
defined to mean a ``short description of the protocol intended for the 
lay public, including a brief statement of the study hypothesis'' [Ref. 
2]. We propose to continue to use that definition. Accordingly, in 
proposed Sec.  11.10(b)(3), Brief Summary is 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.''
    Primary Purpose. 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. Prior to passage of section 402(j) of the PHS Act in 
2007, those submitting information to the registry were requested to 
indicate the primary purpose of the clinical trial. This term was 
defined to mean the ``reason for the protocol'' [Ref. 2], and those 
submitting information were given a choice of selections, including 
``treatment,'' ``prevention,'' ``diagnostic,'' ``supportive care,'' 
``screening,'' ``health services research,'' and ``basic science.'' 
Data submitters could also indicate ``other'' and include a description 
of the purpose in the detailed description portion of the clinical 
trial record. We found this approach effective for indicating the 
primary purpose of the intervention(s) studied in the clinical trials 
registered with ClinicalTrials.gov and believe this approach would 
apply well to clinical trials being registered pursuant to this 
proposed part. Therefore, under proposed Sec.  11.10(b)(4), Primary 
Purpose refers to ``the main objective of the intervention(s) being 
evaluated by the clinical trial.'' We would require a responsible party 
to provide a response selected from the following set of options: 
``treatment'' (for a protocol designed to evaluate one or more 
interventions for treating a disease, syndrome or condition), 
``prevention'' (for a protocol designed to assess one or more 
interventions aimed at preventing the development of a specific disease 
or health condition), ``diagnostic'' (for a protocol designed to 
evaluate one or more interventions aimed at identifying a disease or 
health condition), ``supportive care'' (for a protocol designed to 
evaluate one or more interventions where the primary intent is to 
maximize comfort, minimize side effects or mitigate against a decline 
in the subject's health or function), ``screening'' (for a protocol 
designed to assess or examine methods of identifying a condition, or 
risk factors

[[Page 69613]]

for a condition, in people who are not yet known to have the condition 
or risk factor), ``health services research'' (for a protocol designed 
to evaluate the delivery, processes, management, organization or 
financing of health care), ``basic science'' (for a protocol designed 
to examine the basic mechanism of action, e.g., physiology or 
biomechanics, of an intervention), ``feasibility'' (for a protocol 
designed to determine the feasibility of a device or test prototype 
devices where the primary outcome measure relates to feasibility and 
not to health outcomes), or ``other''. The inclusion of ``feasibility'' 
on the list of options is intended to permit the responsible party for 
a clinical trial of a device to indicate whether such clinical trial is 
a feasibility study. Feasibility studies do not meet the definition of 
an applicable device clinical trial as specified in section 
402(j)(1)(A)(ii) of the PHS Act and Sec.  11.10(a) of this proposed 
part. 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 proposed 
Sec.  11.60.
    Study Design. 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 does not define the term. 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. Hence, we propose to 
require that several components of study design be submitted. Prior to 
FDAAA, those submitting information to ClinicalTrials.gov pursuant to 
FDAMA were requested to include the interventional study 
characteristics of the trial [Ref. 4]. This term was defined to mean 
the ``[p]rimary investigative techniques used in the protocol,'' and 
data submitters were instructed to provide information describing 
several key attributes of the study design, including the study model, 
number of arms, masking, and allocation [Ref. 2]. This definition of 
study design, including the key attributes, conforms to ICH Guidelines 
[Ref. 23] and is consistent with ``study type'' (data item #15) of the 
WHO Trial Registration standard (version 1.0) and ICMJE registration 
policies [Ref. 13, 10]. Consistent with this approach, proposed Sec.  
11.10(b)(5) requires that Study Design include information about 
several important aspects of a clinical trial: interventional study 
model, number of arms, arm information, allocation, masking, and 
whether a single-armed clinical trial is controlled. None of these 
terms is used in section 402(j) of the PHS Act, but we believe each is 
key component of study design. We propose the following meanings for 
these terms.
    (a) Interventional Study Model characterizes the approach used for 
assigning groups of human subjects to interventions during the clinical 
trial. In proposed Sec.  11.10(b)(5)(i), the data item is defined as 
``[t]he strategy for assigning interventions to human subjects.'' In 
ClinicalTrials.gov, 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), or ``factorial'' (i.e., two or more interventions, each alone 
and in combination, are evaluated in parallel against a control group). 
No ``other'' option is proposed. To address those 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, responsible parties would also be 
able to provide voluntarily additional free-text description containing 
more specific details about the interventional study model. We invite 
public comment on whether the proposed set of options adequately 
addresses existing and emerging interventional study models, including 
dose escalation study designs, and whether it would provide suitable 
selections, without an ``other'' option for all types of applicable 
clinical trials and voluntarily registered trials that are subject to 
this proposed regulation.
    (b) Number of Arms specifies the total number of arms in a clinical 
trial. We define the term ``arm'' in proposed Sec.  11.10(a). Some 
clinical trials contain multiple periods or phases, each of which might 
use different numbers of arms. Hence, in proposed Sec.  
11.10(b)(5)(ii), the data element is 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 note that historical controls are not considered 
to be an ``arm'' of a clinical trial and thus are not counted in the 
number of arms.
    (c) Arm Information provides key information about each arm in the 
clinical trial. In proposed Sec.  11.10(b)(5)(iii), the data element 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 to 
differentiate each arm from other arms in the clinical trial.'' 
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.
    (d) Allocation describes how human subjects are assigned to 
interventions. In proposed Sec.  11.10(b)(5)(iv), the data item is 
defined as ``[t]he method by which human subjects are assigned to arms 
in a clinical trial.'' 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 is proposed. We invite 
public comment on whether this limited set of options would provide 
suitable selections for all types of applicable clinical trials and 
voluntarily registered clinical trials that are subject to this 
proposed rule.
    (e) Masking specifies which entities, if any, involved in the 
clinical trial are not informed of the intervention assignments (i.e., 
who is ``blinded'' in the clinical trial). In proposed Sec.  
11.10(b)(5)(v), the data item is 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.'' 
In the data bank,

[[Page 69614]]

responsible parties would be required to select from the following 
limited menu of choices for describing which party(ies) is/are blinded: 
``human subject,'' ``care provider,'' ``investigator,'' and/or an 
``outcomes assessor'' (i.e., another individual who evaluates the 
outcome(s) of interest). No ``other'' option is proposed, but 
responsible parties would have the ability to voluntarily provide 
additional, free-text, information about other parties who might be 
blinded in clinical trial.
    (f) Single Arm Controlled? is not a data element that is explicitly 
listed in section 402(j) of the PHS Act as part of clinical trial 
information, but we propose it as a sub-element part of Study Design to 
enable the Agency to determine whether a registered clinical trial is 
an applicable clinical trial when such a determination cannot be made 
based on other submitted registration data elements. This data element, 
which is described in proposed Sec.  11.10(b)(5)(vi) 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,'' would 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. As explained in 
section IV.A.5 of this preamble, a study of a device that is not a 
pediatric postmarket surveillance of a device can meet the definition 
of an applicable device clinical trial only if it ``compar[es] an 
intervention with a device . . . against a control in human subjects.'' 
(See 402(j)(1)(A)(ii)(I) of the PHS Act.) Similarly, a clinical trial 
of a drug can meet the definition of an applicable drug clinical trial 
only if it is ``a controlled clinical investigation . . .'' (See 
402(j)(1)(A)(iii)(I)).
    As explained in the definition of the term ``controlled'' in 
section IV.A.5 of this preamble, we consider any clinical trial with 
two or more arms to be controlled and/or to compare an intervention 
against a control. A clinical trial with only one arm (a single-armed 
study) may or may not be controlled and/or compare an intervention 
against a control, depending on whether or not the data collected on 
human subjects in the clinical trial will be compared to non-
concurrently collected data. To determine whether a clinical trial with 
only one arm meets this criterion, we propose to require the 
responsible party for a single-armed study to indicate whether the 
clinical trial is controlled, as defined in this part. In doing so, the 
responsible party would consider whether the protocol or statistical 
analysis plan for the clinical trial indicates that data collected in 
the single-arm clinical trial will be compared to non-concurrently 
collected data, such as an historical control group. To reduce the 
burden on responsible parties, we would require this element of Study 
Design to be submitted only if the other clinical trial information 
submitted by the responsible party indicates that the clinical trial 
has one arm and otherwise meets the criteria for an applicable clinical 
trial, as listed in proposed Sec.  11.22(b) (section IV.B.2(b) of this 
preamble). If other submitted registration data elements demonstrate 
that the clinical trial is not an applicable clinical trial or that it 
includes two or more arms, the Single Arm Controlled? data element 
would not need to be submitted.
    Study Phase. 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. Prior to FDAAA, those 
submitting registration information to ClinicalTrials.gov pursuant to 
FDAMA were requested to include the study phase of the clinical trial 
[Ref. 4]. This term was interpreted to mean ``phase of investigation, 
as defined by FDA for trials involving investigational new drugs'' 
[Ref. 2]. In proposed Sec.  11.10(b)(6), the data item is 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.'' 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, they 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 
is 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's regulations (21 CFR 312.21). 
Therefore, we do 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'' should indicate 
the Study Phase as ``phase 1''. Study phases are not intended for use 
in describing clinical trials of devices, and 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.
    Study Type. 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. Prior to FDAAA, those submitting information to the registry 
pursuant to FDAMA were requested to include the study type of the 
record being submitted to the registry by indicating whether the record 
corresponded to an interventional study (i.e., a clinical trial), an 
observational study, or an expanded access program. The study type 
selected would determine which other data elements to submit [Ref. 4]. 
Consistent with prior practice, proposed Sec.  11.10(b)(7) defines the 
Study Type date element as ``the type of study for which clinical trial 
information is being submitted.'' Responsible parties would be required 
to select one of the following limited set of options: 
``interventional,'' ``observational,'' or ``expanded access program.'' 
No ``other'' option is proposed. We believe that all applicable 
clinical trials and all other clinical studies that might be registered 
voluntarily with ClinicalTrials.gov can be characterized accurately as 
either ``interventional'' or ``observational,'' depending on whether 
human subjects studied are assigned to interventions based on a study 
protocol (interventional) or patients receive interventions as part of 
routine medical care, and a researcher studies the effect of the 
intervention (observational). We would consider observational studies 
to include a wide range of non-interventional studies, including 
retrospective reviews of patient records or relevant literature. (See 
the elaboration of the terms applicable device clinical trial and 
applicable drug clinical trial in section IV.A.5 of this preamble). A 
study that is designated as ``interventional,'' as that term is defined 
in this proposed 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''

[[Page 69615]]

would be an applicable clinical trial only if it is a pediatric 
postmarket surveillance of a device as defined in this part. (See the 
proposed definition of pediatric postmarket surveillance of a device in 
Sec.  11.10, the discussion of proposed 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 must always have a Study 
Type of ``interventional.'' An applicable clinical trial that is a 
pediatric postmarket surveillance of a device could have a Study Type 
of ``interventional'' or ``observational.'' The term, ``expanded access 
program,'' is proposed as an option for Study Type because responsible 
parties are required to enter the data elements describing an expanded 
access program that is not an applicable clinical trial by creating an 
expanded access record if there is an expanded access program for the 
drug or biological product under study in the clinical trial being 
registered, consistent with section 402(j)(2)(A)(ii)(II)(gg) of the PHS 
Act, and if such a record does not already exist. As discussed in 
section IV.A.5 of this preamble, we expect that most expanded access 
programs will not meet the definition of an applicable clinical trial. 
The appropriate Study Type for expanded access programs that do not 
meet the definition of applicable clinical trial would be ``expanded 
access program.'' The appropriate Study Type for an expanded access 
program that does meet the definition of applicable clinical trial 
would be ``interventional.'' An expanded access program must be 
registered under only one Study Type. (See discussion of proposed Sec.  
11.28(c)). We invite public comment on our proposal for Study Type, 
including whether the limited set of options proposed would provide 
suitable selections for all types of applicable clinical trials and 
voluntarily registered clinical trials that are subject to this 
proposed rule.
    Whether the Study is a Pediatric Postmarket Surveillance of a 
Device. We propose, in Sec.  11.28(a)(1)(viii), to add a requirement 
for responsible parties of a study of a device to indicate if the study 
is a pediatric postmarket surveillance of a device. As we stated 
previously, 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; 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.
    By indicating that a study is a pediatric postmarket surveillance 
of a device, users of the data bank and the Agency would 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 
(interventional, observational), the Agency could confirm whether the 
pediatric postmarket surveillance of a device 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 is a 
clinical trial, the clinical trial registration information data 
elements set forth at proposed Sec.  11.28(a) are required to be 
submitted. If a pediatric postmarket surveillance of a device is not a 
clinical trial (i.e. it is a form of observational study, including a 
retrospective review of patient records or relevant literature), the 
clinical trial registration information data elements set forth in 
Sec.  11.28(b) are required to be submitted.
    Primary Disease or Condition Being Studied in the Trial, or the 
Focus of the Study. 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 possible (if the other 
terminology is mapped to MeSH, the data bank can be searched using MeSH 
terms and retrieve the correct record(s)). SNOMED CT (Systematized 
Nomenclature of Medicine--Clinical Terms) (http://www.ihtsdo.org/snomed-ct/) meets the criteria of having been mapped to MeSH and has 
been designated as a U.S. standard for certified electronic health 
records that meet specified criteria for meaningful use of health 
information technology. (See http://www.gpo.gov/fdsys/pkg/FR-2012-09-04/pdf/2012-20982.pdf). Other vocabularies have also been mapped to 
MeSH within the NLM's Unified Medical Language System[supreg] 
(UMLS[supreg]) Metathesaurus. While it is possible that not all primary 
diseases or conditions or study foci can be expressed using MeSH, 
SNOMED CT, or another vocabulary that is mapped to MeSH within the UMLS 
Metathesaurus, we believe such terminology would accommodate most 
clinical trials and must be used when available. When a suitable term 
is unavailable in MeSH, SNOMED CT, or another vocabulary that is 
included in the UMLS Metathesaurus, ClinicalTrials.gov can accept 
another English language entry that accurately describes the primary 
disease or condition being studied, or the focus of the study. 
ClinicalTrials.gov could then use the information to enable searching 
by MeSH terms. Therefore, under proposed Sec.  11.10(b)(9), we define 
Primary Disease or Condition Being Studied in the Trial, or the Focus 
of the Study 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 National Library of 
Medicine's Medical Subject Headings (MeSH) controlled vocabulary 
thesaurus http://www.nlm.nih.gov/mesh/, 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 (https://uts.nlm.nih.gov).'' This definition is consistent with ``health 
condition(s) or problem(s) studied'' (data item #12) of the WHO Trial 
Registration standard (version 1.0) and ICMJE registration policies 
[Ref. 13, 10]. It is also consistent with the terminology used in 
ClinicalTrials.gov prior to FDAAA when those submitting information to 
the registry in response to FDAMA were requested to include 
``conditions or focus of study,'' which were described as the ``primary 
disease or condition being studied, or focus of the study,'' and 
submitters were directed to describe the diseases or conditions using 
MeSH controlled vocabulary when possible [Ref. 2, 4].
    Intervention Name(s). 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. 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

[[Page 69616]]

and compare clinical trials by intervention. While some clinical trials 
compare a single intervention against a placebo (which would not need 
to be listed as a separate intervention), many compare multiple 
interventions (e.g., a new drug versus standard treatment, or different 
dosages of the same drug). We believe it is important for the names of 
all interventions studied in a clinical trial to be submitted to the 
data bank. Based on our previous 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. 4]. We believe that non-proprietary names must be provided 
for interventions (e.g., drugs, biological products, and devices) 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. Therefore, under proposed Sec.  11.10(b)(10), 
Intervention Name(s) is 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.'' Examples of a brief descriptive name or 
identifier include a chemical name, company code or serial number. This 
description of Intervention Name is consistent with the 
``intervention(s)'' (data item #13) of the WHO Trial Registration 
standard (version 1.0) and ICMJE registration policies [Ref. 13, 10]. 
It is also consistent with use of the term in ClinicalTrials.gov prior 
to FDAAA when those submitting information to the ClinicalTrials.gov 
registry pursuant to FDAMA were requested to include the intervention 
name for each intervention involved in the trial [Ref. 4], and the term 
was defined to mean the ``generic name of the precise intervention 
being studied. For investigational new drugs that do not yet have a 
generic name, a chemical name, company code or serial number may be 
used on a temporary basis.'' Our current proposal is consistent with 
this approach.
    Other Intervention Name(s) is a term that is not used in section 
402(j) of the PHS Act, but 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 prior 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 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. Under proposed 
Sec.  11.10(b)(11), this term is 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.'' 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 do not believe such additional communication would be 
frequent or onerous. This proposal would not require 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 seek comment on this approach.
    Intervention Description. The term ``intervention description'' is 
not used in section 402(j) of the PHS Act, but we propose 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 users to differentiate among similar 
interventions used in different arms of a clinical trial, or to 
distinguish the intervention used in one clinical trial from a similar 
intervention used in another clinical trial, or to 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 is needed about the intervention, 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 general types of materials used. 
The submission of such information will 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 submission of an Intervention 
Description would improve but not reduce the clinical trial information 
available in the data bank. Under proposed Sec.  11.10(b)(12), the term 
is defined 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.'' The information 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 if 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.
    Intervention Type. 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,

[[Page 69617]]

but it does not define the term. Prior to FDAAA, those submitting 
information to the ClinicalTrials.gov registry were requested to 
specify the intervention type for each intervention studied in the 
clinical trial. Under proposed Sec.  11.10(b)(13) Intervention Type 
would be defined as ``for each intervention studied in the clinical 
trial, the general type of intervention.'' When submitting this 
information, 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.'' Note 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. As 
specified in proposed Sec.  11.28(a)(1)(xiii), selection of an 
Intervention Type would be 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(b) 
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.
    Studies an FDA-Regulated Device. Section 402(j) of the PHS Act does 
not explicitly require submission of a clinical trial registration 
information data element to indicate whether or not a clinical trial 
studies an FDA-regulated device. We propose 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 or not 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 ``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 ``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 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 device). If the responsible party has 
obtained an IDE and submitted an IDE number to ClinicalTrials.gov, it 
would be clear that the clinical trial is an applicable device clinical 
trial as defined in this part (assuming, as discussed previously, that 
the clinical trial is not a clinical trial of a combination product). 
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 per se indicate that a clinical trial is not an applicable 
device clinical trial.
    To avoid this ambiguity and help ensure that applicable clinical 
trials can be properly identified, we propose to require a responsible 
party to specifically indicate whether or not a clinical trial studies 
an FDA-regulated device by submitting the Studies an FDA-regulated 
Device data element. The data element is defined in proposed Sec.  
11.10(b)(39) to mean that ``a clinical trial studies a device that is 
subject to section 510(k), 515, or 520(m) of the Federal Food, Drug, 
and Cosmetic Act.'' Consistent with the elaboration of the term 
applicable device clinical trial in section IV.A.4 of this preamble, we 
interpret 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 U.S.: (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 for the device, or 
(3) a humanitarian device exemption 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 or not 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). 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).
    We are aware that devices 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 devices may not be 
designed to study the effect of these devices. Therefore, when 
considering whether a clinical trial Studies an FDA-regulated Device a 
responsible party should consider whether: (a) The study is designed to 
examine the effect or performance of an FDA-regulated device, or 
differences in the intended use, e.g., 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 (e.g., need for replacement or 
maintenance of the device).
    Studies an FDA-Regulated Drug. Section 402(j) of the PHS Act does 
not explicitly require submission of a clinical trial registration 
information data element to indicate whether or not a clinical trial 
studies an FDA-regulated drug. We propose 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 or not a clinical trial is an applicable 
drug clinical trial using the approach specified in proposed Sec.  
11.22(b)(1). 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.'' It is 
possible that a clinical trial with an Intervention Type of ``drug'' or 
``biological product'' would not be an applicable drug clinical trial 
because the drug is not subject to section 505 FD&C Act (e.g., a non-
prescription drug that is marketed under an over-the-counter drug 
monograph)

[[Page 69618]]

and/or the biological product is not subject to section 351 of the PHS 
Act. Conversely, it is possible that a clinical trial could be an 
applicable drug clinical trial even if none of the specified 
Intervention Types is ``drug'' or ``biological product.'' 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 subject to 
section 505 of the FD&C Act or a biological product subject to section 
351 of the PHS Act. For example, a dietary supplement could be studied 
for 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, then it would be clear (assuming, as 
discussed previously, that the clinical trial is not a clinical trial 
of a combination product) that the clinical trial is an applicable drug 
clinical trial as defined in this part. 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 per se 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 propose to require a responsible party to specifically indicate 
whether or not a clinical trial studies an FDA-regulated drug by 
submitting the Studies an FDA-regulated Drug data element. The data 
element is defined in proposed Sec.  11.10(b)(40) to mean that ``a 
clinical trial studies a drug that is subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or section 351 of the Public 
Health Service Act.'' Consistent with the elaboration of the term 
applicable drug clinical trial in section IV.A.4 of this preamble, we 
interpret this definition to mean that the clinical trial studies a 
drug that is the subject of an approved new drug application (NDA) or 
biologics license application (BLA) or that would require an approved 
NDA or BLA to be legally marketed in the U.S. 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 or not a clinical trial without an IND 
studies an FDA-regulated drug or 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, 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).
    We are aware that a clinical trial may include an FDA-regulated 
drug even though the drug is not a variable of interest. For example, a 
clinical trial of a device may involve the surgical insertion of the 
device under anesthesia, but the anesthesia drug is not studied in the 
clinical trial. In determining whether a clinical trial Studies an FDA-
regulated Drug a responsible party should consider whether: (a) The 
clinical trial is designed to examine the effect of the FDA-regulated 
drug(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(s).
    U.S. FDA Approval, Licensure, or Clearance Status. We propose U.S. 
FDA Approval, Licensure, or Clearance Status to be submitted as 
clinical trial information to indicate whether any intervention 
regulated by FDA and studied in the clinical trial has been approved, 
licensed, or cleared for any use. Such information would help in 
ensuring that the data bank operates in compliance with statutory 
requirements. For example, 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.) This information also would be 
helpful for users of ClinicalTrials.gov, including potential 
participants, who might 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 propose referring 
explicitly to the ``U.S.'' FDA to provide clarification for those 
submitting information about foreign clinical trials to 
ClinicalTrials.gov. In proposed Sec.  11.10(b)(14), we therefore define 
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.'' 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); ``No'' (the product has not been approved, licensed, or 
cleared for any use). No ``other'' option is proposed, but a 
responsible party would also be able to provide voluntarily additional 
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 invite public comment on whether the set of 
proposed options is sufficient to describe the approval, licensure, or 
clearance status of FDA-regulated drugs or devices that would be 
studied in applicable clinical trials or voluntarily registered 
clinical trials that are subject to this proposed rule.
    Product Manufactured in the U.S. Section 402(j) of the PHS Act does 
not explicitly require a data element to be submitted as part of 
clinical trial information to indicate whether a product under study is 
manufactured in the U.S, but we propose 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. This data element, which is defined in Sec.  
11.10(b)(15) as ``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,'' will assist the Agency in determining whether a 
clinical trial meets the definition of an applicable clinical trial. As 
explained above in the definitions of ``applicable device clinical 
trial'' and ``applicable drug clinical trial,'' even if a clinical 
trial is being conducted entirely outside of the U.S. or one of its 
territories, it may be considered an applicable clinical trial where 
the drug or device is subject to regulation under the FD&C Act. A drug 
or device is considered to be subject to regulation under the FD&C Act 
if the product under investigation is

[[Page 69619]]

manufactured in the U.S. or one of its territories and is exported for 
study in another country, either under an IND, pursuant to 21 CFR 
312.110, or any successor regulation, or under section 801(e) or 802 of 
the FD&C Act. Thus, information indicating whether each intervention 
studied in a clinical trial is manufactured in the U.S. or one of its 
territories would be essential in some situations to determine whether 
such trial is subject to FDA jurisdiction and meets the definition of 
an applicable clinical trial.
    To reduce data submission burden, this data element would need to 
be submitted to ClinicalTrials.gov 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 U.S. or its territories. In those situations 
in which a responsible party would be required to submit information 
about whether the product(s) under study is manufactured in the U.S., 
including this information in the data bank would improve and not 
reduce clinical trial information by publicly providing data necessary 
to determine whether or not such trial is an applicable clinical trial. 
Accordingly, we propose the addition of this data element as clinical 
trial registration information pursuant to our authority to modify the 
requirements for clinical trial registration information under section 
402(j)(2)(A)(iii) of the PHS Act.
    Study Start Date. 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 
this term. Prior to passage in 2007 of section 402(j) of the PHS Act, 
those submitting information to ClinicalTrials.gov were requested to 
include the study start date of the trial, which was defined as the 
``date that enrollment to the protocol begins'' [Ref. 2], meaning the 
date on which the clinical trial is open to enrollment, even if no 
subjects are enrolled on that date. The WHO Trial Registration standard 
(version 1.0) and ICMJE registration policies, in contrast, define the 
term study start date (data item #16) as the ``date of first 
enrollment'' [Ref. 13, 10].
    Section 402(j)(2)(C)(ii) of the PHS Act and proposed Sec.  11.24(a) 
generally require 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 might not have information about when the first 
subject will be enrolled or when the first subject was enrolled (for 
example, in a large multi-site trial) but might know only when the 
clinical trial was or will be opened for enrollment. To account for 
these potential scenarios, we propose 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). Not later than 21 days after 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, consistent with proposed Sec.  11.64. 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 likely will be open to 
enrollment. Hence, in proposed Sec.  11.10(b)(16) we define 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.'' The Study Start Date must include the 
day, month, and year. We note that if a clinical trial is registered 
with an estimated study start date but the clinical trial then is 
halted before enrolling the first subject (e.g., because of 
difficulties in recruitment, loss of funding, etc.), the responsible 
party would not be expected to update the study start date; rather, 
responsible party would be expected to update the Overall Recruitment 
Status data element specified in proposed Sec.  11.10(b)(25) to 
indicate that the clinical trial has been ``withdrawn,'' as such term 
is used for the purpose of this regulation, and to update the Why Study 
Stopped data element specified in proposed Sec.  11.10(b)(26).
    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. The public availability of information about 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)(E)(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, as described 
in the discussion of proposed Sec.  11.44, that certain exceptions 
apply to this general deadline for the submission of clinical trial 
results information. In addition, we note that we interpret the phrase 
``estimated completion date,'' as such term is used in section 
402(j)(3)(E)(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 addition, we believe it is important for users to have 
information about the actual completion date of a clinical trial, so 
that they can know when clinical trial results information ordinarily 
would be due under section 402(j)(3)(E)(i) of the PHS Act and proposed 
Sec.  11.44(a), absent certain specified circumstances in which 
submission of clinical trial results information may be delayed. 
Because clinical trial results information generally is required under 
section 402(j)(3)(E)(i) of the PHS Act and proposed Sec.  11.44 to be 
submitted not later than 1 year after the estimated or actual 
completion date, whichever is earlier, we believe it is important for 
the Completion Date data element to be updated promptly after the 
completion date is reached. We therefore propose in Sec.  
11.28(a)(1)(xvii) that when registering a clinical trial, a responsible 
party must submit the Completion Date for the clinical trial, which is 
defined in Sec.  11.10(b)(17) to mean: ``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.'' The Completion Date must include 
the day, month, and year. We would 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(b)(1)(viii)(A), if the

[[Page 69620]]

estimate changes; and (3) update the Completion Date information to 
indicate the actual completion date not later than 30 days after the 
clinical trial reaches its completion date, in accordance with proposed 
Sec.  11.64(b)(1)(viii)(B). Finally, we note that, consistent with the 
requirement in section 402(j)(4)(C)(ii) of the PHS Act, 
ClinicalTrials.gov will maintain an archive of all of the updates made 
to the Completion Date data element.
    Enrollment. 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 believe 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 who will be enrolled in the clinical 
trial. We therefore propose in Sec.  11.28(a)(1)(xviii) to require the 
submission of enrollment information at the time of registration, which 
is described 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.''
    We expect that the estimated or target enrollment in a clinical 
trial might change either before or during the clinical trial, e.g., as 
recruitment continues. Consistent with section 402(j)(4)(C) of the PHS 
Act and proposed 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 in the clinical 
trial changes. This update would be in addition to the requirement in 
proposed Sec.  11.64(b) that a responsible party submit the Actual 
Enrollment data element when recruitment for a clinical trial has 
ended, i.e., when the Overall Recruitment Status of the trial is 
changed to ``active, no longer recruiting'' or ``terminated.'' This 
latter requirement is intended to provide users of ClinicalTrials.gov 
with additional information about the total number of participants 
enrolled in the clinical trial, which may differ from the target 
enrollment. (See proposed Sec.  11.64(b) and the discussion below of 
``Overall Recruitment Status'' for a discussion of this requirement.) 
Our proposal for Enrollment is similar to procedures in place for 
ClinicalTrials.gov prior to FDAAA.
    Primary Outcome Measures and 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 upon earlier in this preamble and in proposed subpart A.
    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. We 
therefore have attempted to develop requirements that are consistent 
with what we believe to be the intent of section 402(j) of the PHS Act, 
with data submission standards for ClinicalTrials.gov prior to passage 
in 2007 of section 402(j) of the PHS Act, and with our understanding of 
common practice in the clinical trials community.
    Under proposed Sec. Sec.  11.28(a)(1)(xix) and (xx), responsible 
parties would be required to submit the information specified in 
Sec. Sec.  11.10(b)(19) and (20) for each primary or secondary outcome 
measure in their clinical trials, namely: (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). These requirements are 
consistent with the WHO Data Elements 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 believe these three elements are key attributes of an outcome 
measure. Not only might certain outcome measures can be assessed in 
different ways (e.g., systolic blood pressure can be measured as a mean 
value 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. 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. It also ensures 
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. Defining Primary Outcome Measure 
Information and Secondary Outcome Measure Information to include these 
three pieces of information also retains consistency with data 
submission prior to FDAAA, when those submitting information to 
ClinicalTrials.gov were requested to provide ``the specific measure 
that will be used to determine the effect of the intervention(s), along 
with the timeframe for taking measurements'' [Ref. 2].
(2) Recruitment Information
    Eligibility criteria. Section 402(j)(2)(A)(ii)(II)(aa) of the PHS 
Act expressly requires ``eligibility criteria'' to be submitted for 
registration in ClinicalTrials.gov, but it does not define the term. We 
believe 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 to 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 interpret 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 a clinical trial and who might be 
interested in seeking additional information about a clinical trial.
    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 the submission of 
all eligibility criteria would be burdensome for responsible parties 
and, instead of helping prospective participants, would instead prove 
confusing or overwhelming. We believe that prospective participants 
would be better served by including a more limited list of inclusion 
and exclusion criteria in the data bank, in order to assist prospective 
participants in identifying clinical trials of possible interest. 
Prospective participants who believe they meet the criteria listed in 
the data

[[Page 69621]]

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. While there may be other users of the data 
bank who wish to have more detailed information about eligibility 
criteria for purposes of interpreting clinical trial results 
information and better understanding the population of human subjects 
studied, they could request such information from the Results Point of 
Contact, whose information would be submitted under proposed Sec.  
11.48(a)(5), and/or request a copy of the protocol.
    Therefore, in proposed Sec.  11.10(b)(21), Eligibility Criteria is 
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.'' For entry 
of eligibility criteria information, we would prefer that responsible 
parties list inclusion and exclusion criteria (e.g., inclusion 
criteria: Clinical diagnosis of Alzheimer's Disease, and must be able 
to swallow tablets; exclusion criteria: Insulin dependent diabetes and 
thyroid disease).
    Our proposed definition of ``eligibility criteria'' is consistent 
with ``key inclusion and exclusion criteria'' (data item #14) of the 
WHO Trial Registration standard (version 1.0) and ICMJE registration 
policies [Ref. 13, 10]. This proposed interpretation is also consistent 
with longstanding practice in ClinicalTrials.gov and the international 
clinical trial community. Prior to FDAAA, those submitting information 
to the ClinicalTrials.gov registry pursuant to FDAMA were requested to 
include ``key eligibility criteria'' for the trial [Ref. 4]. This term 
was defined to mean ``summary criteria for participant selection'' 
including inclusion and exclusion criteria [Ref. 2].
    Gender. 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. In proposed 
Sec.  11.10(b)(22) we define the term to mean, ``the biological sex of 
the human subjects who may participate in the clinical trial.'' This is 
consistent with practice prior to FDAAA, when those submitting 
information to the ClinicalTrials.gov registry were requested to 
include the gender of participants of the trial [Ref. 4], which was 
defined to mean, ``physical gender of individuals who may participate 
in the protocol'' [Ref. 2]. Responsible parties would select from the 
following limited set of choices: ``male,'' ``female,'' or ``both.'' No 
``other'' option is proposed, but responsible parties would be able to 
provide voluntarily additional, free-text information about the gender 
of participants who may participate in the clinical trial.
    Age limits. Section 402(j)(2)(A)(ii)(II)(cc) of the PHS Act 
expressly requires ``age limits'' to be submitted as a clinical trial 
information at the time of registration, but it does not define the 
term. In proposed Sec.  11.10(b)(23) we define the term to mean, ``the 
minimum and maximum age of human subjects who may participate in the 
clinical trial, provided in relevant units of time.'' Examples of 
``relevant units of time'' include but are not limited to years, 
months, or weeks. This description of age limits is consistent with 
that used prior to FDAAA, when those submitting information to the 
ClinicalTrials.gov registry were requested to include the age limits 
for participants in the trial [Ref. 4]. At that time, the term was 
defined to mean a ``minimum age'' and ``maximum age of participants'' 
using ``a number and a unit of time (years, months, weeks, days, hours 
or minutes)'' [Ref. 2].
    Accepts Healthy Volunteers? Section 402(j)(2)(A)(ii)(II)(dd) of the 
PHS Act requires the submission of information about ``whether the 
trial accepts healthy volunteers.'' In proposed Sec.  11.10(b)(24), we 
define a data element called Accepts Healthy Volunteers 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.'' This definition is 
consistent with practice prior to FDAAA, when those submitting 
information to the ClinicalTrials.gov registry were required to 
indicate ``if persons who have not had the condition(s) being studied 
or otherwise related conditions or symptoms, as specified in the 
eligibility requirements, may participate in the study'' [Ref. 4]. 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.
    Overall Recruitment Status. 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 this term. Prior to FDAAA, those submitting registration 
information to ClinicalTrials.gov were requested to indicate the 
overall recruitment status of the trial [Ref. 4]. This term was defined 
to mean ``overall accrual activity for the protocol'' [Ref. 2]. This 
definition of overall recruitment status is consistent with 
``recruitment status'' (data item #18) of the WHO Trial Registration 
standard (version 1.0) and ICMJE registration policies [Ref. 13, 10]. 
Therefore, under proposed Sec.  11.10(b)(25) we define 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.'
    To facilitate user searching by recruitment status and allow 
information to be compared across clinical trials, 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); 
``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 is proposed. We believe this list 
includes all relevant choices for Overall Recruitment Status, but we 
invite public comment on whether the proposed options are sufficient to 
accurately describe the Overall Recruitment Status of applicable 
clinical trials and other voluntarily registered clinical trials that 
would be subject to this proposed rule.
    If a clinical trial is registered before it is open to enrollment, 
we would expect the Overall Recruitment Status to be listed as ``Not 
yet recruiting.'' When the clinical trial opens for enrollment, we 
would expect the Overall Recruitment Status to be listed as ``Enrolling 
by invitation'' if human subjects are selected from a predetermined 
population, or as ``Recruiting'' if the study is open to volunteers who 
meet the study's eligibility criteria. As

[[Page 69622]]

indicated in the discussion of the Study Start Date data element, in 
the context of this rulemaking, 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.''
    When indicating that recruitment to a clinical trial has stopped, 
we believe it is important to distinguish between several different 
situations: (1) ``Active, not recruiting,'' in which enrollment has 
closed, but enrolled human subjects are continuing to be examined or 
treated according to the study protocol; (2) ``Completed,'' in which 
the clinical trial has concluded according to its protocol and human 
subjects are no longer being enrolled, treated, or examined; (3) 
``Suspended,' in which the clinical trial is temporarily halted after 
one or more human subjects is enrolled but may potentially resume 
enrollment and in which enrolled human subjects may continue to be 
treated or examined; and (4) ``Terminated,'' in which the study is 
permanently halted after one or more subjects is enrolled in the 
clinical trial but before the trial is completed as anticipated in the 
protocol. We would therefore require responsible parties to provide 
such information. We believe that updating the Overall Recruitment 
Status data element would provide users of ClinicalTrials.gov with an 
effective means of tracking the progress of clinical trials, as the 
data bank is intended to do (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., withdrawn), this information would explain why no 
results information is to be expected or is required to be submitted. 
In the case of a clinical trial for which recruitment is prematurely 
halted (i.e., suspended or terminated), this information would allow 
potential human subjects to determine whether enrollment is likely to 
resume. Such information would 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.
    Why Study Stopped? In situations in which a clinical trial is 
suspended, terminated, or withdrawn prior to its completion as 
anticipated by the protocol, we propose to require that responsible 
parties not only submit or update the Overall Recruitment Status data 
element but also provide a brief explanation for why the clinical trial 
was stopped. While this information is not required for submission by 
section 402(j) of the PHS Act, we believe it is important to 
communicate to users of the data bank why a clinical trial was 
suspended, terminated, or withdrawn, e.g., because of safety concerns, 
difficulties in recruitment, or for 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.'' For these reasons, requiring this information 
improves and does not reduce the clinical trial information available 
in the data bank, consistent with section 402(j)(2)(A)(iii) of the PHS 
Act.
    In our experience operating ClinicalTrials.gov, we have found that 
users often wish to have information describing why a clinical trial 
stopped prematurely and that clinical trial sponsors often wish to 
submit such information voluntarily so they may explain why a clinical 
trial was prematurely stopped. We are concerned that if submission of 
this information is not required then some responsible parties might 
submit it selectively, resulting in users having information about why 
clinical trials are stopped for only some registered clinical trials. 
In order to reduce confusion and inconsistencies in the information 
available for registered clinical trials, we believe that submission of 
such information should be required in each instance in which a 
clinical trial is stopped prematurely (i.e., not according to the 
protocol). Accordingly, proposed Sec. Sec.  11. 28(a)(2)(vi) and 
11.64(b) specify that a brief explanation for why the clinical trial 
was stopped must be submitted if the overall recruitment status is 
``suspended'' or ``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., ``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 overall 
recruitment status to ``suspended,'' ``terminated,'' or ``withdrawn.'' 
(The Why Study Stopped data element would be presented neither 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, we note that 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 proposed Sec.  11.64(b), 
submit the Why Study Stopped data element not later than 30 calendar 
days after the date of such suspension, termination, or withdrawal, to 
explain why the study stopped. We propose to allow responsible parties 
to enter this information as free-text, to provide them with the 
flexibility to explain the reason(s) why a clinical trial stopped 
prematurely. We define the data to be submitted in proposed Sec.  
11.1(b)(26) as ``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.''
    Actual Enrollment. When enrollment of human subjects to a clinical 
trial ends because recruitment was completed in accordance with the 
protocol or because the clinical trial was terminated prior to its 
completion as anticipated by the protocol, we propose to require 
responsible parties to submit the actual number of human subjects 
enrolled in the clinical trial by completing the Actual Enrollment data 
element. The actual enrollment data element does not need to be 
completed until such time as the overall recruitment status data 
element is updated to ``active, not recruiting'' or ``terminated.'' See 
proposed Sec.  11.64(b). (The Actual Enrollment data element would be 
presented neither 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 ``active, not recruiting'' or ``terminated.'') We believe 
submission of actual enrollment information is consistent with the 
objective of the expanded registry data bank to ``provide a mechanism 
to track subsequent progress of clinical trials'' (section 
402(j)(2)(A)(i) of the PHS Act). It would offer a means of measuring 
how actual enrollment compares with the target or estimated enrollment 
in the clinical trial (collected under proposed Sec.  
11.28(a)(1)(xviii)).
    Our proposal would require a responsible party to submit the actual 
enrollment figure only after enrollment is closed. Although requiring 
more frequent updates while recruitment is ongoing would allow tracking 
of enrollment progress, we believe it would be burdensome for 
responsible parties, especially for clinical trials with multiple 
sites, and provide limited value to users. The data could become 
quickly outdated as enrollment for the clinical trial continues, 
potentially

[[Page 69623]]

leading users to believe that enrollment is lower than is the case. We 
believe that providing the actual enrollment figure once, at the time 
recruitment ends, would provide an effective means for tracking the 
progress of clinical trials registered in ClinicalTrials.gov. When 
combined with information about target enrollment, the actual 
enrollment data would indicate the degree to which the clinical trial 
met its enrollment target. By requiring the submission of actual 
enrollment data when enrollment closes, rather than when results 
information is submitted (which could be several years after enrollment 
closed), users would be able to gauge in advance their level of 
interest in the results of the clinical trial: The results of a 
clinical trial for which actual enrollment is substantially below the 
target enrollment might be of less interest than one in which 
recruitment targets were met. In proposed Sec.  11.10(b)(27) we define 
Actual Enrollment 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.''
    Individual Site Status. 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 this term. Prior to FDAAA, those submitting information to the 
ClinicalTrials.gov registry were requested to include a recruitment 
status for each site of the trial [Ref. 4]. This term was defined to 
mean ``protocol accrual activity at a facility'' [Ref. 2]. In proposed 
Sec.  11.28(a)(2)(viii), we would require the submission of Individual 
Site Status, which is defined in Sec.  11.10(b)(28) as ``the 
recruitment status of each participating facility in a clinical 
trial.'' Consistent with the proposed Overall Recruitment Status data 
element, responsible parties would be required to indicate 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 is proposed, but 
we invite public comment on whether the proposed options are sufficient 
to accurately describe the Individual Site Status of applicable 
clinical trials and other voluntarily registered clinical trials that 
would be subject to this proposed rule. (See the discussion of Overall 
Recruitment Status for a description of these categories.)
    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 investigated 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 
Federal Food, Drug, and Cosmetic Act for those who do not qualify for 
enrollment in the clinical trial''; and, if so, (2) ``how to obtain 
information about such access.'' 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 an expanded access program under section 561 of the FD&C Act 
and to be directed to additional information about the expanded access 
program. Therefore, we propose that responsible parties meet the 
requirements of section 402(j)(2)(A)(ii)(II)(gg) by indicating in the 
clinical trial record whether expanded access is available for the drug 
under study (i.e., ``yes'' or ``no'') and, if so, 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.
    We propose 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 is 
a data element that a responsible party is required to submit under 
section 402(j)(2)(A)(ii)(II) and thus meets the definition of 
``clinical trial information'' in section 402(j)(1)(A)(iv). We believe 
the additional data elements describing expanded access 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 conclude that we have 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 will ensure that the public may more easily use the data bank to 
determine whether there is expanded access to a drug and to compare 
different expanded access programs.
    Prior to FDAAA, those submitting information to the 
ClinicalTrials.gov registry were requested 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 [Ref. 3]. The data bank 
also permitted submission of information about expanded access to 
devices. At that time, the data bank included a ``Has Expanded 
Access?'' data field, which asked data submitters to ``indicate whether 
any non-protocol access is to be provided for the investigational drug 
or device.'' If expanded access were available, data submitters were 
requested to create an expanded access record via ClinicalTrials.gov. 
These expanded access records provided information to users of 
ClinicalTrials.gov about treatment access to investigational drugs or 
devices for patients for whom there was no satisfactory therapy 
available for their condition or who were unable to participate in 
ongoing clinical trials. Expanded access records were used to register 
all types of non-protocol access to investigational treatments [Ref. 
2].
    We propose a similar approach in this rule. 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 is 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 Federal Food, Drug, and Cosmetic 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 via a yes/no designation in ClinicalTrials.gov. If 
the NCT number is not available, because an expanded access record has 
not yet been created, the responsible party would enter ``pending'' for 
the NCT number.
    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, the

[[Page 69624]]

responsible party would be required to create an expanded access 
record, consisting of the information specified in proposed Sec.  
11.28(c). As was the case prior to FDAAA, the manner in which the 
responsible party would submit the data elements describing the 
expanded access program would be to create an expanded access record in 
ClinicalTrials.gov. Upon completion of the quality control process for 
the expanded access record, the 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. We would expect the sponsor of the expanded access program 
to be responsible for informing the responsible party(ies) of any 
applicable clinical trial that studies the drug available under 
expanded access that an expanded access record has been created and 
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 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. If an expanded access 
program is in place but an expanded access record has not been created 
at the time an applicable clinical trial of a drug is registered, the 
responsible party would not be required to submit the expanded access 
data elements under proposed Sec.  11.28(c) prior to the date on which 
clinical trial registration information under proposed Sec.  11.28(a) 
is due (i.e., in order to have the expanded access program NCT number 
available at the time of registration of the applicable clinical 
trial). Rather, the responsible party would be required at the time of 
registration to indicate that expanded access is available, to submit 
the data elements required by Sec.  11.28(c), and to indicate that the 
NCT number for the expanded access record is ``pending.'' As described 
previously, within 30 days of receipt of the NCT number for the 
expanded access record, the responsible party would be required to 
update the applicable clinical trial record with the NCT number 
assigned to the Expanded Access record.
    We note 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. 
Because requests for individual patient access generally are 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. In cases where 
expanded access is only available for individual patients on a case-by-
case basis, we would not require the responsible party to submit the 
expanded access record, as described below, and we expect that users of 
ClinicalTrials.gov may direct inquiries regarding individual patient 
access to the facility contact.
    Finally, we note both that expanded access to a drug 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 completion date of an applicable clinical trial. We believe 
that information about changes in the availability of expanded access 
should be conveyed to users of ClinicalTrials.gov in a timely manner 
and thus that the availability of expanded access is a data element 
that should be updated more frequently than once every 12 months. 
Accordingly, as explained in further detail in section IV.D.3 of this 
preamble, we propose that the availability of expanded access data 
element be updated within 30 calendar days of either the initiation or 
termination of an expanded access program, consistent with proposed 
Sec.  11.64(b).
(3) Location and Contact Information
    Name of the Sponsor. 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. Proposed Sec.  11.28(a)(3)(i) implements this provision. 
In this part, 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.'' 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. Hence, 
in proposed Sec.  11.10(b)(30), 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).''
    Responsible Party, by Official Title. 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. We recognize that the 
responsible party for an applicable clinical trial may be the sponsor 
of the clinical trial (a term defined by this regulation to include the 
sponsor or the sponsor-investigator, as each is defined in 21 CFR 50.3) 
or a designated principal investigator. A responsible party that is the 
sponsor will typically be an organizational entity (e.g., a drug or 
device manufacturer that is the sponsor of an applicable clinical 
trial). A responsible party that is a sponsor-investigator will be an 
individual. A responsible party that is a designated principal 
investigator will be an individual. When an organizational entity is 
the responsible party, we believe that the official name of the entity 
(e.g., company name, university name, name of government agency) should 
be included to satisfy the requirement for the Responsible Party, by 
Official Title. When the responsible party is an individual, we believe 
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 believe it is important 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. In light of these considerations, 
proposed Sec.  11.10(b)(31) defines Responsible Party, by Official 
Title to mean an ``[i]ndication 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'' (this 
indication would be provided by selecting among these three options) 
and either ``the official name of the entity'' if the responsible party 
is an organizational entity, or ``the official title and primary 
organizational affiliation of the individual'' if the responsible party 
is an individual. An

[[Page 69625]]

individual who serves as a responsible party and has multiple 
affiliations (e.g., a research university and a teaching hospital, or a 
research institution and a private company), would be required to 
submit only one such affiliation; namely, the affiliation they consider 
their primary affiliation. We note that proposed Sec.  11.10(b)(38) 
defines a related data element, Responsible Party Contact Information.
    Facility Information. 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.'' In considering how to implement this provision, we 
took into consideration section 402(j)(2)(B)(i) of the PHS Act, which 
requires the Director to ensure that the public may search the entries 
in ClinicalTrials.gov by one or more of several enumerated criterion, 
one of which is ``location of the clinical trial.'' 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.'' In order for users of ClinicalTrials.gov to be able to 
search the data bank by each location of the clinical trial, the 
responsible party must submit to the data bank the location of each 
facility at which the applicable clinical trial is conducted. 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.
    For these reasons, we believe including this information 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 
propose in Sec.  11.28(a)(3)(iii) to modify 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, which we define in 
proposed Sec.  11.10(b)(32) 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) either 
``[for each facility location submitted], 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.''
    As noted above, the Agency intends to exercise its authority under 
section 402(j)(2)(B)(i) to enable the public to search the data bank by 
the location of the clinical trial and, 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, our proposal to allow (but 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, would help prospective 
human subjects obtain additional, specific information about a clinical 
trial at a particular location. Our proposal to permit responsible 
parties to submit a Central Contact in lieu of Facility Contact is 
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. This 
approach is similar to the one used prior to FDAAA, when those 
submitting information to the ClinicalTrials.gov registry were 
requested to include each facility name and facility contact 
information for the registered clinical trial and were permitted to 
include a ``central contact'' rather than contact information for each 
facility of the trial [Ref. 4]. At the time, the term ``facility name'' 
was defined to include the ``full name of the organization where the 
protocol is being conducted'' and central contact was defined as a 
``person providing centralized, coordinated recruitment information for 
the entire study'' [Ref. 2].
(4) 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 descriptions below of 
each administrative data element, the Agency indicates whether it 
proposes to make the information publicly available through 
ClinicalTrials.gov.
    Unique Protocol Identification Number. 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. We propose in Sec.  11.10(b)(33) to define ``unique 
protocol identification number'' as ``any unique identification number 
assigned to the protocol by the sponsor.'' Once entered into 
ClinicalTrials.gov, that unique protocol identification number cannot 
be assigned to another protocol for another clinical trial in the 
sponsor's ClinicalTrials.gov account. In cases in which multiple 
identification numbers 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), we believe that 
interpreting this term as a number ``assigned by the sponsor'' will 
remove any ambiguity for responsible parties about which number to 
submit as the unique protocol identification number for purposes of 
registration on ClinicalTrials.gov. We also expect that the unique 
protocol identification number would be readily available to the 
responsible party, whether the sponsor or a designated PI, who would 
have access to the protocol itself and/or be able to obtain the unique 
protocol number from the sponsor. Further, these numbers often are used 
in other clinical trial documentation, which will enable cross-
referencing of information submitted to different data systems. To 
enable such cross-referencing, we plan to make this data element 
publicly available in ClinicalTrials.gov.
    This approach is consistent with that used in ClinicalTrials.gov 
prior to FDAAA, when those submitting information to the registry were 
requested to include the unique protocol ID of the trial [Ref. 4]. This 
term was defined to mean any ``unique identification assigned to the 
protocol by the sponsoring organization, usually an accession number or 
a variation of a grant number. Multiple studies conducted under the 
same grant must each have a unique number'' [Ref. 2]. The wording of 
our proposed description modifies the previous one by, among other 
things, removing the

[[Page 69626]]

reference to ``a variation of a grant number'' because all grant-
related information is proposed to be collected under the Secondary IDs 
data element.
    Secondary IDs. 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 does not define 
this term. Prior to FDAAA, those submitting information to 
ClinicalTrials.gov were requested to include secondary IDs of the 
clinical trial. This term was defined as ``other identification numbers 
assigned to the protocol, including ISRCTN . . . and NIH grant numbers, 
if applicable'' [Ref. 2]. This definition is consistent with 
``secondary identification number(s)'' (data item #3) of the WHO Trial 
Registration standard (version 1.0) and ICMJE registration policies 
[Ref. 13, 10]. To maintain consistency with these widely used terms and 
definitions, we propose in proposed Sec.  11.10(b)(34) to define 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 . . .'' We also propose that the 
Secondary IDs include ``any unique clinical trial identification 
numbers assigned by other publicly available clinical trial 
registries,'' such as EudraCT in the European Union. We intend to post 
publicly the Secondary IDs, as such information will enable users to 
locate additional information about the clinical trial that may be 
included in other registries; it also will enable users to determine if 
registration information listed in another registry refers to the same 
trial that is registered in ClinicalTrials.gov, thereby avoiding 
potential confusion.
    In addition, we propose that Secondary IDs 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. 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, CDC, 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 proposed Part before they release any remaining funding for a 
grant or provide funding for a future grant to such grantee. Such 
verification procedures are 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, although the requirement of section 
402(j)(5)(A)(ii) of the PHS Act applies only to the agencies of the 
Department, 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 to develop comparable procedures for 
verification of compliance with the requirements of sections 402(j)(2) 
and (3) of the PHS Act.
    Finally, in order that users can interpret the various Secondary 
IDs that might be provided in response to this requirement, we propose 
to require responsible parties to submit ``[a] description of the type 
of Secondary ID'' for each Secondary ID submitted. 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 will include a list of several common 
identifier types in ClinicalTrials.gov, while permitting free-text 
entries, as well. 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 granting organization or a brief description of the identifier.
    Food and Drug Administration IND or IDE number. 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 
propose to use the term ``Food and Drug Administration IND or IDE 
number'' to identify this data element in ClinicalTrials.gov. We also 
recognize that not all applicable clinical trials will be conducted 
under an IND or IDE (e.g., because they are exempt).
    Because CDER, CBER, and CDRH each issues IND or IDE numbers using a 
similar format, we believe 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, for example, 
each such clinical trial may have a different serial number assigned to 
it. We believe that any such serial number must also be specified to 
avoid confusion. Moreover, 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.
    Taking the foregoing into consideration, we propose in Sec.  
11.10(b)(35) to define 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) ``Name 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(e), or any successor regulation), if any, 
assigned to the clinical trial.'' In specifying the FDA center with 
which the IND or IDE is filed, responsible parties would select from 
the following limited set of options: CDER, CBER, or CDRH. These 
abbreviations correspond to the FDA Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, and Center for 
Devices and Radiological Health, respectively, which are the three FDA 
centers with which INDs and IDEs are filed.
    Our proposed approach for IND or IDE numbers is consistent with 
that used prior to FDAAA, when those submitting information to the 
ClinicalTrials.gov registry were requested to include ``the IND number 
and serial number and designate whether the IND is located in the 
Center for Drug Evaluation and Research (CDER) or the Center for 
Biologics Evaluation and Research (CBER)'' [Ref. 4]. Also consistent 
with previous ClinicalTrials.gov practice, we do not intend to make the 
Food and Drug Administration IND or IDE number available to the public. 
Section 402(j)(2)(A)(ii)(IV) of the PHS Act indicates that 
administrative data submitted as part of clinical trial information may 
be made publicly available ``as necessary.'' We do not consider public 
posting of information in this field to be necessary for the effective 
use of ClinicalTrials.gov or for

[[Page 69627]]

understanding of the information submitted.
    Human Subjects Protection Review Board Status. We propose to 
require the submission of information about human subjects protection 
review board status as part of clinical trial information. Submission 
of this information is not required by section 402(j) of the PHS Act, 
but we propose 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 
believe that submission of the Human Subjects Protection Review Board 
Status, as specified below, to ClinicalTrials.gov would improve and not 
reduce clinical trial information by indicating to users of the data 
bank whether a clinical trial registered in ClinicalTrials.gov is 
undergoing or has undergone human subjects protection review board 
review.
    We believe that the submission of Human Subjects Protection Review 
Board Status is consistent with the purpose of the data bank ``to 
enhance patient enrollment,'' as described in section 402(j)(2)(A)(i) 
of the PHS Act. While review and approval by a human subjects 
protection review board, such as an IRB, cannot guarantee the 
scientific merit of a clinical trial or the safety of human subjects 
enrolled in it, it may provide some assurance that such factors are 
considered by a group of individuals who are not directly involved in 
the conduct of the clinical trial and who are charged to consider the 
safety of human subjects. Inclusion of such information in 
ClinicalTrials.gov would demonstrate to potential human subjects 
whether the clinical trials they find in ClinicalTrials.gov have 
undergone at least one human subjects protection review board review, 
have received necessary approvals for human subjects research from at 
least one human subjects protection review board, or were exempt from 
such review. For clinical trials conducted in the United States or 
under an IND or IDE, human subjects review would be conducted by an IRB 
as described in 45 CFR 46 and 21 CFR 50 and 56, as applicable, or any 
successor regulations. For clinical trials conducted outside the United 
States, we would expect the review to be conducted by a human subjects 
protection review board that is charged with providing independent 
ethics review that is aimed at ensuring the protection of the rights, 
safety, and well-being of human subjects involved in a clinical 
investigation by a group that is adequately constituted to provide 
assurance of that protection.
    Inclusion of this data element is consistent with longstanding 
Agency practice. Prior to FDAAA, those submitting information to 
ClinicalTrials.gov were requested to include information regarding 
human subjects review [Ref. 4]. Human subjects protection review board 
approval information was not required to be submitted if the data 
submitter indicated that the trial was conducted under an IND or IDE 
because IRB approval is a requirement for conducting a clinical trial 
under an IND or IDE. We therefore interpreted the presence of an IND or 
IDE number as an acceptable indication that the trial had received 
necessary human subjects protection review board review. For trials not 
conducted under an IND or IDE, data providers were requested to submit 
information for only one human subjects protection review board even if 
multiple boards had reviewed the trial. Although it did not provide 
information on the status of review by every human subjects protection 
review board with authority over a trial, we viewed submission of 
information about one human subjects protection review board as 
establishing a minimum floor for studies listed in ClinicalTrials.gov 
by indicating whether they had been approved by at least one human 
subjects protection review board, or were seeking approval from such a 
board, or were exempt from such review.
    Our current proposal requires submission of Human Subjects 
Protection Review Board Status for all applicable clinical trials and 
other clinical trials registered with ClinicalTrials.gov, but it does 
not require information about the specific review board. Under proposed 
Sec.  11.28(a)(4)(v), responsible parties would be required to submit 
Human Subjects Protection Review Board Status as part of clinical trial 
information at the time of registration. We define Human Subjects 
Protection Review Board Status in Sec.  11.10(b)(36) 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 would be provided by the Responsible Party 
selecting from a limited set of options described in ClinicalTrials.gov 
that are intended to cover all of the possible types of status: 
``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 is proposed. We request comment 
on whether the above menu of options adequately captures all possible 
types of review status for applicable clinical trials and voluntarily 
registered trials that would be subject to this regulation. The status 
must be listed as ``approved'' if at least one human subjects 
protection review board has approved the clinical trial. An applicable 
clinical trial could be registered prior to human subjects protection 
review board approval by indicating that the status is, for example, 
pending, not yet submitted, or exempt. If the status subsequently 
changes, the responsible party would be required, consistent with 
proposed Sec.  11.64(b), to update the Human Subjects Protection Review 
Board Status not later than 30 calendar days after the change.
    Consistent with longstanding practice, responsible parties would be 
required to indicate that the clinical trial is approved when at least 
one human subjects protection review board has granted approval. 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 in 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 that is submitted as part of clinical trial 
information under proposed Sec.  11.28(a)(3)(iii)) in order to 
determine the status of human subjects protection review board review 
at other sites of interest. We believe this approach will provide users 
with important information about human subjects review without 
burdening responsible parties with updating information on multiple 
sites.
    Our proposal deviates from current practice with regard to the 
information that would be necessary for clinical trials conducted under 
an IND or IDE. We considered maintaining the current requirement that 
human subjects protection review board information (which is currently 
more extensive than

[[Page 69628]]

the single status element) be submitted only for clinical trials that 
are not conducted under an IND or IDE. We believe, however, that there 
would be an advantage in applying a consistent requirement across all 
registered clinical trials. Doing so would reduce confusion among 
responsible parties who might otherwise face different information 
submission requirements for different clinical trials and among users 
who might not be sure why certain clinical trials contain human 
subjects review information but others do not (as indicated above, we 
do not propose to make information about IND or IDE numbers publicly 
available in the data bank). We do not expect the burden of providing 
the human subjects protection review board status for a particular 
clinical trial to be significant, especially as it would be limited to 
a single data element about one human subjects protection review board.
    Record Verification Date is a data element 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 the statute 
does not define this term. The statutory provision calls for the 
submission of ``the Food and Drug Administration IND/IDE protocol 
number and the record verification date.'' We believe 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 or not it may be out of date. We therefore intend to collect 
and post publicly the Record Verification Date data element in 
ClinicalTrials.gov. Our interpretation of this term is consistent with 
that used prior to FDAAA when those submitting information to the 
registry were requested to list the ``record verification date'' of the 
trial, meaning the ``date the protocol information was last verified'' 
[Ref. 4].
    We propose to require responsible parties to include the Record 
Verification Date data element as part of an 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. For example, if a responsible party 
examines the entire record as part of a monthly or annual review and 
determines that no additional or updated information needs to be 
submitted, the responsible party would be required to update the Record 
Verification Date data element to indicate the date on which the review 
occurred. Or, if a responsible party updates a data element and also 
reviews the rest of the record for accuracy, the responsible party 
would also be required to update the Record Verification Date data 
element. 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 would not be updated. This 
proposal 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 proposed 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 were reviewed for accuracy 
during such an update. This proposal is consistent with current 
practice. Starting prior to FDAAA, those submitting data to 
ClinicalTrials.gov were requested to update the verification date when 
reviewing the record for accuracy and completeness, even if no other 
changes were made'' [Ref. 2]. At the time, we also suggested that 
records be reviewed at least every six months to help ensure that 
information available to the public in the data bank was up-to-date. 
Under proposed Sec.  11.10(b)(37), we define 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.''
    Responsible Party Contact Information. 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 . . 
.'' We propose that the mechanism whereby the responsible party 
communicates the identity and contact information to the Secretary 
shall be via submission of such information at the time clinical trial 
information is first submitted to ClinicalTrials.gov. Using the 
authority in section 402(j)(2)(A)(iii) of the PHS Act, we propose to 
modify the requirements for clinical trial information submitted at the 
time of registration to require responsible parties to submit 
Responsible Party Contact Information. In proposed Sec.  11.10(b)(38), 
we describe 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.'' 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 do not intend to post the 
physical address, mailing address, phone number or email address of the 
responsible party. The system will contain other information, such as 
central or site-specific contact information that interested parties 
can use to request additional information about a clinical trial or 
inquire about participation. In general, we do 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, which section 402(j)(2)(A)(ii)(III)(bb) of the PHS Act requires 
to be made publicly available. We believe that posting of the 
individual's name is necessary to avoid ambiguity, e.g., if the 
responsible party is a university professor, there might be numerous 
individuals with the same title and affiliation (professor of medicine 
at ABC University). Posting the name of the individual when the 
individual is the responsible party would also be consistent with 
posting of the name of an entity when an entity is the responsible 
party of an applicable clinical trial. Responsible Party Contact 
Information would be required to be updated as specified in proposed 
Sec.  11.64.
    (b) Data elements required to register a pediatric postmarket 
surveillance of a device that is not a clinical trial. Proposed Sec.  
11.28(b) specifies 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

[[Page 69629]]

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 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. The Agency intends this and the other discussions in 
this preamble related to pediatric postmarket surveillances of a device 
to serve as draft guidance that will be finalized when the final rule 
is issued.
    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 interprets 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)(E)). 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) 
might not apply to them. Therefore, proposed Sec.  11.28(b) specifies 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 modifies the definitions of certain of the data 
elements that are defined in Sec.  11.10(b).
    As set forth in proposed Sec.  11.28(b), to register a pediatric 
postmarket surveillance of a device 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) 
Whether the Study is a Pediatric Postmarket Surveillance of a Device; 
(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) 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 IDs; (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 this preamble, 
for a pediatric postmarket surveillance of a device that is not a 
clinical trial the Study Type must be designated as ``observational'' 
and Whether the Study is a Pediatric Postmarket Surveillance of a 
Device must indicate ``yes.''
    In general, the definitions of these data elements are consistent 
with the definitions of the named data elements in proposed Sec.  
11.10(b); however, we have 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 is 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, is 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; hence, in proposed Sec.  11.28(b)(1)(xii), we 
propose to require submission of the Completion Date data element, 
which is 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 considers 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 a pediatric postmarket surveillance of a device that 
is not a clinical trial by searching using a number of relevant 
criteria, retrieve basic descriptive information about the 
surveillance, and find a point-of-contact for additional surveillance 
information.
    We do 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 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 might 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 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.
    In addition, for pediatric postmarket surveillances of a device 
that are not clinical trials, we would 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 that takes the form of a prospective 
observational study, information such as the location(s) of the 
surveillance, its eligibility criteria, recruitment status, and 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 devices were included in 
the data bank, but, given the lack of experience to date, we cannot at 
this time specify which additional information would be relevant to a 
particular type of pediatric postmarket surveillance of a device that 
is not a clinical trial. We invite public comments on alternative 
approaches to specifying the registration requirements for a pediatric 
postmarket surveillances of a device that is not a clinical trial, 
including specific information that should be required to be submitted 
for such a surveillance and approaches to help ensure that important 
information is not missing from the record when such information might 
not be relevant to all pediatric postmarket surveillances of a device 
that are not clinical trials.
    (c) Data elements required to create expanded access records. 
Proposed Sec.  11.28(c) describes the clinical trial information that 
must be submitted to ClinicalTrials.gov to register an

[[Page 69630]]

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 a clinical trial. Under our proposal in Sec.  
11.28(c), the following set of data elements would be required to be 
submitted to ClinicalTrials.gov at the time of registration of such 
clinical trials: (1) Brief Title; (2) Official Title; (3) Brief 
Summary; (4) Study Type (which would be ``expanded access program'' 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 would be a drug, including 
biological products, for applicable clinical trials that are required 
to submit such information under the proposed part, but could be a 
device if clinical trial information is submitted voluntarily for an 
expanded access program for a device); (10) Eligibility Criteria, (11) 
Gender, (12) Age Limits, (13) Expanded Access Status; (14) Name of the 
Sponsor; (15) Responsible Party, by Official Title; (16) Contact 
Information; (17) Unique Protocol Identification Number; (18) Secondary 
IDs; (19) Food and Drug Administration IND Number; (20) Record 
Verification Date; and (21) Responsible Party Contact Information.
    We consider the proposed set of data elements to be the most 
inclusive set of data elements that would be relevant to all expanded 
access programs (other than individual patient access), regardless of 
design, and would be helpful to users of ClinicalTrials.gov who wish to 
determine whether they might be eligible to receive treatment through 
the expanded access program and obtain additional information about 
such access. The proposed list is, in most part, a subset of the data 
elements that would be required to register an applicable clinical 
trial of a drug. The descriptions of the data elements generally 
parallel 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 have been modified to refer to 
expanded access programs rather than clinical trials and to be limited 
to expanded access programs for drugs and biologics. One data element 
that is not defined in proposed Sec.  11.10(b) and would be required to 
be submitted only for expanded access records is the Expanded Access 
Status data element. It is defined in proposed Sec.  11.28(c)(2)(iv) to 
mean ``[t]he status of availability of the investigational drug through 
the expanded access program.'' When submitting this data element, 
responsible parties would be required to select from the following 
limited set of options for describing the current status of 
availability of the investigational drug 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 the Food and Drug 
Administration). No ``other'' option is proposed. These proposed 
options are consistent with those used in ClinicalTrials.gov prior to 
enactment of FDAAA [Ref. 2] and would provide patients and other users 
of ClinicalTrials.gov with what we believe is more valuable information 
about expanded access status than a simple ``yes'' or ``no'' 
indication. We invite comment on whether this list of options is 
sufficient to describe the status of an expanded access program for 
which information would be submitted to ClinicalTrials.gov under this 
proposed rule.
    We note that, notwithstanding the foregoing, if some form of 
expanded access were offered to a medical device that is studied in an 
applicable clinical trial, such information could be submitted 
voluntarily under section 402(j)(4)(A) of the PHS Act to create an 
expanded access record for the device. Accordingly, even though the 
expanded access data elements are intended for expanded access programs 
for drugs, a responsible party who voluntarily submits information 
about an expanded access program for a device would be able to submit 
the IDE number that CDRH assigns to the expanded access program. We 
would require that a responsible party who voluntarily creates an 
expanded access record for a device expanded access program submit all 
of the data elements that are required for a drug expanded access 
program. In other words, an expanded access record may be created 
voluntarily, but it must be complete. In addition, we would require 
that an expanded access record that is submitted voluntarily must be 
updated following the same requirements that would apply to an expanded 
access record that is required to be submitted under this part. See 
proposed 11.64(b)(1(iv).
    We propose to require 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 believe the 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 conclude 
that we have 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 will 
ensure that the public may 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 is consistent with 
the practice followed prior to enactment of FDAAA when those 
registering trials in compliance with FDAMA submitted expanded access 
information in the form of expanded access records at 
ClinicalTrials.gov. As discussed above in section IV.A.5 of this 
preamble, in the rare instance in which an expanded access program for 
a drug is controlled and meets all of the elements of an applicable 
drug clinical trial, the expanded access program must be registered as 
an applicable drug clinical trial.
    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 believe that such an approach would not ensure 
that complete information is

[[Page 69631]]

available in a consistent form and would not allow users of 
ClinicalTrials.gov to as quickly and easily review eligibility criteria 
and the disease or condition for which expanded access is available. In 
addition, by including such information as part of clinical trial 
registration information, we can better ensure that the information is 
kept up-to-date because it would be subject to the updating 
requirements described in proposed Sec.  11.64. We also believe that 
our proposal could reduce the burden a responsible party faces when 
providing information about expanded access. An 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, 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, and thereafter, any responsible party could link 
the expanded access record to his or her clinical trial record(s) using 
the NCT number assigned to the expanded access record. As explained 
further in section IV.D.3 in this preamble, only that responsible party 
who registered the initial clinical trial that included the expanded 
access record would be responsible for updating the expanded access 
program information in the expanded access record.
    As explained in section IV.B.4, in the discussion of the 
Availability of Expanded Access data element, the expanded access 
record generated in 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 to which expanded access is offered. To establish 
the 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. The expanded access record could be linked in this fashion to 
several applicable clinical trials that study the drug or biological 
product that is available via the expanded access program.
    We seek comment on the proposed approach.
5. By when will NIH post clinical trial information submitted under 
Sec.  11.28?--Sec.  11.35.
    Proposed Sec.  11.35 describes the timelines by which NIH will post 
publicly on ClinicalTrials.gov the clinical trial information that is 
required to be submitted for registration of applicable drug clinical 
trials and applicable device clinical trials, respectively. Proposed 
Sec.  11.35 takes into account the timelines described for posting 
registration information in section 402(j)(2)(D) of the PHS Act.
    The timelines in proposed Sec.  11.35 apply only to clinical trials 
that are required to register with ClinicalTrials.gov under 
402(j)(2)(C) of the PHS Act. If a clinical trial is registered with 
ClinicalTrials.gov and appears to be a voluntary submission according 
to the approach specified in proposed Sec.  11.22(b), we will post the 
registration information as soon as practicable after it has been 
submitted and reviewed as part of our quality review procedures.
    (a) Applicable drug clinical trials. For applicable drug clinical 
trials, section 402(j)(2)(D)(i) of the PHS Act requires NIH to publicly 
post registration information not later than 30 days after it is 
submitted in accordance with section 402(j) of the PHS Act. Proposed 
Sec.  11.35(a) implements this provision, stating that NIH will post 
publicly the registration information ``not later than 30 calendar days 
after the responsible party has submitted such information in 
accordance with Sec.  11.24 of this part.''
    (b) Applicable device clinical trials of devices that previously 
were approved or cleared. For applicable device clinical trials of 
devices that previously were approved or cleared by FDA for any 
indication, section 402(j)(2)(D)(ii)(II) of the PHS Act requires that 
registration information be posted ``not later than 30 days after'' 
results information is required to be posted. The Agency interprets 
section 402(j)(2)(D)(ii)(II) of the PHS Act as providing a deadline by 
which such registration information must be posted. In other words, the 
Agency considers 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.
    The Agency believes that for applicable device clinical trials of 
devices that previously were approved or cleared it is permissible and 
appropriate to post registration information prior to the deadline. 
Posting this information prior to the deadline would be 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. (See 
sections 402(j)(2)(A)(i) and (3)(D)(i) of the PHS Act.) Conversely, 
waiting to post registration information for applicable device clinical 
trials of devices that previously were 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.
    The Agency proposes in Sec.  11.35(b)(1) to post registration 
information for an applicable device clinical trial of a device that 
previously was approved or cleared ``not later than 30 calendar days 
after clinical trial results information is required to be posted in 
accordance with Sec.  11.52 of this part.'' However, in light of the 
objectives of the data bank discussed above we intend, in practice, 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.
    (c) Applicable device clinical trials of devices that have not been 
approved or cleared previously. Section 402(j)(2)(D)(ii)(I) of the PHS 
Act provides that for applicable device clinical trials of devices that 
have not previously been approved or cleared (i.e., unapproved or 
uncleared devices), registration information must be posted publicly 
not earlier than the date of approval or clearance of the device and 
not later than 30 days after such date. Proposed Sec.  11.35(b)(2) 
reflects this statutory provision. In order to help us meet the posting 
deadline and identify the set of applicable device trials for which 
registration information needs to be posted after approval or clearance 
of a device, we have 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 clinical 
trials that study the device that was approved or cleared.
    (d) Exception to posted information. Section 402(j)(2)(A)(ii)(IV) 
of the PHS Act specifies that the Secretary ``may make publicly 
available as necessary'' (emphasis added) administrative data that are 
submitted as part of clinical

[[Page 69632]]

trial registration information. We interpret this provision as 
permitting the Secretary not to post certain administrative data in the 
data bank if the data are not considered necessary for understanding 
the clinical trial or for recruitment. As explained more fully in 
section IV.B.4(a) 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). Note that Responsible Party, by Official Title, which is 
proposed in Sec.  11.28(a)(3)(ii), is not considered an element of 
administrative data and will be publicly posted in the data bank as 
required by section 402(j)(2)(A)(ii)(III)(bb) of the PHS Act.

C. Results Submission--Subpart C

    Proposed subpart C establishes requirements and procedures related 
to the submission of results information. In addressing what 
constitutes results information, proposed subpart C does not specify 
what results information must be collected during an applicable 
clinical trial or other clinical trial, but which elements of the 
collected data must be submitted and in what required format. Proposed 
Subpart C also specifies when NIH will post results information in 
ClinicalTrials.gov. Finally, proposed subpart C specifies the 
procedures that may be used to request a waiver of any applicable 
requirements for results submission.
1. Who must submit results information?--Sec.  11.40
    Proposed Sec.  11.40 requires that the responsible party for an 
applicable clinical trial specified in proposed Sec.  11.42 submit 
results information for that clinical trial. This approach is 
consistent with section 401(j)(3)(E)(i) of the PHS Act.
2. For which applicable clinical trials must results information be 
submitted?--Sec.  11.42
    Proposed Sec.  11.42 identifies the applicable clinical trials for 
which results information must be submitted to ClinicalTrials.gov, 
according to this proposed rule unless the requirement is waived under 
proposed Sec.  11.54. Pursuant to section 402(j)(3)(D)(ii)(I)of the PHS 
Act, we propose 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 for 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. For reasons described in section III.C.5 
of this preamble, we also propose to require 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). This proposal is consistent with the requirement in section 
402(j)(3)(D)(ii)(II) of the PHS Act 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.
    In order to maintain consistency with the registration requirements 
proposed in this rule, the proposed requirements for results submission 
would apply to those applicable clinical trials that are required to be 
registered with ClinicalTrials.gov under the requirements of proposed 
Sec.  11.22 and that meet the criteria under proposed Sec.  11.42, 
unless a waiver were granted in accordance with proposed Sec.  11.54. 
We note as described in section III.D of this preamble, responsible 
parties would not be required to submit results information under this 
proposed subpart if the completion date of the applicable clinical 
trial is prior to the effective date of this rule, except if any of the 
following situations applies: (1) The completion date is prior to the 
effective date of the rule, but results information is neither due 
under proposed Sec.  11.44 nor submitted until on or after the 
effective date of the rule; or (2) the completion date is prior to the 
effective date of the rule, but secondary outcome measures are neither 
due under proposed Sec.  11.44 nor submitted until on or after the 
effective date of the rule.
3. When must results information be submitted for applicable clinical 
trials subject to Sec.  11.42-Sec.  11.44?
    Proposed Sec.  11.44 specifies the deadlines for submitting results 
information for applicable clinical trials. Subsection (a) specifies 
the standard submission deadlines for applicable clinical trials that 
are clinical trials. Subsections (b) and (c) specify procedures for 
delaying the standard submission deadlines when seeking initial 
approval or approval of a new use of a drug or device studied in an 
applicable clinical trial. Subsection (d) describes procedures for 
requesting a good-cause extension of the submission deadline. 
Subsection (e) establishes the timeline for submitting results of a 
pediatric postmarket surveillance of a device that is not a clinical 
trial.
    (a) Standard submission deadlines. Proposed Sec.  11.44(a) 
prescribes the standard deadlines for submitting results information 
for applicable clinical trials that are clinical trials subject to 
proposed Sec.  11.42. This proposed deadline would apply to all 
applicable clinical trials for which the responsible party does not 
submit a certification to delay results submission, as permitted under 
proposed Sec.  11.44(b) or (c), or for which the Director has not 
granted a good-cause extension of the results submission deadline 
pursuant to proposed Sec.  11.44(e).
    (1) In general. Proposed Sec.  11.44(a)(1) specifies that, in 
general, the deadline for submitting results information for applicable 
clinical trial would be 1 year after the completion date of the 
clinical trial. 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. Under proposed Sec.  11.64(b)(1), however, we 
would require responsible parties to update the completion date not 
later than 30 calendar days after a change has occurred or after the 
clinical trial has reached its completion date. Therefore, the 
estimated completion date would be updated to reflect the actual 
completion date not later than 30 calendar days after the applicable 
clinical trial has reached its completion date and results would be due 
not later than 1 year after the actual completion date of the 
applicable clinical trial.
    The 1 year deadline would apply to applicable clinical trials of 
drugs and devices, whether or not approved, licensed, or cleared, 
except as described in (2) and (3) below. 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 . . .'' As discussed 
further in section III.C.5 of this preamble, our proposal would apply 
the same general deadline for results submission to both applicable 
clinical trials of approved, licensed, or cleared products and 
applicable clinical trials of unapproved, unlicensed, or uncleared 
products in order to simplify

[[Page 69633]]

results submission procedures and provide consistency between the 
deadlines for applicable clinical trials, regardless of the approval 
status of the products under study. Applicable clinical trials of 
unapproved, unlicensed, or uncleared drugs and devices (and of 
approved, cleared, and licensed drugs and devices that are studied for 
a new use) may, however, qualify for delayed submission of results, as 
described in section IV.C.3(b) below.
    Section 402(j)(3)(D)(iv)(I) of the PHS Act requires the Secretary 
to determine whether to increase the general deadline for results 
submission from 1 year to ``a period not to exceed 18 months'' after 
the earlier of the estimated or actual completion date. We solicited 
comment on this topic as part of the public meeting held in April 2009 
but received few comments on this issue. Comments that supported a 
longer deadline cited concerns about applicable clinical trials for 
which data collection for secondary outcome measures and adverse events 
would continue beyond the completion date of the clinical trial. During 
the time that we have been operating the data bank, we have seen only 
few clinical trials in which this situation occurs. Rather than 
extending the general results submission deadline to as long as 18 
months in order to accommodate what we believe would be a small number 
of such trials, we propose instead alternative methods for addressing 
such trials in proposed Sec.  11.44(a)(2).
    (2) Submitting results information following initial product 
approval, licensure, or clearance. Proposed Sec.  11.44(a)(2) specifies 
the timeline for submitting results information for any applicable 
clinical trial of an FDA-regulated drug (including biological product) 
or device that is unapproved, unlicensed, or uncleared as of its 
completion date. It would require that results information as specified 
in proposed Sec.  11.48(a) must be submitted for such trials 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. This proposal is consistent 
with section 402(j)(3)(E)(iv) of the PHS Act.
    (b) Delayed results submission with certification. Proposed 
Sec. Sec.  11.44(b) and (c) establish procedures whereby responsible 
parties may delay submission of results information for a particular 
applicable clinical trial beyond the general deadline specified in 
proposed Sec.  11.44(a)(1) (i.e., 1 year after the completion date).
    (1) Seeking approval, licensure, or clearance of a new use for the 
drug or device. Consistent with section 402(j)(3)(E) (iii) and (v) of 
the PHS Act, we propose 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 seeking approval, licensure, or 
clearance of the use being studied in the applicable clinical trial (a 
use that is not included in the labeling of the approved, licensed, or 
cleared product). As proposed, this certification would be required to 
be submitted to ClinicalTrials.gov before the general results 
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. (See section 
IV.C.3 of this preamble).
    In accordance with section 402(j)(3)(E)(v) of the PHS Act, once a 
certification has been submitted, proposed Sec.  11.44(b)(2) would 
permit a delay in the submission of results information of up to two 
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 studied in the applicable clinical trial for 
the use studied in the clinical trial; (2) FDA issues a letter that 
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 product studied in applicable clinical trial for the use 
studied in the clinical trial; or (3) the manufacturer, which is also 
the sponsor of the applicable clinical trial, withdraws the application 
or premarket notification and does not resubmit it within 210 calendar 
days. In the event that any one of these ``triggering events'' occurs, 
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).
    If the responsible party for an applicable trial for which a new-
use certification has been submitted is not the sponsor/manufacturer of 
the drug (including biological product) or device studied in the 
clinical trial, the sponsor/manufacturer may need to notify the 
responsible party of the occurrence of these triggering events in order 
to help ensure that the responsible party is aware that results 
submission is required. As discussed in section IV.A.2 of this 
preamble, the sponsor may designate a principal investigator as 
responsible party under proposed Sec.  11.4 only if, among other 
things, the principal investigator ``has 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 sponsor will only be able to comply with the results submission 
requirements subsequent to a certification under sections 
402(j)(3)(E)(iii) and (v) of the PHS Act, if notified by the sponsor 
when one of these triggering events occurs. In a situation in which a 
sponsor is not willing or able to provide the principal investigator 
with this information, the conditions for designation under proposed 
Sec.  11.4 cannot be met.
    In addition, consistent with section 402(j)(3)(E)(v)(II) of the PHS 
Act, if a manufacturer makes a certification to delay submission of 
results information because the manufacturer is seeking or will seek 
within 1 year approval of a new use for a drug or device, the 
responsible party shall make such a certification ``with respect to 
each applicable clinical trial that is required to be submitted in an 
application or report for licensure, approval, or clearance'' of the 
use studied in the clinical trial. Proposed Sec.  11.44(b)(3) 
implements this provision. For purposes of this requirement, we 
interpret ``manufacturer'' to mean ``manufacturer/sponsor who is the 
responsible party'' because section 402(j)(3)(E)(v) of PHS Act applies 
only when the manufacturer is the sponsor of the applicable clinical 
trial, and under section 402(j)(3)(E)(iii) of the PHS Act, it is the 
responsible party who must submit the certification for delayed 
submission of clinical trial results information.
    (2) Seeking initial approval, licensure, or clearance for the drug 
or device. Proposed requirements for delayed submission of results 
information with certification when seeking initial approval, 
licensure, or clearance of a drug or device are described in proposed 
Sec.  11.44(c). As discussed above in section III.C.5 of this preamble, 
this proposal reflects our efforts to adhere to

[[Page 69634]]

the statutory requirement 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.'' See section 402(j)(3)(D)(iv)(III) of the PHS Act.
    We propose in Sec.  11.44(c) that submission of results information 
may be delayed if the responsible party certifies that the following 
criteria apply: (1) The drug (including biological product) or device 
studied in the applicable clinical trial previously 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 
product under study. As proposed, this certification would be required 
to be submitted to ClinicalTrials.gov before the general results 
submission deadline specified in proposed Sec.  11.44(a)(1), i.e., 1 
year or less after the completion date.
    The intent of this certification is to permit delayed results 
submission only if the sponsor of the applicable clinical trial intends 
to continue with product development of the drug (including biological 
product) or device under study, such that there is an expectation that 
marketing approval or clearance will be sought. We do not believe that 
results submission should be delayed for applicable clinical trials of 
products that the sponsor has no intention of marketing or for which 
product development has been abandoned.
    Hence, our proposal would permit 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 marketing approval, licensure, or 
clearance. We recognize that 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 approval, licensure, or clearance for a 
product studied in an applicable clinical trial, but 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. When the responsible party is not the sponsor of the 
applicable clinical trial and wishes to delay results submission, we 
would expect the responsible party to obtain such information from the 
sponsor before submitting a certification, in order to help ensure the 
truthfulness of the certification.
    Under our proposal, submission of a certification would delay the 
deadline for submitting results for the applicable clinical trial by up 
to two years from the date on which the certification is submitted to 
ClinicalTrials.gov. However, in the event that 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 within this 
two-year period, the responsible party would be required to submit 
results information not later than 30 calendar days after such 
approval, licensure, or clearance. Similarly, if the sponsor withdraws 
the application or premarket notification without resubmission for 210 
calendar days during this two-year period, the responsible party would 
be required to submit results information not later than 30 calendar 
days after such date. The agency believes that this latter situation 
represents a significant enough interruption to product development to 
trigger the submission of results information.
    We note that, unlike delayed results submission with certification 
that the sponsor of the applicable clinical trial is seeking approval, 
licensure, or clearance of a new use, we do not propose to require the 
submission of results 30 days after FDA issues a letter not approving, 
licensing, or clearing the product under study because we do not think 
that the issuance of such a letter necessarily indicates abandonment of 
product development. For the reasons set forth above in ``(1) ``Seeking 
approval, licensure, or clearance of a new use for the drug or 
device[,]'' a responsible party who is not the sponsor (i.e., a 
responsible party who is a principal investigator) will be able to 
comply with the results submission requirements subsequent to a 
certification under sections 402(j)(3)(E)(iii) and (iv) of the PHS Act, 
only if notified by the sponsor when one of the triggering event 
occurs. In a situation where the sponsor is not willing or able to 
provide the principal investigator with this information, then the 
conditions for designation under proposed Sec.  11.4 cannot be met, 
and/or the responsible party will not be eligible to delay results 
submission.
    (3) Two-Year Limitation of Delay. With regard to the maximum delay 
pursuant to a certification submitted under section 402(j)(3)(E)(iii) 
of the PHS Act, the agency expects that in most situations a delay of 
an additional two years beyond the date the certification is submitted 
(i.e., up to three years after the completion date of the clinical 
trial, if the certification is submitted 1 year after the completion 
date) provides sufficient time for the sponsor of the applicable 
clinical trial to protect its competitive advantage, a concern 
expressed in public comments. Within this time frame, a sponsor would 
likely make a decision about whether to halt product development, 
initiate another clinical trial (e.g., a phase 3 clinical trial to 
follow a phase 2 clinical trial), or submit a marketing application or 
premarket notification to FDA. Subsequent trials would most likely be 
required to register at ClinicalTrials.gov and, for applicable drug 
clinical trials, the clinical trial registration information for those 
subsequent trials would be posted publicly in the data bank, thereby 
providing some information to competitors about the outcome of previous 
trials and the objectives of future trials. As discussed further in 
Section III.C.5 of this preamble, we believe any competitive 
disadvantage caused by the disclosure of summary results information 
three years or more after the completion date of the trial would be 
limited and outweighed by the public health benefits of making such 
information publicly available. We invite public comment on this 
approach.
    For applicable clinical trials that meet the criteria for delayed 
results submission with certification--whether seeking initial 
approval, licensure, or clearance or seeking approval, licensure, or 
clearance of a new use--measuring the maximum delay of two years from 
the date on which the certification is submitted may result in 
responsible parties submitting certifications as close as possible to 
the general results submission deadline under proposed Sec.  
11.44(a)(1) (i.e., 1 year after the completion date). Submitting a 
certification just before the general results submission deadline would 
postpone results submission until as late as three years after the 
completion date of the clinical trial, while submitting a certification 
on the completion date of the clinical trial would extend the results 
submission deadline only as long as two years beyond the completion 
date. We believe that users of ClinicalTrials.gov would benefit from 
knowing as early as possible that results submission for an applicable 
clinical trial of interest

[[Page 69635]]

would be delayed. Until a certification is submitted, users may expect 
that results will be submitted not later than 1 year after the 
completion date. If a certification were submitted soon after the 
completion date, the clinical trial record could be updated at that 
time to indicate that results submission would be delayed, and users 
could adjust their expectations accordingly.
    The statute does not appear to permit us to change the timeline for 
results submission when a responsible party submits a certification 
when seeking approval of a new use for the drug or device under section 
402(j)(3)(E)(v) of the PHS Act and proposed Sec.  11.44(b). For delayed 
submission of results when seeking initial approval, licensure, or 
clearance, however, the statute offers greater flexibility in 
establishing the timeline: 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. We considered 
establishing the maximum available delay with certification when 
seeking initial approval, licensure, or clearance to be three years 
from the completion date of the applicable clinical trial, regardless 
of when during the one-year period following the completion date the 
certification is submitted. Such a provision would accomplish 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 three 
years beyond the completion date of a clinical trial, without creating 
a disincentive to submit the certification early. We did not include 
this provision in this proposed rule so that we could keep the same 
maximum delay for results submission whether seeking initial approval, 
licensure, or clearance or seeking approval, licensure, or clearance of 
a new use. We invite public comments on the advantages and 
disadvantages of establishing maximum different timelines for results 
submission under the two delayed-results-with- certification 
provisions. We also invite public comment on alternative approaches we 
could take to encourage early submission of certifications in a way 
that is consistent with the statutory requirement for seeking approval, 
licensure, or clearance of a new use, without causing a responsible 
party to have to submit results information earlier than the latest 
deadline they could have under the statute.
    We note that the maximum delay of two years pursuant to a 
certification submitted under section 402(j)(3)(E)(iii) of the PHS Act 
applies to all primary outcomes and any secondary outcomes for which 
the final subject was examined or received an intervention for the 
purposes of final data collection by the completion date. In the event 
that data collection for any secondary outcome measure(s) will not be 
completed as of the completion date, clinical trial results information 
for such secondary outcome measure(s) shall be due under proposed Sec.  
11.44(b) and (c) by the later of: (1) ``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 such secondary outcome 
measure(s), whether the applicable clinical trial was concluded 
according to the pre-specified protocol or was terminated;'' or (2) 
``the date on which the primary outcomes are due pursuant to . . . 
[proposed Sec. Sec.  11.44(b) or (c).''
    (c) Explanation of ``initial approval,'' ``initial clearance,'' and 
approval or clearance of a ``new use.'' For purposes of proposed 
Sec. Sec.  11.44(b) and (c), we interpret 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 conclude 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 that are 
``not included in the labeling of the approved drug'' (See section 
402(j)(3)(E)(v) of the PHS Act). Accordingly, ``initial approval'' 
pertains to the approval or licensure of an original NDA, abbreviated 
new drug application (ANDA) or BLA, and ``new use'' pertains to the 
approval or licensure of a supplemental NDA, ANDA, or BLA for an 
additional indication for that particular drug product or biological 
product. Similarly, we interpret ``initial approval'' of a device under 
sections 515 or 520(m) of the FD&C Act to pertain to the approval of an 
original premarket approval application (PMA) or humanitarian device 
exemption application (HDE) and ``new use'' to pertain to the approval 
of a supplemental PMA for an additional indication for that particular 
device.
    In addition, for purposes of proposed Sec.  11.44(c), the first 
510(k) cleared for a particular device type would be considered 
``initial clearance'' of the device. For example, when a device is 
reclassified from Class III to Class II, then the first 510(k) that is 
cleared as having demonstrated substantial equivalence to the 
reclassified device would be considered 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 
be considered clearance of a new use.
    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 as opposed to a supplemental 
NDA, ANDA, BLA, PMA, or HDE, or whether a clinical trial will be used 
to support a 510(k) seeking initial clearance of a device 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 which type of certification is 
appropriate. We solicit comments on whether these are appropriate 
interpretations and distinctions for purposes of proposed Sec. Sec.  
11.44(b) and (c).
    (d) Submitting partial results. Proposed Sec.  11.44(d) specifies 
procedures for submitting results 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. Under the definition of completion date in proposed Sec.  
11.10(a), whether or not a clinical trial is completed is determined by 
the status of data collection for solely 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)(i). If a certification to 
delay results submission has not been submitted under proposed Sec.  
11.44(b) or (c), results 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

[[Page 69636]]

pre-specified protocol or was terminated. If the responsible party has 
submitted a certification to delay results submission under proposed 
Sec.  11.44(b) or (c), results of the secondary outcome measures could 
be submitted by the later of the date specified proposed Sec.  
11.44(d)(i) or the date on which the primary outcome measures would be 
required to be submitted. We note 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 the primary 
outcome measure(s).
    With respect to adverse event information (which is 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 believe that this approach provides 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.
    We recognize that this approach may not be suitable for all 
applicable clinical trials for which data collection for secondary 
outcome measures extends more than 1 year beyond the completion date. 
In some circumstances, submitting results information for the primary 
outcomes not later than 1 year after the completion date might 
compromise the scientific integrity of the applicable clinical trial, 
for example, by requiring the applicable clinical trial to be unblinded 
before all data for the secondary outcome measures are collected. In 
those circumstances, we would expect a responsible party to seek a 
good-cause extension of the results submission deadline in proposed 
Sec.  11.44(a)(1), following the procedures specified in proposed Sec.  
11.44(e).
    We clarify in proposed Sec.  11.44(d)(2) the way to handle results 
submission if results related to the primary outcome(s) were submitted 
prior to the effective date of the rule, but results data for the 
secondary outcome(s) are 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 this proposed rule. We believe that 
consistent data must be provided for all outcome measures in a single 
clinical trial and therefore would apply the requirements of proposed 
Sec.  11.48 to the clinical trial as a whole.
    (e) Requesting a good-cause extension of the results submission 
deadline. Proposed Sec.  11.44(e) outlines procedures for requesting 
good-cause extensions of the deadline for submitting results 
information. 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 interpret this authority 
as allowing the Director to grant an extension of any results 
submission deadline that may be in effect for a given applicable 
clinical trial, e.g., the general 12-month results 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 good-
cause extension. As for the latter, section 402(j)(3)(E)(vi) of the PHS 
Act explicitly allows the Director to ``grant more than one [good-
cause] extension for a clinical trial.'' For a pediatric postmarket 
surveillance of a device that is not a clinical trial, the agency also 
proposes to allow more than one good-cause extension for such a 
surveillance. Good-cause extensions apply only in the context of 
applicable clinical trials subject to the results submission 
requirements of section 402(j)(3) of the PHS Act because the good-cause 
extension provision specifically refers to results submission under 
402(j)(3)(E)(i) of the PHS Act. Accordingly, good-cause extensions do 
not apply to clinical trial results that are submitted under section 
402(j)(4)(A) of the PHS Act, i.e., voluntarily submitted trials (see 
proposed rule Sec.  11.60(a)(2)(i)) and triggered trials (see Sec.  
11.60(a)(2)(iii) of this proposed rule).
    Section 402(j)(3)(E)(vi) of the PHS Act does not define ``good 
cause.'' Similarly, this proposed rule does not contain specific 
proposals for determining which situations will and will not be 
considered good cause for an extension. Instead we intend to develop 
guidance (which would be subject to public comment) as the agency gains 
more experience with extension requests and communicate with the 
regulated community via other channels, including the 
ClinicalTrials.gov Web site. In order to assist responsible parties who 
are considering submitting a good-cause extension request, we intend to 
prepare, update periodically, and post on ClinicalTrials.gov a 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). The list 
would not necessarily be an exhaustive list of reasons for which 
applicable clinical trials have or have not been granted an extension, 
but would contain those reasons that we believe would serve as useful 
examples for responsible parties of other applicable clinical trials. 
All good-cause 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.
    In general, we believe 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). To-date, 
we have identified only two situations that we believe would constitute 
good cause, as follows:
    (1) The need to preserve the scientific integrity of an applicable 
clinical trial for which data collection is ongoing. This would include 
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 recognize that permitting an 
extension in such circumstances could provide an incentive for someone 
wishing to delay results submission to add to their applicable clinical 
trial a secondary outcome measure with a very long data collection time 
frame, even if the outcome measure has limited significance or 
relevance to the clinical trial. Because protocols are typically 
revised by outside entities (e.g., human subjects protection review 
boards), one way to protect against such behavior is to ensure that the 
secondary outcome measures are pre-specified in the protocol or 
statistical analysis plan. Accordingly, in order to demonstrate good 
cause, we believe that an extension should be granted only in those 
situations in which it can be demonstrated that the data collection for 
the secondary outcome(s) of interest

[[Page 69637]]

extends more than 1 year beyond the completion date, that the secondary 
outcome(s) is pre-specified in the protocol or statistical analysis 
plan (consistent with the definition of secondary outcomes in this 
proposed part), and the planned analysis of the outcome measure is also 
described in the protocol or statistical analysis plan. The responsible 
party could provide this information either by voluntarily submitting 
copies of the protocol or statistical analysis plan with the good-cause 
extension request or describing them in the extension request itself.
    (2) Emergencies that prevent timely submission of clinical trial 
results information. This would include situations in which one or more 
data collection sites are affected by natural disasters or other 
catastrophes outside the responsible party's or sponsor's control. In 
such cases we generally would 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).
    The following non-exhaustive list enumerates scenarios that we 
generally do not believe ordinarily would constitute good cause:
     Pending publication. The ICMJE has asserted that results 
submission to ClinicalTrials.gov in compliance with section 402(j) of 
the PHS Act will not be considered ``prior publication'' and would not 
preclude future publication [Ref. 10].
     Delay in data analysis for unspecified causes. A general 
statement that provides no specific reason for a delay in data 
analysis, e.g., ``data could not be analyzed fully within 12 months,'' 
would not be considered to have demonstrated good cause.
    If the estimated completion date displayed in the applicable 
clinical trial record is earlier than the actual (or current estimated) 
completion date, a responsible party must update the estimated 
completion date in the clinical trial record to reflect the actual (or 
revised estimated) completion date within 30 calendar days, as required 
by 11.64(b)(1)(viii) and should not request an extension based on the 
outdated completion date posted in the data bank. The fact that the 
responsible party has updated the completion date will be reflected in 
ClinicalTrials.gov, consistent with the handling of all updates under 
proposed Sec.  11.64.
    We invite public comment on these specific situations and on more 
general criteria that could be used to determine what constitutes good 
cause for an extension.
    Proposed Sec.  11.44(e)(1) outlines procedures for submitting a 
good-cause extension request. It indicates that extension requests must 
be submitted to NIH via ClinicalTrials.gov prior to the date on which 
results information would otherwise be due in accordance with the 
results submission deadlines established in proposed Sec.  11.44(a), or 
Sec.  11.44(b), or Sec.  11.44(c), if the relevant certification has 
been submitted. The proposed process for submission of extension 
requests calls for direct electronic submission to ClinicalTrials.gov 
at http://prsinfo.clinicaltrials.gov/. Consistent with section 
402(j)(3)(E)(vi) of the PHS Act, our proposal would require an 
extension request to include a 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. 
Requests missing either piece of information would be considered 
incomplete and the responsible party would be notified that the request 
would not be considered by the agency until missing information is 
provided. The submitted extension request would be reviewed by an NIH 
official designated by the Director.
    Proposed Sec.  11.44(e)(2) specifies that a response to the good-
cause extension request would be communicated electronically to the 
responsible party, providing notice as to whether or not the requested 
extension has been granted. This communication would take place via 
ClinicalTrials.gov. As indicated, if a request were granted, a revised 
deadline for results submission would be communicated in the notice, 
taking into account the particulars of the request. We note that the 
agency may grant a deadline that is earlier than that requested by the 
responsible party in the good-cause extension request. If a request 
were denied, the deadline for submitting results would be the later of 
the original submission deadline (e.g., 1 year after the completion 
date or the delayed submission deadline if a certification has been 
filed under subparts (b) or (c)) or 15 calendar days after the date the 
electronic notice of the denial of the request is sent to the 
responsible party.
    Proposed Sec.  11.44(e)(3) establishes an appeals process that 
would permit a responsible party a single opportunity to appeal the 
decision of the agency to deny an extension request or the deadline 
specified in a granted extension request. An appeals process was a 
feature that was requested at the public meeting in April 2009 (see, 
Ref. 1). Under proposed Sec.  11.44(e)(3), a responsible party who 
appeals a denied extension request must submit the appeal in letter 
form to the Director not later than 15 calendar days after the date on 
which electronic notification of grant 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, unless 
such information was not available at the time of the initial request. 
The submitted appeal will be considered by the Director.
    If an appeal is granted, a revised deadline for results submission 
would be set by the Director, based on the particulars of the request, 
and provided to the responsible party in an electronic notification. If 
the appeal of a denied extension request is denied, the deadline for 
submitting results would be the later of the original submission 
deadline or 15 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 
would be the later of the deadline specified in the notification 
granting the extension request or 15 calendar days after the electronic 
notification of the denial of the appeal is sent to the responsible 
party.
    (f) Posting of information about certifications for delayed 
submission and about good-cause extensions. We believe that 
ClinicalTrials.gov should indicate when the results submission deadline 
for a particular applicable clinical trial has been postponed because 
an extension request has been granted or the responsible party has 
submitted a certification for delayed submission. Without such an 
indication, users who view a clinical trial record that contains no 
results information more than 1 year after the completion date might be 
led to believe, incorrectly, that the responsible party has not 
complied with the results submission requirements of section 
402(j)(3)(E) of

[[Page 69638]]

the PHS Act or this proposed rule, or that the agency has failed to 
post such information.
    We believe that there would be value in posting information about 
the specific mechanism that has been used to delay the submission of 
clinical trial results information, i.e., a certification under 
proposed Sec.  11.44(c) seeking initial approval, licensure, or 
clearance; a certification under proposed Sec.  11.44(b) seeking 
approval, licensure, or clearance of a new use; or a good-cause 
extension under proposed Sec.  11.44(e). Doing so would provide a 
mechanism to track the progress of clinical trials by informing users 
why clinical trial results information is not yet publicly available.
    However, we recognize that the public posting of information about 
the specific mechanism used to delay results submission could result in 
the posting of information that might in some circumstances be 
considered confidential. For example, the fact that a responsible party 
had submitted a certification under proposed Sec.  11.44(b) would 
indicate that the sponsor or 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. Such certification could be submitted 
to ClinicalTrials.gov prior to any public statement by the sponsor or 
manufacturer about its plans to apply for a new use. Similarly, the 
reasons underlying a request for a good-cause extension might contain 
details about the applicable clinical trial that previously have not 
been made public.
    Our proposed approach attempts to balance the desire to indicate 
that the submission of clinical trial results information has been 
postponed for reasons that are permitted by statute and the need to 
avoid disclosure of confidential information. In order to avoid putting 
responsible parties in a position where they must agree to the release 
of information that would otherwise be considered confidential in order 
to delay results submission in accordance with a mechanism specified in 
section 402(j) of the PHS Act and this proposed part, we would post 
only minimal information about delayed results submissions in these 
circumstances. If a responsible party delays results submission via 
certification or is granted a good-cause extension of the deadline for 
submitting clinical trial results information, we propose to indicate 
in the clinical trial record only that results submission has been 
delayed. We would not indicate which mechanism was used to delay 
submission or the reason for which an extension may have been granted 
for a particular applicable clinical trial. In order to provide 
responsible parties with insight into the general types of reasons that 
have and have not been considered to constitute good cause for an 
extension, we propose to post and update periodically on the 
ClinicalTrials.gov Web site a generalized list of reasons for which 
extensions have and have not been granted. The listing would not 
indicate which applicable clinical trials have been granted or denied 
extensions based on the listed reason(s), and we would attempt to 
remove from the list any information that might allow a user to 
identify a specific applicable clinical trial.
    We invite public comments on our proposed approach and whether more 
specific information could be provided about extensions and 
certifications for an individual applicable clinical trial (e.g., 
whether submission was delayed via extension or certification, and, if 
so, which type of certification) without releasing confidential 
information, what types of certification and extension information 
responsible parties would consider confidential, and 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 specifically invite comments on the advantages 
and disadvantages of providing more specific information about 
extension requests, e.g., that a request has been submitted for a 
clinical trial, the specific reason for the extension request, the 
responsible party's estimate of the date on which clinical trial 
results information could be submitted, whether or not the request was 
subsequently granted or denied, whether a denial has been appealed, and 
whether the appeal was granted or denied. Making such information 
available in ClinicalTrials.gov would further increase transparency 
into agency decisions and would provide an alternative means of 
informing interested parties about the types of situations that we 
consider good cause for an extension. We additionally invite public 
comment on whether extension requests could be submitted without 
containing any information that would be considered confidential and 
thus not suitable for release to the public.
    (g) Results submission deadline for a pediatric postmarket 
surveillance of a device that is not a clinical trial. We recognize 
that the proposed deadlines for submitting clinical trial results 
information under proposed Sec. 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 
FDA, as specified in the approved postmarket surveillance plan. Hence 
for a pediatric postmarket surveillance of a device that is not a 
clinical trial, we propose in Sec.  11.44(e) that results information 
be submitted not later than 30 calendar days after the date that the 
final report is submitted to FDA. We believe that 30 days is sufficient 
additional time to allow the responsible party to format data as 
required by this part and submit it to ClinicalTrials.gov.
4. What constitutes results information?--Sec.  11.48
    Proposed Sec.  11.48 specifies procedures for submitting results 
information for an applicable clinical trial. Proposed Sec.  11.48(a) 
specifies the general requirements 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) describes 
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) separates the data elements into 
the following general categories of information: (1) Participant flow, 
(2) demographic and baseline characteristics of the study population; 
(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. Note that whenever possible ClinicalTrials.gov will use 
information that was submitted during registration to pre-populate 
column and row names of the tables of information that required as part 
of results submission. Doing so would reduce the data entry burden on 
responsible parties and minimize the possibility of clerical errors. 
However, in all cases, the responsible party would be required to 
revise the information, as needed, so that the results information 
appropriately and accurately reflects the way data were collected and 
analyzed in the clinical trial. Each of the categories of results 
information that is required to

[[Page 69639]]

be submitted is addressed, in turn, below.
    (a) Participant flow: As part of the requirements related to the 
demographic and baseline characteristics of the patient sample, 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.'' We consider this information to be part of what we call 
``participant flow.'' Participant flow refers to information, organized 
by arm of the clinical trial that documents the progression of human 
subjects through the clinical trial.
    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, we 
propose in Sec.  11.48(a)(1) to require 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 participants through the clinical trial, including a 
descriptive title used to identify each arm[;]'' (2) Pre-assignment 
Information, which consists of ``[a] description of any significant 
events affecting the number of human subjects enrolled in the clinical 
trial but not assigned 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.'' This information permits the construction 
of a table that shows the flow of participants through the clinical 
trial.
    In our proposed approach, information about the number of 
participants excluded from the analysis is not contained within 
participant flow, but would be submitted as part of the information 
about outcome measures, described below. We propose this approach 
because the number of participants excluded from analysis generally 
depends on the particular outcome measure being analyzed. A participant 
who drops out midway through a clinical trial, for example, may be 
included in the analysis of one outcome measure for which data 
collection was completed early in the study, but excluded from the 
analysis of another outcome measure for which data collection occurred 
(or continued) after the drop out. Hence, the aggregate number of 
participants excluded from the analysis could not generally be 
calculated by arm and the information by outcome measure would give a 
more accurate representation of the flow of human subjects through the 
clinical trial.
    We intend to continue to provide responsible parties with a means 
of providing, on a voluntary basis, additional details about 
participant flow in a manner consistent with CONSORT guidelines [Ref. 
24]. This information would consist of details about the flow of 
participants through different periods or milestones that might have 
been defined for a 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 reasons why participants did 
not complete the clinical trial or reach a particular milestone, if 
applicable, could improve users' understanding of the clinical trial 
data. Because clinical trials vary considerably in their design and may 
or may not include specific periods or milestones, there are no 
generally accepted approaches for submitting such information; nor is 
there consensus on how best to classify reasons for non-completion 
using categories that are comprehensive and not overlapping. Therefore, 
we do not propose a requirement to submit such information in this 
proposed rule; instead, we would allow such information to be submitted 
voluntarily by the responsible party. We have built into 
ClinicalTrials.gov the capability to accept such information, and we 
expect that continued experience with the voluntary submission of such 
information and continued efforts by the clinical trial research 
community may, over time, lead to the development of more widely 
accepted approaches to organize such information. We welcome public 
comment on the value of providing such additional information in 
ClinicalTrials.gov and on approaches for collecting it.
    (b) Demographic and baseline characteristics: Section 
402(j)(3)(C)(i) of the PHS Act requires submission of the following 
results information: ``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 . . .''
    ClinicalTrials.gov provides pre-formatted rows that enable 
responsible parties to submit common demographic characteristics, 
including age, gender, race, ethnicity, and region of enrollment (with 
countries and geographic regions, such as Europe, Middle East, South 
America, listed on a pull-down menu), by arm or comparison group and 
overall for the clinical trial. Race and ethnicity data are submitted 
in accordance with the classification system of the Office of 
Management and Budget (OMB) (See 62 FR 58782, Oct. 30, 1997). We do not 
propose to require the submission of information describing all of 
these demographic characteristics because they may not all be collected 
as part of a particular clinical trial, and we do not wish to impose 
requirements on the data that must be collected during a clinical 
trial. Instead, in Sec.  11.48(a)(2)(iii), we propose as a minimum 
requirement that responsible parties submit information describing the 
age and gender of the human subjects enrolled in the clinical trial. 
Age information can be provided as either a continuous variable (e.g., 
average age is 52 years) along with a measure of dispersion (e.g., 
standard deviation is 4.5 years) or a categorical variable (e.g., 
pediatrics, adults, seniors). Such information is generally collected 
in clinical trials and can be expected to be available for applicable 
clinical trials.
    In addition, ClinicalTrials.gov accommodates the submission of 
information to describe an unlimited number of customized demographic 
and baseline characteristics. In general, we cannot specify in advance 
which other demographic and baseline characteristics must 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 actually were collected. We do believe it is important, 
however, that demographic and baseline measures be provided for any 
characteristic that is used in assessing outcome measures. For example, 
if an outcome measure compares a subject's blood pressure after 6 weeks 
of treatment with a particular intervention, we believe the baseline 
measure of blood pressure must be submitted. Similarly, if a clinical 
trial includes a statistical analysis that uses baseline data as part 
of the calculation (e.g., a regression analysis) we believe it is 
necessary to submit the relevant baseline data. The use of this 
baseline data in analyzing the outcome measure indicates that it would 
have been collected during the clinical trial and thus would be 
important to the interpretation of results.
    We specify this requirement in proposed Sec.  11.48(a)(2)(iii) 
which requires, in addition to age and gender, the submission of 
information for each baseline or demographic characteristic measured in 
the clinical trial that is used in the analysis of any of the

[[Page 69640]]

outcome measures (See section IV.C.4.c of this preamble for a 
discussion of outcome measures). In order for submitted demographic and 
baseline characteristic information to be meaningful to users, we 
specify that the responsible party must submit the following 
information for each demographic or baseline measure submitted to 
ClinicalTrials.gov: the Name of the measure (e.g., gender) and 
Description of the measure (e.g., ``male'' and ``female''); the type of 
measure (Measure Type) and an associated Measure of Dispersion; and the 
unit of measure (e.g., milligrams). When specifying the Measure Type, 
the responsible party would have to select from the following limited 
list of options: ``number,'' ``mean,'' ``median,'' ``least squares 
mean,'' ``geometric mean,'' or ``log mean.'' When specifying the 
associated Measure of Dispersion, the responsible party would have to 
select from the following limited list of options: ``standard 
deviation,'' ``inter-quartile range,'' ``full range,'' or ``not 
applicable'' (which would be permitted only if the specified measure 
type is ``number''). No ``other'' option is proposed for either the 
Measure Type or Measure of Dispersion, but responsible parties would 
have the option of providing voluntarily additional information about 
the baseline measures as part of a free-text Baseline Measure 
Description. We believe that this approach would allow a responsible 
party to accurately describe the baseline characteristics of an 
applicable clinical trial or other clinical trial that is subject to 
this proposed rule. We invite public comment on the sufficiency of the 
proposed approach for submitting baseline characteristics.
    Collecting the information in the structured manner proposed is 
intended to improve the comparability of information across clinical 
trials and to ensure complete data collection. For example, if a 
responsible party indicates that the measure of dispersion for a 
measure is interquartile range, for example, ClinicalTrials.gov could 
prompt the submission of the two data elements needed to specify the 
upper and lower bounds of the interquartile range; if a responsible 
party indicates that the measure of dispersion is a standard deviation, 
ClinicalTrials.gov could prompt the submission of that single value. 
Note that baseline characteristic information may also be submitted as 
a number instead of a central tendency (e.g. number of participants), 
in which case the measure of dispersion must be indicated as ``Not 
Applicable.''
    We invite comments on whether or not we should require the 
submission of additional demographic or baseline characteristics that 
were collected during the clinical trial, the advantages and 
disadvantages of requiring the submission of such information, and, if 
so, how such information can be specified in the rule. We also invite 
comments on other types of demographic information that could be 
required for all clinical trials, for example, country-of-origin or 
country-of-residence, which are collected in many clinical trials. We 
invite comment on whether the fixed list of proposed choices for 
measures of central tendency and of dispersion is adequate to provide 
an accurate description of the measures used in any clinical trial.
    Our proposal for demographic and baseline characteristics indicates 
that responsible parties should submit such information by ``arm or 
comparison group.'' The reference to comparison group recognizes that 
when analyzing data collected during clinical trials, data are often 
aggregated into groupings of human subjects (i.e., comparison groups) 
other than the arms into which they were assigned for the study. This 
is often the case in clinical trials that use a cross-over study design 
in which human subjects in different arms of the clinical trial receive 
the same interventions in a different order; the results are often 
analyzed not by arm but by intervention (See the discussion of 
comparison group in section IV.A.5). We believe it is appropriate when 
submitting demographic and baseline characteristics, as well as other 
results information, that the information to be submitted according to 
the same groupings by which it was analyzed, whether the arm of the 
clinical trial or a different comparison group. So that users of 
ClinicalTrials.gov can understand how information about human subjects 
was aggregated for analysis, proposed Sec.  11.48(a)(2)(i) requires 
submission of a Baseline Characteristic Arm/Group Information data 
element, which consists of ``[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.''
    We also propose in Sec.  11.48(a)(2)(ii) to require submission of 
Overall Number of Baseline Participants, ``[t]he total number of human 
subjects for whom baseline characteristics were measured, by arm or 
comparison group and overall.'' This information 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.
    (c) Outcomes and statistical analyses: Section 402(j)(3)(C)(ii) of 
the PHS Act requires the following as results information: ``The 
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.'' 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 pre-specified outcome 
measure (primary or secondary) in separate tables organized by arm or 
comparison group. The responsible party determines the rows and columns 
of each outcome measure table: The columns represent arms or comparison 
groups, and the rows represent data categories (e.g., for categorical 
data types) and data attributes (e.g., mean and standard deviation). 
The responsible party populates the table cells with data from the 
clinical trial. In this way, the system can accommodate either 
continuous or categorical data, as desired by the responsible party 
based upon the design of the clinical trial as specified in the 
protocol and statistical analysis plan. 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 at five-years).
    In order to enhance the ability of users to understand and 
interpret the submitted clinical trial results information and to help 
ensure that submitted information is complete, we propose in Sec. Sec.  
11.48(a)(3)(i)-(v) that the responsible party submit the following 
information to create and populate the outcome data tables:
    (1) Outcome Measure Arm/Group Information, which is described 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 the section IV.C.4(b) on demographic and baseline 
characteristics, this information would describe the grouping of human 
subjects for purposes of analysis, whether by arm

[[Page 69641]]

of the clinical trial or other comparison group.
    (2) Analysis Population Information, which must include the Number 
of Participants Analyzed, meaning ``[t]he number of human subjects for 
which an outcome was measured and analyzed, by arm or comparison 
group.'' If the analysis is based on a unit other than human subjects 
(e.g., lesions, eyes, implants), the responsible party would also be 
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 in an arm 
or comparison group differs from the number of human subjects assigned 
to the arm or comparison group, the responsible party would also be 
required to provide an Analysis Population Description, which would 
briefly describe the reason(s) for the difference (e.g., if a clinical 
trial is terminated after participants are assigned to arms but before 
one of the outcome measures is assessed, the responsible party would 
include a statement in the Analysis Population Description indicating 
that the clinical trial was terminated before the outcome measure was 
collected). This entry would explain why the total Number of 
Participants Analyzed is zero even though participants had been 
assigned to the relevant arm or comparison group.
    (3) Outcome Measure Information, which includes the following 
components: (A) Name of the specific outcome measure, including the 
titles of any categories into which outcome measure data 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 measure: Primary outcome measure, secondary outcome measure, 
other pre-specified outcome measure, or post-hoc outcome measure; (E) 
Outcome Measure Reporting Status, which indicates whether the data for 
the outcome measure are included in the present submission and, if not, 
the anticipated submission date; (F) Measure Type, which indicates 
whether the outcome is measured as a number (e.g., number of subjects 
with a measured value of hemoglobin 5% above the baseline value) or a 
measure of central tendency, and the associated Measure of Dispersion 
or precision; and (G) Unit of Measure (e.g., blood pressure in 
``millimeters of mercury'' or ``percent change''). In specifying a 
Measure Type, the responsible party would be required to select from 
the following limited list options: ``number,'' ``mean,'' ``median,'' 
``least squares mean,'' ``geometric mean,'' or ``log mean.'' In 
specifying the associated Measure of Dispersion, the responsible party 
would be required to select from the following limited set of options: 
``standard deviation,'' ``inter-quartile range,'' ``full range,'' 
``standard error,'' ``95% confidence interval,'' ``90% confidence 
interval,'' ``geometric coefficient of variation'' (which would be 
permitted only if the specified Measure Type is ``geometric mean''), or 
``not applicable'' (which would be permitted only if the specified 
Measure Type is ``number''). No ``other'' option is proposed for either 
the Measure Type or Measure of Dispersion entries, but responsible 
parties would have the option of voluntarily providing additional 
descriptive information about the outcome measure type and measure of 
dispersion as part of a free-text Outcome Measure Description. We 
propose to collect Measure Type and Measure of Dispersion in this 
manner to improve the ability to compare submitted information across 
clinical trials and to ensure complete data submission, e.g., if the 
responsible party indicates that the Measure of Dispersion is 
interquartile range, ClinicalTrials.gov can prompt the submission of 
two values corresponding to the upper and lower bounds of the 
interquartile range, instead of just the single value needed to submit 
a standard deviation. We invite public comment on this proposal and 
whether the proposed options for Measure Type and Measure of Dispersion 
are sufficient for collecting data from the full range of applicable 
clinical trials or voluntarily submitted trials that would be subject 
to this proposed rule.
    In most cases, items (A), (B), and (C) above would have been 
submitted at the time of clinical trial registration and updated during 
the course of the clinical trial, as specified in proposed Sec.  11.64. 
Proposed Sec.  11.64(c) specifically requires that responsible parties 
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 would 
automatically pre-populate the results data tables with the previously 
submitted (and updated) values and allow the responsible party to make 
further updates, as necessary or desired (e.g., to provide further 
clarification that would enable a user to better interpret the 
submitted results values). If data were not collected for an outcome 
measure in a clinical trial, i.e., the Number of Participants Analyzed 
in all arms or comparison groups is zero for that outcome measure, the 
responsible party would not be required to submit items (F) and (G) for 
that outcome measure, as no Outcome Measure Data would be submitted. 
This situation might occur, for example, if a clinical trial is 
terminated before data are collected for all pre-specified outcome 
measures.
    (4) Outcome Measure Data, which consists of the measurement values 
for each outcome measure for which data were collected, by arm or 
comparison group. The information provided under Outcome Measure Data 
must use the Unit of Measure and correspond to the Outcome Measure Type 
submitted under (3) above, i.e., be a number or a central tendency plus 
a measure of dispersion or precision.
    (5) Statistical analyses, which are specified in proposed Sec.  
11.48(a)(v) as the ``[r]esults of scientifically appropriate 
statistical analyses, if any . . .'' performed on the primary or 
secondary outcome measure(s). In implementing this requirement we 
clarify the meaning of ``scientifically appropriate'' as it relates to 
statistical analyses. We believe that the scientific appropriateness of 
a statistical analysis in a clinical trial is inherently subjective. 
For purposes of this rule, we propose that a statistical analysis that 
meets any of the following criteria be considered scientifically 
appropriate in the context of a particular applicable clinical trial: 
(1) The statistical analysis is pre-specified in the protocol or 
statistical analysis plan; (2) the statistical analysis is made public 
by the sponsor or responsible party in written form (e.g., in a journal 
publication) prior to the date on which results submission is otherwise 
completed for all primary and secondary outcome measures studied in the 
clinical trial; or (3) the statistical analysis is conducted in 
response to a specific request from the FDA that is made before 
complete results information is submitted for all of the primary 
outcome measures studied in the clinical trial. We limit the 
requirement to submit FDA-requested statistical analyses to those 
analyses that are requested prior to the submission of results 
information for primary outcome measures only, so as to avoid causing a 
responsible party to have to submit analyses that are requested on data 
that were previously submitted to ClinicalTrials.gov. We propose that 
statistical analyses that meet any of

[[Page 69642]]

these criteria be submitted to ClinicalTrials.gov at the time of 
results submission. We clarify that a responsible party would not be 
required to submit a statistical analysis that is not pre-specified in 
the protocol or statistical analysis plan, is published after complete 
results information is submitted to ClinicalTrials.gov, or is requested 
by the FDA after the date on which complete results information is 
submitted for all of the primary outcome measures studied in the 
clinical trial. We further clarify that the requirement to submit 
results of any scientifically appropriate statistical analyses would 
not cause a responsible party to conduct a statistical analysis that 
was not otherwise planned or required. We invite public comments on 
these proposals and on other criteria the agency should consider 
determining what constitutes a ``scientifically appropriate'' 
statistical analysis.
    We specify in proposed Sec.  11.48(a)(3)(v) the information that a 
responsible party must submit for any scientifically appropriate 
analysis:
    (A) Statistical Analysis Overview: The responsible party would 
identify the arms or comparison groups compared in the statistical 
analysis (by selecting the arms or comparison groups already defined 
for the outcome measures) and specify 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 ``not applicable,'' where ``not applicable'' would 
be appropriate for a single group analysis, for example. No ``other'' 
option is proposed. If the type of analysis selected is ``non-
inferiority'' or ``equivalence,'' the responsible party would be 
required to also 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 would be offered to allow the responsible 
party to voluntarily submit additional information about the 
statistical analysis. We invite comment on whether the list of proposed 
options is sufficient for all applicable clinical trials or voluntarily 
submitted clinical trials for which statistical analysis information 
might be submitted to ClinicalTrials.gov under this proposed rule.
    (B) Statistical Test of Hypothesis: The responsible party would 
submit the p-value and specify the procedure used for statistical 
analysis of the outcome data. For convenience in specifying the 
procedure used for the statistical analysis, ClinicalTrials.gov 
includes a 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 ``other'' and submit the 
name of another method that was used. Additional comment fields would 
be available in ClinicalTrials.gov to allow the responsible party to 
submit voluntarily 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.
    (C) Method of Estimation: The responsible party would provide a 
description of the method of estimation that specifies: The estimation 
parameter, the estimated value, and a confidence interval. For 
convenience in describing the method of estimation, ClinicalTrials.gov 
includes a 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 specify ``other'' and provide the name of 
another estimation parameter using free text. In specifying a 
confidence interval, the responsible party would 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 would be 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 would also 
have the option of submitting voluntarily a dispersion value for the 
confidence interval. If a dispersion value is submitted, the 
responsible party would be 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 is 
proposed. An additional comment field would be available to allow the 
responsible party to submit voluntarily additional information about 
the method of estimation, such as the direction of the comparison 
(e.g., for a relative risk).
    These proposed requirements for submitting statistical analysis 
information attempt to balance the benefits of structured data with 
minimal narrative text against the need to describe what was evaluated 
in the statistical analysis. In addition to the information specified 
above, responsible parties also would 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 would not include interpretation of results or conclusions, 
just a description of the statistical test(s) conducted. Submitted 
statistical analyses would be linked to each submitted outcome measure. 
Although a responsible party would not be limited in the number of 
statistical analyses that could be submitted for each outcome measure, 
only statistical analyses that are related to a submitted outcome 
measure could be described.
    In specifying requirements for outcome measures and statistical 
analyses under proposed Sec.  11.48(a)(3), two situations merit further 
clarification. The first is a clinical trial that is terminated before 
data are collected for one or more of the pre-specified outcome 
measures. Certain information would still be required to be submitted 
for outcome measures for which data were not collected. Under proposed 
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. As noted in (3) above 
and specified in proposed Sec.  11.48(a)(3)(iii)(F) and (G), the 
responsible party would not be required to submit the Measure Type and 
Unit of Measure data elements 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 proposed Sec.  
11.48(a)(3)(iii). As specified in proposed Sec.  11.48(a)(3)(iv), the 
responsible party would not be required to submit Outcome Measure Data 
for the outcome measure(s) for which no data were collected, but would 
be required to submit Outcome Measure Data for any

[[Page 69643]]

other outcomes for which data were collected. The responsible party 
would nevertheless still be required to meet the requirements specified 
in proposed Sec. Sec.  11.48(a)(1), (2), and (4) for the submission of 
information for the Participant Flow, Baseline Characteristics, and 
Adverse Events modules. Note, that if a clinical trial enrolls no 
participants, the information to be submitted for the Actual Enrollment 
data elements under proposed Sec.  11.64(b)(1)(v)(B) would be zero 
(``0'') and no results information would be required to be submitted 
for that clinical trial.
    The second situation consists of a clinical trial in 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 some participants are 
enrolled and outcomes are measured. We believe that even in such 
situations collected results information must be submitted to 
ClinicalTrials.gov as specified in this proposed rule (taking into 
consideration the privacy considerations discussed in section III.C.16 
of this preamble if actual enrollment is very small). 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 means 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 human health and 
safety. In order to reduce the chance that users of ClinicalTrials.gov 
might misinterpret submitted results information, we would encourage 
the responsible party to voluntarily submit additional information 
about the clinical trial in the Analysis Population Description data 
element and/or in the Limitations and Caveats module of 
ClinicalTrials.gov. The submitted information would highlight that 
enrollment in the clinical trial was insufficient to produce 
statistically reliable results. We would also take steps to highlight 
in the public display the fact that actual enrollment fell far short of 
expected enrollment. We would expect that in these situations, no 
statistical analysis information would be submitted for the affected 
outcome measure(s) because none would have been conducted or would be 
considered scientifically valid. We invite public comments on other 
ways in which the limitations of the submitted data could be 
highlighted.
    (d) Adverse event information. Proposed Sec.  11.48(a)(4) requires 
the submission of summary information on adverse events that occurred 
during an applicable clinical trial. Such information is considered 
part of results information. Our proposal derives from the default 
provisions in sections 402(j)(3)(I)(ii)-(iii) of the PHS Act, which 
require the submission of information necessary to complete two tables: 
(1) A table of all anticipated and unanticipated serious adverse 
events, and (2) a table of all anticipated and unanticipated adverse 
events other than serious adverse events with a frequency of more than 
5 percent in any arm of the clinical trial (i.e., ``other frequent 
adverse events''). Sections 402(j)(3)(I)(ii)-(iii) of the PHS Act 
further specify that the information submitted for each table be 
grouped by organ system and include the number and frequency of events 
in each arm of the clinical trial. As explained in greater detail in 
section III.C.15 of this preamble, our proposal for the submission of 
adverse event information derives from the default provisions in 
sections 402(j)(3)(I)(ii)-(iii) of the PHS Act, but includes additional 
requirements intended to assist users in understanding and interpreting 
the submitted adverse event information.
    In implementing the statutory default provisions, we propose in 
Sec.  11.48(a)(4) that responsible parties submit the following 
information for all serious adverse events and for other adverse events 
with a frequency of more than 5 percent in any arm or comparison group 
of the clinical trial: (1) A description of each arm or comparison 
group from which adverse event information was collected (see proposed 
Sec.  11.48(a)(4)(ii)(A)); (2) for each arm or comparison group, a 
description of each serious adverse event or other adverse event with a 
frequency of more than 5 percent in any arm of the clinical trial, 
along with the organ system that is associated with the adverse event 
(see proposed Sec.  11.48(a)(4)(ii)(F)); (3) the number of participants 
experiencing the adverse event (see proposed Sec.  
11.48(a)(4)(ii)(G)(1)), and (4) the number of participants at risk for 
the adverse event (see proposed Sec.  11.48(a)(4)(ii)(G)(2)). In most 
cases, the number of participants at risk will equal the number of 
participants who started that arm of the clinical trial, but the two 
numbers could differ if 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. Using the data submitted for number of 
participants experiencing the adverse event and the number of 
participants at risk, ClinicalTrials.gov will automatically calculate 
the percentage of participants who experienced the event. We believe 
that this approach will help reduce calculation errors and help users 
interpret the frequency information in those cases in which the full 
study population may not have been at-risk.
    To assist users of ClinicalTrials.gov in better understanding the 
number of participants affected by adverse events, we also propose in 
Sec.  11.48(a)(4) that responsible parties be required to submit the 
following information both for all serious adverse events and for other 
adverse events with a frequency of more than 5 percent in any arm or 
comparison group of the clinical trial: (1) The overall number of human 
subjects affected, by arm or comparison group, by one or more serious 
adverse events or other adverse events above the specified threshold 
(see proposed Sec.  11.48(a)(4)(ii)(B)), (2) the overall number of 
participants at risk for any adverse event, by arm or comparison group 
(see proposed Sec.  11.48(a)(4)(ii)(C)), (3) for each organ system 
class that has one or more adverse events listed in either table, the 
overall number of participants affected, by arm or comparison group, by 
any adverse event in that organ system class (see proposed Sec.  
11.48(a)(4)(ii)(D)), and (4) for each organ system class that has one 
or more adverse events listed in either table, the number of 
participants at risk, by arm or comparison group, for any adverse event 
in that organ system class (see proposed Sec.  11.48(a)(4)(ii)(E)). 
ClinicalTrials.gov will automatically calculate the percentage of those 
at risk that experienced any adverse event and the percentage of those 
at risk that experienced any adverse event in each organ system class. 
We believe that this approach will help reduce calculation errors and 
help users interpret the frequency information in those cases in which 
the full study population may not have been at-risk for any adverse 
event or for adverse events affecting particular organ systems.
    As explained in section III.C.5 of this preamble, we propose to 
require responsible parties to submit adverse event information 
classified according to the scheme specified in ClinicalTrials.gov, 
which includes the following 26 categories adapted from the Medical 
Dictionary for Regulatory Affairs (MedDRA) system (http://www.meddramsso.com/): Blood and lymphatic system disorders; Cardiac

[[Page 69644]]

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; 
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. No 
``other'' option is proposed. ``Social circumstances'' is a not an 
organ class (like most of the other categories) 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 ``automobile accident,'' 
``homicide,'' or ``fall''. Adverse events that affect multiple systems 
should 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 explanation may be provided in the optional 
free-text field, Adverse Event Term Additional Description. Our 
experience with submission of adverse event information since September 
2008 indicates that responsible parties are able to use these classes 
effectively to classify the adverse event information submitted to 
ClinicalTrials.gov. We request comment on whether this organ system 
classification is sufficient for submitting adverse event information 
for all applicable clinical trials and voluntarily registered trials 
that are subject to this rule, or whether additional categories or an 
``other'' option are necessary.
    As specified in the statutory default provisions, the adverse event 
information submitted under proposed Sec.  11.48(a)(4)(ii)(G)(1) and 
(2) would be required to include information on anticipated and 
unanticipated adverse events. We understand that protocols sometimes 
specify the collection of only a more limited set of adverse events in 
a clinical trial, e.g. only unanticipated events, or only events 
associated with a particular organ system. We do not intend this 
proposed rule to cause investigators or responsible parties to collect 
information that is not specified in the clinical trial protocol. 
Therefore, in those situations in which the protocol specifies a more 
limited collection of adverse events, we would require the responsible 
party to submit the specified information about serious and other 
adverse events with a frequency greater than 5 percent in any arm of 
the trial for those adverse events that were collected during the 
trial. To help ensure that users of ClinicalTrials.gov know when 
adverse event collection was limited, the responsible party would be 
further required, as indicated in proposed Sec.  11.48(a)(4)(ii)(H), to 
submit an Additional Description that briefly describes how the scope 
of adverse events for which information was submitted differs from the 
broader definitions of adverse event and serious adverse event proposed 
in this rule.
    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 information for 
all clinical trials, including applicable clinical trials and 
voluntarily-submitted clinical trials.
    (e) Administrative information: Proposed Sec.  11.48(a)(5) 
describes certain administrative information that we propose to require 
to be submitted as results information data elements. Section 
402(j)(3)(C)(iii) of the PHS Act requires that ``a point of contact for 
scientific information about the clinical trial results'' be submitted 
as part of clinical trial results information. Proposed Sec.  
11.48(a)(5)(i) implements this provision by requiring the following 
information: (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. We believe that this is the 
information is needed in order to allow a user to inquire about the 
results of the clinical trial. This information would be required to be 
submitted, even if the point of contact is the same as the responsible 
party because we do not otherwise plan to make public the responsible 
party contact information.
    Section 402(j)(3)(C)(iv) of the PHS Act 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 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. Consistent with the definition of PI proposed in 
this part, we interpret this provision as applying to a PI who has 
oversight over the entire applicable clinical trial, not to site-
specific investigators or other investigators (such as those on grant-
funded studies) who might be referred to as principal investigators in 
other contexts but who do not meet the definition of ``principal 
investigator'' under this part.
    In implementing the requirement under section 402(j)(3)(C)(iv) of 
the PHS Act, we propose in Sec.  11.48(a)(5)(ii) to require responsible 
parties to indicate (yes/no) whether the PI is an employee of the 
sponsor. If the PI is an employee of the sponsor, then no further 
information must be provided, although it may be provided voluntarily. 
If the responsible party indicates that the PI is not an employee of 
the sponsor, then the responsible party would be required to indicate 
(yes/no) whether or not 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 PI that restricts in any manner the 
ability of the PI, after the 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.
    Although we are only requiring, consistent with section 
402(j)(3)(C)(iv) of the PHS Act, that the responsible party indicate 
whether such an agreement exists, we also propose to permit responsible 
parties to provide voluntary additional information about existing 
agreements. 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 exist routinely in the clinical trials community, although they 
may vary in their terms and the duration of their limitations on the 
PI. Such agreements typically permit the sponsor or its agent to review 
results communications prior to public release and to impose a short-
term embargo of 60 days or less, from the date the communication is 
submitted to the sponsor for review, but other agreements can impose

[[Page 69645]]

restrictions that have much longer durations or are broader in scope. 
In order to provide responsible parties with an opportunity to provide 
additional information about the agreements that are in place between 
the sponsor or its agent and the PI, we propose to permit the voluntary 
submission of additional, structured information about the agreement. 
Currently in ClinicalTrials.gov, a responsible party who wishes to 
provide this additional information may select among the following 
choices:
    (1) The only disclosure restriction on the PI 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 the communication 
is submitted to the sponsor for review. The sponsor cannot require 
changes to the communication and cannot extend the embargo.
    (2) The only disclosure restriction on the PI 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 the communication is submitted to the sponsor for review. The 
sponsor cannot require changes to the communication and cannot extend 
the embargo.
    (3) Other disclosure agreement that restricts the right of the PI 
to discuss or publish clinical trial results after the trial is 
completed. The responsible party may provide additional description of 
the disclosure agreement.
    Based on our experience to-date in operating ClinicalTrials.gov and 
on feedback we have received from responsible parties, these categories 
appear to provide an acceptable way to describe these agreements in a 
consistent form and manner that can help identify those that deviate 
from standard practice. These categories could be modified over time in 
order to reflect changes in clinical trials practice or provide other 
information of interest to users. We invite public comment on the 
proposed approach, experience to date with the current approach, and 
other information that might be collected on a voluntary basis.
    (f) Additional results information for applicable device clinical 
trials of unapproved or uncleared devices. For applicable device 
clinical trials of unapproved or uncleared devices, the results 
information specified in (a) through (e) above would be submitted to 
ClinicalTrials.gov and publicly posted prior to the date on which 
clinical trial information submitted at the time of registration would 
have been publicly posted. As a result, users of ClinicalTrials.gov 
would lack access to certain descriptive information that is necessary 
to enhance access to and understanding of the submitted results 
information and to determine whether complete results information has 
been submitted (e.g., for all arms of the study).
    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.'' Thus, the Secretary can require, 
through rulemaking, submission of not only that results information 
that is required under section 402(j)(3)(C) of the PHS Act, but also 
``such other categories'' of information as the Secretary determines 
appropriate. We interpret ``such other categories'' of results 
information for applicable device clinical trials of unapproved or 
uncleared devices to include, among other things, certain descriptive 
information that is the same type of information that was required to 
be submitted under section 402(j)(2)(A)(ii) of the PHS Act.
    In order ``to enhance patient access to and understanding of the 
results of clinical trials'' (See section 402(j)(3)(D)(i) of the PHS 
Act), we propose to exercise the authority 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 the same type of 
information that is submitted at the time of registration. This 
descriptive information, defined as part of results information, would 
be posted not later than 30 calendar days after submission, pursuant to 
section 402(j)(3)(G) of the PHS Act. A more detailed discussion of how 
the specified data elements would enhance access to and understanding 
of clinical trial results information is contained in section III.C.5 
of this preamble.
    Proposed Sec.  11.48(a)(6)(i) lists the descriptive information we 
propose that responsible parties must submit as part of the clinical 
trial results information submitted for applicable device clinical 
trials of unapproved or uncleared devices. We believe that the listed 
data elements are necessary to enhance access to and understanding of 
the results of applicable clinical trials of unapproved or uncleared 
devices for which information submitted at registration would not have 
been posted publicly in ClinicalTrials.gov. We interpret this necessary 
standard broadly to enhance access to and understanding of study 
results by the lay public, as well as users of the data bank who have 
high levels of expertise in evaluating the results of clinical trials. 
Moreover, we interpret this necessary standard broadly to enhance 
access to and the understanding of results of clinical trials that are 
posted in ClinicalTrials.gov as well as those that are not posted in 
ClinicalTrials.gov; for example: the comparison of the results of 
multiple clinical trials of the same or similar devices may be 
necessary to understand the results of a clinical trial. We further 
believe that information indicating the status of any necessary human 
subjects protection review board approval must be submitted so that 
users can understand whether results information voluntarily submitted 
to ClinicalTrials.gov and available in the data bank derives from 
clinical trials that were reviewed and approved for ethical and 
scientific considerations, or were exempt from such review.
    Because responsible parties for applicable device clinical trials 
of unapproved or uncleared devices will already have provided this 
descriptive information to the data bank when submitting (and updating, 
as necessary) registration information, the agency believes that it 
would be an unnecessary burden on these responsible parties to require 
them to resubmit descriptive information as part of clinical trial 
results information. Instead, we propose under Sec.  11.48(a)(6)(ii) to 
require responsible parties to affirm that they have verified and 
updated as necessary the descriptive information that is the same type 
of information that is submitted when the trial is registered and that 
this descriptive information is ready to be posted along with the 
results information. Doing so would allow information that previously 
had been submitted to the data bank to automatically populate the data 
elements for these clinical trial results. This approach would also 
reduce inconsistencies between information that previously had been 
submitted at registration and information that would be submitted with 
results, and increase administrative efficiency by reducing the need 
for the agency to conduct a quality review of this information. In this 
manner, we can help ensure that the results information necessary ``to

[[Page 69646]]

enhance patient access to and understanding of the results of clinical 
trials,'' section 402(j)(3)(D)(i) of the PHS Act, is submitted and made 
available publicly, but can reduce the burden placed on responsible 
parties.
    (g) Results information for a pediatric postmarket surveillance of 
a device that is not a clinical trial. Subsection (b) of proposed Sec.  
11.48 specifies 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 recognize that a pediatric postmarket 
surveillance of a device 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, we do not believe that it is possible to specify 
particular data elements or tables of data, similar to those for 
applicable clinical trials that are clinical trials, that could be 
required as results information for all types of pediatric postmarket 
surveillances of a device that are not clinical trials. We are aware, 
however, that for each pediatric postmarket surveillance of a device 
that is required by FDA, a final report must be submitted to FDA 
according to 21 CFR 822.38 (or any successor regulation). Thus, for 
each pediatric postmarket surveillance of a device that is not a 
clinical trial, we believe that the final report would contain a 
suitable summary of the surveillance results, and we propose that it be 
submitted to ClinicalTrials.gov in a form that can be made available to 
the public, e.g., after redacting: (a) Any personally identifiable 
information (other than that required to be submitted under this part), 
and (b) information that is not required to be submitted under this 
part and that is commercial confidential information. Any information 
not redacted would be included in the public data bank. The final 
report would be required to be submitted in a common electronic 
document format, such as Portable Document Format (PDF) or Microsoft 
Word, specified in ClinicalTrials.gov at http://prsinfo.clinicaltrials.gov/. The set of acceptable formats may be 
updated periodically to include new formats that become commonly used 
in the regulated community. This proposed requirement is included in 
section 11.48(b). We invite public comment on this approach.
5. When will NIH post submitted results information?--Sec.  11.52
    Proposed Sec.  11.52 provides that the Director will post results 
information not later than 30 days after the date on which the 
information is submitted to the agency for an applicable clinical 
trial. This proposal corresponds to the posting deadline established in 
section 402(j)(3)(G) of the PHS Act. Proposed Sec.  11.52 does not 
apply to clinical trials that are not required to register under 
402(j)(2)(C) of the PHS Act. For such trials that voluntarily register 
with ClinicalTrials.gov, regardless of whether they are subject to the 
requirements for voluntary submission under proposed 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 reviewed as part of our quality 
review procedures.
6. Under what circumstances will the Secretary grant a waiver of the 
requirements of this subpart?--Sec.  11.54
    Section 402(j)(3)(H) of the PHS Act provides that ``[t]he Secretary 
may waive any applicable requirements of this paragraph 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 . . 
.'' Proposed Sec.  11.54, implements 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 in extraordinary circumstances where provision of the 
waiver is consistent with protecting public health or in the interest 
of national security.
    We expect that waivers would be requested and granted in only a 
very limited number of situations. As described in section III.C.16 of 
this preamble, one example of a situation in which a waiver might be 
granted is if results information could be submitted only in a manner 
that would be likely to enable the re-identification of clinical trial 
participants. We invite 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.
    The proposal specifies that waiver requests must be submitted in 
the form of a written letter to the Secretary or a delegated official 
and indicate the NCT Number, Brief Title, and Sponsor of the trial. 
This information is necessary to identify positively the specific trial 
for which the waiver is requested (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). Because the 
statute grants the Secretary the authority to waive ``any applicable 
requirements'' of this subpart if justified by ``extraordinary 
circumstances'', we also propose that the responsible party identify 
the specific provisions(s) for which a waiver is requested and provide 
a description of the circumstances that are believed to justify the 
waiver.
    The responsible party would not be required to comply with those 
provisions of subpart C for which the waiver was granted. Such 
provisions could include all or just some of the provisions for which 
the waiver was requested. The responsible party would be expected to 
comply with any remaining provisions of subpart C for which the waiver 
was not requested or not granted. The deadline for submitting results 
information to ClinicalTrials.gov would be the later of the original 
submission deadline or 15 calendar days after the notification denying 
the waiver is sent to the responsible party.
    In subsection (b), we propose an appeals process that would permit 
a responsible party to appeal a denied waiver request by writing to the 
Secretary or delegated official. The delegated official for deciding 
upon waiver appeals would, as a matter of practice, differ from the 
delegated official for reviewing the initial waiver request. As with 
the original request, the responsible party would not be required to 
comply with specific provisions of subpart C for which the waiver is 
granted upon appeal; for those provisions for which a waiver is not 
granted upon appeal, the responsible party would be required to submit 
results information by the later of the original results submission 
deadline or 15 calendar days after the notification denying the appeal 
is sent to the responsible party.
    As required by section 402(j)(3)(H) of the PHS Act, 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 any part 
of the waiver is granted. A notation would be made in the record for 
the applicable clinical trial in ClinicalTrials.gov to indicate that 
certain requirements for results submission have been waived, pursuant 
to section 402(j)(3)(H) of the

[[Page 69647]]

PHS Act. This notation is 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. Because the waiver would be based on extraordinary 
circumstances that could include considerations of public health and/or 
national security, the agency proposes not to post publicly information 
describing the reason for the waiver. We invite public comment on this 
proposal.

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

    Proposed subpart D describes requirements for additional 
submissions of clinical trial information to ClinicalTrials.gov, 
including: (1) Voluntary submission of clinical trial information for 
certain clinical trials that are not otherwise subject to the 
registration and results submission requirements of this proposed rule; 
(2) submission of clinical trial information when it is determined that 
posting of such information is necessary to protect public health; and 
(3) timelines for updating clinical trial information.
1. What requirements apply to the voluntary submission of clinical 
trial information for clinical trials of FDA-regulated drugs and 
devices?--Sec.  11.60
    Proposed Sec.  11.60 describes requirements that would apply to 
certain voluntary submissions of clinical trial information to 
ClinicalTrials.gov, specifically, submissions of information for 
clinical trials that are not otherwise subject to the registration and 
results submission requirements of section 402(j) of the PHS Act. This 
proposed section implements section 402(j)(4)(A) of the PHS Act which 
specifies certain requirements that apply to voluntary submissions of 
clinical trial information for two types of clinical trials for which 
submission of information is not otherwise required, as follows: (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 section 402(j)(2)(C) of 
the PHS Act or proposed 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).
    If a responsible party wishes to submit clinical trial information 
voluntarily for one of these two types of clinical trials, the 
responsible party must: (1) Submit complete registration information as 
specified in proposed Sec.  11.60(a)(2)(i)(A) or complete results 
information as specified in proposed Sec.  11.60(a)(2)(i)(B) for the 
voluntarily-submitted clinical trial; and (2) submit 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 [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.'' (See section 402(j)(4)(A) of the PHS 
Act.) While the Agency encourages submissions of complete registration 
information and complete 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 conditions 
before deciding whether to register a clinical trial or submit results 
information voluntarily.
    In considering which clinical trials fall under this provision, we 
believe that section 402(j)(4)(A) of the PHS Act should be interpreted 
in a way that is consistent with the scope of FDA's regulatory 
authorities and the scope of this proposed regulation. Hence, we 
interpret the phrase ``a clinical trial that is not an applicable 
clinical trial,'' in section 402(j)(4)(A) of the PHS Act, to be limited 
to a clinical trial of an FDA-regulated drug (including biological 
product) or device that is not an applicable clinical trial. We do not 
interpret this phrase to include clinical trials of other types of 
interventions, whether regulated by FDA or not, that would not meet the 
definition of an applicable clinical trial. Thus, proposed Sec.  11.60 
would apply, for example, to a phase 1 trial of an FDA-regulated drug, 
or to a clinical trial that evaluates the feasibility of an FDA-
regulated device, but not to a clinical trial that studies only 
behavioral interventions that are not drugs, biological products, or 
devices. In addition, 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. This would mean 
that proposed Sec.  11.60, and not proposed subparts B and/or C, would 
apply to submissions of clinical trial information for such applicable 
clinical trials.
    In considering the information that must be submitted to 
ClinicalTrials.gov for a voluntarily-submitted clinical trial under 
section 402(j)(4)(A) of the PHS Act, we interpret section 402(j)(4)(A) 
of the PHS Act as permitting a responsible party to submit voluntarily 
registration information for a clinical trial without having to submit 
results information. Section 402(j)(4)(A) of the PHS Act uses the term 
``or'' when referring to the submission of ``clinical trial 
registration information described in paragraph (2) [clinical trial 
registration information] or (3) [clinical trial results information]'' 
[emphasis added]. While we encourage those who register clinical trials 
voluntarily to also submit results information voluntarily, we see 
value in having voluntarily submitted registration information in 
ClinicalTrials.gov even if associated results information is not 
submitted. Clinical trial registration information can, for example, 
assist with recruitment and indicate the existence of a clinical trial. 
Similarly, we believe section 402(j)(4)(A) of the PHS Act permits a 
responsible party to submit voluntarily results information without 
having to have previously submitted registration information. Hence, 
proposed Sec.  11.60(a)(2)(i) expressly permits the submission of 
registration information, results information, or both.
    In specifying requirements for the voluntary submission of results 
information, proposed Sec.  11.60(a)(2)(i)(B) requires the submission 
of the results information set forth at proposed Sec.  11.48(a). 
However, we believe that certain descriptive information ordinarily 
submitted at the time of registration would be necessary to enhance 
access to results information, render it meaningful to the public, and 
demonstrate that the clinical trial is not an applicable clinical trial 
subject to proposed Sec. Sec.  11.22 and 11.42. Thus, we propose that a 
responsible party who voluntarily submits only results information for 
a clinical trial under proposed Sec.  11.60(a)(2)(i)(B), must submit 
the data elements set forth at proposed Sec.  11.60(a)(2)(i)(B), in 
addition to the data elements set forth at proposed Sec.  11.48(a), as 
clinical trial results information.
    Sections III.C.5(b) and IV.C.4(f) of this preamble describe our 
rationale for requiring much of the descriptive information set forth 
at proposed Sec.  11.60(a)(2)(i)(B). Those sections of the preamble, 
however, address only those data elements that we believe are necessary 
to enhance access to and understanding the results of a clinical trial 
of a device for which complete registration information has been 
previously submitted to ClinicalTrials.gov. We believe that

[[Page 69648]]

additional descriptive information is necessary to enhance access to 
and understanding of the results of a clinical trial of a drug (or a 
biological product): ``Study Phase'' is necessary to enable a user to 
understand the relative stage of development of an experimental drug 
(including biological product) studied in a clinical trial; and 
``Availability of Expanded Access'' is necessary to provide patients 
with access to information about the availability of the drug to those 
who do not qualify for enrollment in the clinical trial.
    In addition, we believe that several other data elements must be 
submitted with voluntarily submitted results information in order for 
users of the data bank and/or the Agency to confirm that a clinical 
trial for which information is submitted voluntarily is not an 
applicable clinical trial subject to mandatory registration or results 
submission under this part. Specifically, we believe that the following 
data elements are necessary: ``Single Arm Control?,'' ``Whether the 
Study is a Pediatric Postmarket Surveillance of a Device,'' ``Product 
Manufactured in 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, we propose to use our authority under section 
402(j)(3)(D)(iii)(IV) of the PHS Act to interpret results information 
to include the data elements under proposed Sec.  11.60(a)(2)(i)(B) in 
addition to the data elements set forth at proposed Sec.  11.48(a).
    As stated, section 402(j)(4)(A) of the PHS Act specifies that 
voluntary submissions of information must consist of ``complete'' 
clinical trial registration or results information. We interpret the 
reference to ``complete'' in section 402(j)(4)(A) to mean that as a 
condition of voluntary submission under section 402(j)(4)(A) and 
proposed Sec.  11.60, responsible parties must submit all registration 
information or results information data elements specified in proposed 
Sec. Sec.  11.60(a)(2)(i)(A) or (B), as applicable. We note, however, 
that we propose in Sec.  11.60(a)(2)(iv)(A) that a responsible party 
may submit results information for a voluntarily-submitted clinical 
trial once results information is available for the primary outcome 
measure(s). If data collection for the secondary outcome measure(s) for 
such clinical trials is not completed by the completion date of the 
voluntarily-submitted clinical trial, then results information for the 
secondary outcome measure(s) must be submitted by the later of the date 
that the 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 measure(s), whether the 
clinical trial was concluded according to the pre-specified protocol or 
was terminated.
    Section 402(j)(4)(A) of the PHS Act also specifies that a 
responsible party who voluntarily registers or submits results 
information for a clinical trial must also submit 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.'' We believe 
this condition of section 402(j)(4)(A) of the PHS Act may be intended 
to help prevent selective voluntary submissions, for example, if a 
responsible party voluntarily submitted clinical trial information only 
from clinical trials that showed positive results for a particular 
product, but not from clinical trials that showed negative or uncertain 
results for the same product. Voluntary submissions under section 
402(j)(4)(A) of the PHS Act only trigger the required submission of 
clinical trial information for clinical trials that are applicable 
clinical trials (e.g., not phase 1 trials of a drug or small 
feasibility studies of a device) that were not required to be submitted 
to ClinicalTrials.gov under sections 402(i) or 402(j) of the PHS Act 
(e.g., those applicable clinical trials that were initiated on or 
before September 27, 2007, and reached their completion date prior to 
December 26, 2007).
    One challenge in implementing this provision of section 
402(j)(4)(A) of the PHS Act is that a responsible party who voluntarily 
submits clinical trial information about a clinical trial may not know 
at the time the voluntary submission is made which applicable clinical 
trials subsequently will be required to be included in a marketing 
application or premarket notification to FDA for the product for the 
use studied in the voluntarily-submitted clinical trial. Such a 
marketing application could be submitted many years after the 
completion date of the voluntarily-submitted clinical trial. Another 
challenge is that the responsible party for the voluntarily-submitted 
clinical trial might not be the responsible party for some or any of 
the applicable clinical trial(s) for which the submission of clinical 
trial information is triggered by the voluntary submission. As such, 
the responsible party voluntarily submitting clinical trial information 
for a clinical trial under section 402(j)(4)(A) of the PHS Act may not 
be aware of the triggered applicable clinical trial(s) and/or may not 
have access to the clinical trial information required to be submitted 
for such trials. In addition, a manufacturer who ultimately submits a 
marketing application or premarket notification may not be the 
responsible party for all of the applicable clinical trials that are 
required to be included in the marketing application or premarket 
notification, and might not have access to clinical trial information 
for those clinical trials.
    To address these concerns, we propose in Sec.  11.60(a)(2)(ii) to 
require a submission of clinical trial information for any triggered 
trials (i.e., for applicable clinical trials required to be included in 
a marketing application or premarket notification to FDA for approval, 
licensure, or clearance of the drug or device and that study the same 
use studied in the voluntarily-submitted clinical trial) only when the 
responsible party for the voluntarily-submitted clinical trial is also 
the manufacturer submitting the marketing application or premarket 
notification. This approach would reduce the likelihood of a 
responsible party making selective voluntarily submissions, consistent 
with our understanding of the intent of section 402(j)(4)(A) of the PHS 
Act, while ensuring that a responsible party would not be required to 
submit clinical trial information for a triggered applicable clinical 
trial for which he or she is not also the responsible party and does 
not have access to the relevant data. This approach also would avoid a 
situation in which one responsible party would be unaware that its 
clinical trials are subject to the requirements of section 402(j)(4)(A) 
of the PHS Act by virtue of a previous voluntary submission of clinical 
trial information made by another responsible party. We request public 
comment on our proposed approach in Sec.  11.60(a)(2)(ii).
    Section 402(j)(4)(A) of the PHS Act does not specify when 
information from each triggered applicable clinical trial must be 
submitted to ClinicalTrials.gov. At the time clinical trial information 
is submitted for a voluntarily-submitted clinical trial, a marketing 
application or premarket notification that includes such triggered 
trials may or may not have been submitted to FDA; thus, it may not be 
apparent at the time the voluntarily-submitted clinical trial is 
submitted to ClinicalTrials.gov which applicable clinical trials are 
triggered

[[Page 69649]]

under section 402(j)(4)(A) of the PHS Act. Therefore, rather than 
requiring information on the triggered applicable clinical trials to be 
submitted at the time the clinical trial information is submitted for 
the voluntarily-submitted clinical trial, we propose in Sec.  
11.60(a)(2)(iv)(B), that the information be submitted not later than 
the date on which the application or premarket notification is 
submitted to FDA or the date on which clinical trial information is 
submitted for the voluntarily-submitted clinical trial to 
ClinicalTrials.gov, whichever is later. This approach would prevent a 
responsible party from having to submit information for a clinical 
trial that is not subsequently included in the marketing application or 
premarket notification. We note that, in many cases, we expect that a 
triggered applicable clinical trial will have reached its completion 
date by the time clinical trial information for the voluntarily-
submitted clinical trial is submitted because, given the scope of 
applicable clinical trials subject to 402(j) or the PHS Act, generally, 
most or all applicable clinical trials for which submission would be 
triggered by a voluntary submission would have been initiated on or 
before September 27, 2007, and reached their completion dates prior to 
December 26, 2007.
    Proposed Sec.  11.60(a)(2)(iii) specifies which clinical trial 
information must be submitted for a triggered applicable clinical 
trial. Section 402(j)(4)(A) requires that the responsible party submit 
``clinical trial information'' for all triggered applicable clinical 
trials. Because section 402(j)(1)(A)(iv) of the PHS Act defines 
``clinical trial information'' to mean ``. . . those data elements that 
the responsible party is required to submit under paragraph (2) 
[clinical trial registration information] or under paragraph (3) 
[clinical trial results information],'' the information required to be 
submitted for a triggered applicable clinical trial could include 
registration information, results information, or both. The 
construction of this requirement mirrors that in section 402(j)(4)(A) 
of the PHS Act, which specifies that clinical trial information that is 
voluntarily submitted to ClinicalTrials.gov may consist of registration 
information or results information. Hence, we propose that the type(s) 
of clinical trial information required to be submitted for a triggered 
applicable clinical trial be, at minimum, the same as that for the 
voluntarily-submitted clinical trial. In other words, if a responsible 
party voluntarily submits registration information for a clinical trial 
pursuant to section 402(j)(4)(A) of the PHS Act and proposed Sec.  
11.60(a), the responsible party must submit complete registration 
information specified under proposed Sec.  11.28(a) for any triggered 
applicable clinical trial(s). Likewise, if a responsible party 
voluntarily submits results information for a clinical trial pursuant 
to section 402(j)(4)(A) of the PHS Act and proposed Sec.  11.60(a), 
then the responsible party must submit complete results information 
specified under proposed Sec. Sec.  11.60(a)(2)(i)(B) for any triggered 
applicable clinical trial(s). Because the submission of clinical trial 
information for a triggered applicable clinical trial is a condition of 
voluntary registration under section 402(j)(4)(A) of the PHS Act, the 
Agency does not propose to treat the submission of such information as 
a voluntary submission under section 402(j)(4)(A) or proposed Sec.  
11.60(a)(2)(ii) that itself could trigger the submission of clinical 
trial information for other applicable clinical trials. However, as 
indicated in proposed Sec.  11.60(a)(2)(v), responsible parties who 
voluntarily submit clinical trial information to ClinicalTrials.gov 
would be required to update submitted information, including 
information submitted for triggered trials, in accordance with proposed 
Sec.  11.64. As noted in section IV.C.5 of this preamble, clinical 
trial information submitted under proposed Sec.  11.60 will be posted 
on ClinicalTrials.gov as soon as practicable after it has been 
submitted and reviewed as part of our quality review procedures. 
Corrections would be required, in accordance with proposed Sec.  11.66.
    We clarify that because section 402(j)(4)(A) of the PHS Act has 
been in effect since September 27, 2007, any voluntarily-submitted 
clinical trial submitted on or after September 27, 2007, is subject to 
the requirements of section 402(j)(4)(A) of the PHS Act. We interpret 
the relevant marketing application or premarket notification under 
section 402(j)(4)(A) of the PHS Act to be any marketing application or 
premarket notification submitted to FDA on or after September 27, 2007. 
However, we propose that the requirements of proposed Sec.  11.60 apply 
only to clinical trial information submitted to ClinicalTrials.gov on 
or after the effective date of this rule. We do not propose to impose 
the requirements of proposed Sec.  11.60 with respect to any 
voluntarily-submitted clinical trial or any triggered applicable 
clinical trial that was submitted under section 402(j)(4)(A) of the PHS 
Act, prior to the effective date. The Agency is aware that many 
clinical trials were registered on a voluntary basis at 
ClinicalTrials.gov before publication of this proposed rule in an 
effort to comply with other policies (e.g., the policy of the ICMJE), 
to enhance recruitment, or to enhance transparency related to such 
clinical trials. To the extent that a responsible party complied with 
section 402(j)(4)(A) of the PHS Act prior to the effective date of the 
final rule, we do not believe it is reasonable to require the 
responsible party to comply with the requirements of proposed Sec.  
11.60.
    Proposed Sec.  11.60(b) specifies the text of ``a statement to 
accompany the entry for an applicable clinical trial when the primary 
and secondary outcome measures for such clinical trial are submitted 
under [section 402(j)(4)(A) of the PHS Act] after the date specified 
for the submission of such information in paragraph (2)(C) [clinical 
trial registration information submission].'' (See section 
402(j)(3)(D)(v)(V) of the PHS Act.) Because primary and secondary 
outcome measures are data elements under both clinical trial 
registration and results information (See sections 
402(j)(2)(A)(ii)(I)(ll) and (3)(C)(ii).), we interpret section 
402(j)(3)(D)(v)(V) of the PHS Act to require submissions of 
registration information or results information under section 
402(j)(4)(A) of the PHS Act and/or proposed Sec.  11.60(a) for 
applicable clinical trials to be accompanied by a statement to clarify 
that the submission was not subject to the deadlines imposed by section 
402(j) of the PHS Act for 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 proposed Sec.  11.60(a). 
Accordingly, the proposed statement is as follows: ``Clinical trial 
information for this applicable clinical trial was submitted under 
section 402(j)(4)(A) of the PHS Act and 42 CFR 11.60 and is not subject 
to the deadlines established by sections 402(j)(2) or (3) of the Public 
Health Service Act or 42 CFR 11.24 or 11.44.''
2. 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--Sec.  11.62
    Proposed Sec.  11.62 implements the requirement in section 
402(j)(4)(B) of the PHS Act for 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.

[[Page 69650]]

Section 402(j)(4)(B)(i) of the PHS Act specifically authorizes the 
Secretary to ``require by notification'' 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 of NIH (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 submission under section 
402(j)(3)(E)(iii) of the PHS Act. (See section 402(j)(4)(B)(i)(II) of 
the PHS Act.) Proposed Sec.  11.62(a) implements 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). We invite 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.
    Proposed Sec.  11.62(b) implements 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 
this 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 such 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;'' or (2) ``an applicable 
clinical trial that is described by both by paragraph (2)(C) and 
paragraph (3)(D)(ii)(II)) [sic].'' As explained in section III.D of 
this preamble, we interpret the approval status of a product studied in 
an applicable clinical trial (i.e., either ``unapproved, unlicensed, or 
uncleared'' or ``approved, licensed, or cleared'') to be the approval 
status of the product on any given date. In this context, we interpret 
the approval status of the product to be the approval status 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 proposed Sec.  11.62. The clinical 
trials specified in (1) would consist of applicable clinical trials of 
approved, licensed, or cleared drugs (including biological products) or 
devices that reached their completion dates on or after September 27, 
1997. We note that this set of clinical trials would include applicable 
clinical trials that reach their completion dates on or after the date 
of enactment of FDAAA, many of which already would be subject to the 
registration and results 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 (2) would consist of applicable clinical trials that are 
required to register at ClinicalTrials.gov pursuant to section 
402(j)(2)(C) of the PHS Act and proposed Sec.  11.22(a) of this part 
and that study drugs (including biological products) or devices that 
are unapproved, unlicensed, or uncleared by 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 are not required to submit clinical trial results information to 
ClinicalTrials.gov under section 402(j) of the PHS Act because they are 
not subject to the results provision in section 402(j)(3)(C) of the PHS 
Act. However, many of these applicable clinical trials would be 
required to submit results information under this proposed rule. (See, 
e.g., proposed Sec.  11.42 and the discussion of effective date 
implementation in section III.D of this preamble.)
    Proposed Sec.  11.62(c) specifies which information must be 
submitted to ClinicalTrials.gov and the timelines for submitting such 
information pursuant to a notification from the Director under section 
402(j)(4)(B)(i) of the PHS Act. In general, we interpret the references 
to ``clinical trial information'' in section 402(j)(4)(B)(i) of the PHS 
Act 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 enumerated in proposed 
Sec. Sec.  11.28(a) and 11.48(a). Consistent with section 
402(j)(4)(B)(i)(II) of the PHS Act, such information generally must be 
submitted ``not later than 30 days after the date specified by the 
[Director] in the notification.'' We are interpreting ``the date 
specified . . . in the notification'' to mean the date established by 
the Director for submission of clinical trial information under 
proposed Sec.  11.62. We note that section 402(j)(4)(B)(i)(II) of the 
PHS Act permits an exception to the submission deadline if a 
certification for delayed results submission is submitted not later 
than 30 days after the submission date specified by the Director in the 
notification and in accordance with section 402(j)(3)(E)(iii) of the 
PHS Act. Because a certification under section 402(j)(3)(E)(iii) of the 
PHS Act would delay only the submission of results information, we 
propose that if the responsible party has submitted such a 
certification, only the submission of results information may be 
delayed. Accordingly, if a responsible party for an applicable clinical 
trial subject to proposed Sec.  11.62 submits a certification under 
section 402(j)(3)(E)(iii) of the PHS Act 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 proposed Sec. Sec.  11.44(b) or (c).
    To clarify the submission requirement in those situations in which 
registration information was submitted to ClinicalTrials.gov before a 
notification under section 402(j)(4)(B)(i)(I) of the PHS Act was sent 
to the responsible party, we indicate in proposed Sec.  11.62(c)(3) 
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, we propose that the 
requirements of proposed Sec.  11.64 would apply to clinical trial 
information submitted pursuant to proposed Sec.  11.62.
    All clinical trial information submitted to ClinicalTrials.gov 
under proposed Sec.  11.62 would be subject to the quality review 
procedures described in section III.C.12 of this preamble. We would 
intend to post such information as soon as practicable after it has 
completed quality review. This timeline for posting would apply to all 
clinical trial information submitted under

[[Page 69651]]

proposed Sec.  11.62, including registration information for an 
applicable clinical trial of a device that has not previously been 
approved or cleared by 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 in 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 
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. We therefore believe 
that registration information for all applicable clinical trials 
subject to section 402(j)(4)(B) of the PHS Act may be posted as soon as 
practicable after it has completed quality review, regardless of the 
approval, licensure, or clearance status of the devices studied.
    We do not interpret the waiver provisions in section 402(j)(3)(H) 
of the PHS Act or proposed Sec.  11.54 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 section 
402(j)(4)(B) of the PHS Act or proposed Sec.  11.62. The waiver 
provisions in section 402(j)(3)(H) of the PHS Act and proposed Sec.  
11.54 apply only to submissions of results information that would be 
required by section 402(j)(3) of the PHS Act or proposed subpart C. We 
invite public comment on this proposed interpretation.
3. When must clinical trial information submitted to ClinicalTrials.gov 
be updated?--Sec.  11.64
    Proposed Sec.  11.64 establishes requirements for updating clinical 
trial information that has been submitted to ClinicalTrials.gov. 
Section 402(j)(4)(C)(i) of the PHS Act requires responsible parties for 
applicable clinical trials to submit updates to ClinicalTrials.gov to 
reflect changes to previously submitted registration information. 
Section 402(j)(4)(C)(i)(I) of the PHS Act provides that, in general, 
updates must be made ``not less than once every 12 months, unless there 
were no changes to the clinical trial information during the preceding 
12-month period.'' Section 402(j)(4)(C)(i)(III) of the PHS Act 
specifies that the responsible party must update recruitment status not 
later than 30 days after a change in the recruitment status of a 
registered applicable clinical trial, and section 402(j)(4)(C)(i)(IV) 
of the PHS Act specifies that the responsible party must update the 
completion date not later than 30 days after the completion date of the 
applicable clinical trial. We believe the shorter update time frames 
specified for these two elements of registration information in section 
402(j)(4)(C) of the PHS Act are intended to help ensure that 
information in ClinicalTrials.gov of particular importance to 
prospective human subjects is updated in a timely fashion. Section 
402(j)(4)(C)(i)(II) of the PHS Act indicates updates to submitted 
clinical trial information ``shall include identification of the dates 
of any such changes.''
    In addition, section 402(j)(3)(D)(v)(IV) of the PHS Act requires 
the Secretary to establish, by regulation, ``the appropriate timing and 
requirements for updates of clinical trial information.'' Pursuant to 
this authority, we propose to modify the updating requirements under 
section 402(j)(4)(C)(i) of the PHS Act. First, we propose to require 
updates for all clinical trials that are subject to section 402(j) of 
the PHS Act and/or this proposed rule with a record in 
ClinicalTrials.gov, not just the applicable clinical trials that are 
specified in section 402(j)(4)(C)(i) of the PHS Act. This would include 
those clinical trials for which clinical trial information was 
voluntarily submitted under section 402(j)(4)(A) of the PHS Act and/or 
proposed Sec.  11.60 and those for which clinical trial information was 
required to be submitted to protect the public health under section 
402(j)(4)(B) of the PHS Act and/or proposed Sec.  11.62. Second, we 
propose to require updates for all clinical trial information submitted 
to ClinicalTrials.gov. This would include the registration information 
that is referenced in section 402(j)(4)(C)(i) of the PHS Act, the 
additional registration data elements, and expanded access record 
information proposed in Sec.  11.28, and results information.
    Proposed Sec.  11.64(a)(1) establishes 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. We emphasize that this requirement to update 
clinical trial information not less than once every 12 months includes 
a requirement to update the estimated Completion Date data element, 
unless there have been no changes in the preceding 12 months. 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 recommend that the complete clinical 
trial record in 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)(2) specifies 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, submitted clinical trial 
information would continue to be subject to the corrections provisions 
in proposed Sec.  11.66, and responsible parties would be required to 
submit corrected information when the responsible party becomes aware 
of any errors or needed corrections in the clinical trial information.
    Proposed Sec.  11.64(b) establishes requirements for a responsible 
party to update certain clinical trial information more rapidly after a 
change in the status or conduct of a clinical trial or pediatric 
postmarket surveillance of a device. We recognize 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 section 402(j) of the PHS Act requires 
more rapid changes of some elements, and we believe that changes to 
other data elements are sufficiently time-sensitive to require updates 
more rapidly than once every 12 months.
    Proposed Sec.  11.64(b)(1) would require that the following data 
elements be updated not less than 30 days after a change has occurred:
    (1) Study Start Date. We propose that the Study Start Date data 
element be updated not later than 30 calendar days after the first 
human subject is enrolled in the clinical trial. This requirement would 
apply to clinical trials for which an estimated study start date was 
provided at the time of registration, rather than an actual study start 
date, i.e., clinical trials that were registered prior to enrollment of 
the first human subject. The update would ensure that potential human 
subjects know in a timely fashion that recruitment has begun. It also 
would ensure that the record reflects the actual start date, as opposed 
to an estimated start date, and it would provide a mechanism to 
demonstrate whether a clinical trial had

[[Page 69652]]

been registered not later than 21 days after enrollment of the first 
subject.
    (2) Intervention Name(s). We propose that the Intervention Name(s) 
data element 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 would 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. We propose that the clinical 
trial information submitted under the Availability of Expanded Access 
data element in proposed Sec.  11.10(b)(29) be updated not later than 
30 calendar days after an expanded access program is initiated or 
terminated, or an NCT number is assigned to an expanded access record. 
This data element informs patients whether access to a drug to treat 
serious or life-threatening diseases or conditions is available outside 
of the clinical trial. Expanded access may not be available at the time 
a clinical trial is registered, and an expanded access program may be 
terminated on a date other than the completion date of the clinical 
trial. We therefore propose three specific update requirements:
    First, for clinical trials registered on or after the effective 
date of this regulation, we propose that when an expanded access 
program for a particular drug is implemented after the clinical 
trial(s) of that drug is (are) registered, the responsible party must 
change the indication in proposed Sec.  11.10(b)(29)(i) of whether 
there is expanded access to the drug not later than 30 calendar days 
after expanded access becomes available.
    Second, we propose that not later than 30 calendar days after the 
initiation of the expanded access program, the responsible party must 
create an expanded access record by submitting the data elements 
required under proposed Sec.  11.28(c), unless an expanded access 
record for the drug already was already created by another responsible 
party. The responsible party would be 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. In the event that there are multiple 
clinical trials of the same drug that is available through an expanded 
access program, the responsible party who first changes the 
Availability of Expanded Access data element from ``yes'' to ``no'' 
would be required to create the expanded access record under proposed 
Sec.  11.28(c); once the NCT number is assigned, responsible parties 
for other clinical trials of that drug would be required to update 
their clinical trial records by changing the Availability of Expanded 
Access data element and providing the NCT number. We would expect the 
sponsor to inform these relevant responsible parties that an expanded 
access record has been created and provide them with the NCT number.
    Third, we propose that if expanded access is terminated, a 
responsible party must update the Availability of Expanded Access data 
element not later than 30 calendar days after termination of the 
program. We note that the expanded access record, including the NCT 
number, would remain available in ClinicalTrials.gov as archived 
information. We would expect the sponsor to inform relevant responsible 
parties that the drug is no longer available through an expanded access 
program so that the responsible parties may update their clinical trial 
records accordingly. To help sponsors and responsible parties in this 
process, we could consider developing procedures to send electronic 
notification to responsible parties of all applicable clinical trials 
that list the NCT number of the expanded access record of the 
discontinued terminated expanded access program.
    Consistent with the discussion in the Effective Date/Compliance 
Date in section III.D of this preamble, the responsible party for an 
applicable clinical trial that is registered under section 402(j) of 
the PHS Act and reaches its completion date prior to the effective date 
of this regulation would be required to update the expanded access 
program information required under section 402(j)(2)(A)(ii)(II)(gg) of 
the PHS Act not later than 12 months after a change in the availability 
of expanded access, as specified in the updating requirement in section 
402(j)(4)(C) of the PHS Act. The responsible party of such a clinical 
trial would not be subject to the requirement to submit the expanded 
access record data elements listed in proposed Sec.  11.28(c) or to 
update them as specified in proposed Sec.  11.64. If a responsible 
party registers an applicable drug clinical trial prior to the 
effective date of the regulation, however, and such trial is ongoing 
after the effective date of the regulation, the responsible party would 
need to submit the necessary expanded access program information by the 
compliance date for the clinical trial registration information in the 
databank to comply with proposed Sec.  11.28(c). In addition, the 
responsible party would be subject to the requirement to provide 
updates to expanded access program information within 30 calendar days 
of any change, consistent with proposed Sec.  11.64(b).
    (4) Expanded Access Status. We propose that Expanded Access Status, 
under Sec.  11.28(c)(2)(iv), must be updated not later than 30 calendar 
days after a change in the status of an expanded access program, 
whether or not access to the investigational drug or device is 
currently available. This data element plays a role in expanded access 
programs that is similar to the role of Overall Recruitment Status in 
applicable clinical trials, indicating whether a particular expanded 
access program is still open to participants. We believe that a timely 
update of any change in status is important to have reflected in the 
data bank and is consistent with the requirement in section 
402(j)(4)(C)(III). Note that we propose to apply this update 
requirement to expanded access records that are submitted voluntarily 
(e.g., for an expanded access record submitted for an applicable device 
clinical trial) as well as to those that are required to be submitted 
under this part.
    (5) Overall Recruitment Status. We propose that the Overall 
Recruitment Status data element be updated not later than 30 days after 
a change in the overall recruitment status of the clinical trial. This 
proposal is consistent with section 402(j)(4)(C)(i)(III) of the PHS 
Act. We believe 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, we propose that 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. We believe that 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. We propose to allow a responsible party 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. We 
believe such information is consistent with the statutory objective in 
section 402(j)(2)(A)(i) of the PHS Act to enable

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users ``to track subsequent progress of clinical trials.''
    Similarly, we propose that if Overall Recruitment Status is updated 
to ``terminated'' or ``active, not recruiting,'' the responsible party 
also must update the Actual Enrollment data element. In either of these 
situations, recruitment of human subjects is complete. As explained in 
more detail in section IV.B.4 of this preamble, submission of actual 
enrollment information will provide users of ClinicalTrials.gov with a 
mechanism for tracking the progress of registered clinical trials by 
enabling comparison of the actual enrollment information with the 
target or estimated enrollment information. More rapid updating is 
expected to contribute to more accurate reporting of the Actual 
Enrollment information and to permit users of ClinicalTrials.gov to 
know more quickly whether the clinical trial achieved its target 
enrollment.
    (6) Individual Site Status. We propose that Individual Site Status 
be updated not later than 30 calendar days after a change in status of 
any individual site. We believe this proposal is consistent with the 
requirement in section 402(j)(4)(C)(III) of the PHS Act. It also 
supports the purpose of ClinicalTrials.gov to ``enhance patient 
enrollment'' (See section 402(j)(2)(A)(I) of the PHS Act) 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. We propose that 
Human Subjects Protection Review Board Status 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, we believe it 
must be updated in a timely fashion.
    (8) Completion Date. Pursuant to section 402(j)(4)(C)(i)(IV) of the 
PHS Act, proposed Sec.  11.64(b) specifies that the Completion Date 
data element must be updated not later than 30 calendar days after a 
clinical trial reaches its actual completion date.
    (9) Responsible Party, by Official Title. We propose the 
Responsible Party, by Official Title data element be updated not later 
than 30 calendar days after a change in either the name of the 
responsible party of in the responsible party's official title. We 
believe this update is necessary to enable NIH and other users of the 
data bank to accurately identify the responsible party for the clinical 
trial.
    (10) Responsible Party Contact Information. Consistent with (9) 
above, we propose that Responsible Party Contact Information be updated 
not later than 30 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, we consider it 
essential 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 would ensure that the Agency 
has contact information for the appropriate person responsible for 
submitting clinical trial information about the applicable clinical 
trial or clinical trial.
    In addition, we propose in Sec.  11.64(b)(2) that responsible 
parties be required to update the U.S. FDA Approval, Licensure, or 
Clearance Status data element not later than 15 calendar days after a 
change in the approval, licensure, or clearance status of the product 
under study. Products may appear in the market place or manufacturers 
may announce the pending availability of a product soon after they 
receive FDA approval, licensure, or clearance. We believe that a prompt 
update to the information in ClinicalTrials.gov is necessary to help 
avoid confusing users who seek information about a drug or device in 
ClinicalTrials.gov after finding the product in the market place (e.g., 
after being prescribed a new drug) or finding other public information 
about it (e.g., a news release announcing a new product). In addition, 
a shorter update period for this data element would enable users to 
better anticipate when clinical trial results information would be due 
for an applicable clinical trial. Furthermore, a change in the approval 
or clearance status of a device can trigger a requirement for the 
Agency to post previously-submitted clinical trial registration 
information within 30 days of the change in status. Updating the U.S. 
FDA Approval, Licensure, or Clearance Status data element not later 
than 15 calendar days would provide the Agency timely notice that it 
must post publicly clinical trial registration information.
    In Sec.  11.64(b)(3) we propose that relevant clinical trial 
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. We believe that protocol amendments that are 
communicated to enrolled participants could be important to those 
considering enrollment and should be communicated quickly through an 
update to the record in ClinicalTrials.gov. Rapid updating of this 
information would be consistent with the stated purpose of 
ClinicalTrials.gov to ``enhance patient enrollment and provide a 
mechanism to track subsequent progress of clinical trials.'' (See 
section 402(j)(2)(A) of the PHS Act.) If such key changes were not 
reflected in the record in ClinicalTrials.gov for as long as 12 months 
after the change, the value of ClinicalTrials.gov as a source of 
reliable, accurate information for the public and potential 
participants in clinical trials would be compromised. We recognize that 
other thresholds could be used to determine which protocol changes are 
significant enough to warrant 30-day updating of affected clinical 
trial information. For example, updating of relevant data elements 
could also be required any time a protocol amendment is reported to a 
human subjects protection review board. We invite public comments on 
our proposed approach and alternatives.
    In Sec.  11.64(b)(4), we propose that the Record Verification Date 
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 section IV.B.4 of this preamble, a responsible 
party would be required to update the Record Verification Date if he or 
she examines the complete set of submitted clinical trial information 
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 would 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 would not be required to update the Record Verification date if 
he or she submits updates to one or more data elements without 
reviewing the

[[Page 69654]]

accuracy of the rest of the record. This proposal would not require a 
responsible party to review records more frequently or regularly than 
would be needed in order to update submitted information as otherwise 
required by proposed Sec.  11.64, but it would require that the Record 
Verification Date be updated if the complete record were reviewed for 
accuracy during such an update. Doing so would indicate to users of 
ClinicalTrials.gov the currency of the information and provide an 
additional assurance that it is not out-of-date.
    In addition, we propose in Sec.  11.64(c) 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). 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 would then 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 and internally consistent.
    We note that the updating requirements under proposed Sec.  11.64 
would be prompted by changes in the clinical trial and not by changes 
in the information submission requirements for ClinicalTrials.gov or 
the form and manner in which data must be submitted to 
ClinicalTrials.gov. For example, if clinical trial results information 
were submitted prior to the effective date of the rule consistent with 
the requirements of section 402(j)(3)(C) of the PHS Act, the 
responsible party would not be required as a result of the updating 
requirements to submit clinical trial results information for the 
expanded results data elements required under proposed Sec.  11.48. 
Similarly, if the Agency were to make administrative changes to the 
manner in which clinical trial information is submitted to 
ClinicalTrials.gov after the responsible party has submitted clinical 
trial information in accordance with section 402(j) of this PHS Act and 
this proposed part, the Agency's revisions to ClinicalTrials.gov would 
not themselves give rise to a requirement that the responsible party 
update the 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 would be 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 they could do so 
voluntarily. However, if a responsible party makes a required update to 
previously submitted clinical trial information, e.g., to reflect a 
change in the conduct or progress of a clinical trial, he or she would 
be required to submit the updated information in the form and manner 
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 
would be required to select from the new set of options.
    Updates to clinical trial registration information and clinical 
trial results information will be posted in accordance with proposed 
Sec. Sec.  11.35 and 11.52, respectively. Previously submitted clinical 
trial information will remain publicly available through the 
ClinicalTrials.gov archive. See proposed Sec.  11.64(d)(1) and (2).
4. What are the requirements for corrections of clinical trial 
information?--Sec.  11.66
    Proposed Sec.  11.66 sets out requirements for responsible parties 
to correct clinical trial information submitted to ClinicalTrials.gov. 
This would include 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. We consider corrections of information to be 
different from updates to information, as described in proposed Sec.  
11.64. In our view, updates modify clinical trial information to 
reflect changes in the status or conduct of an ongoing clinical trial 
or the associated analysis. Corrections revise submitted clinical trial 
information that is found to be false, invalid, incorrect, 
inconsistent, or incomplete.
    Proposed Sec.  11.66 addresses several types of corrections. First, 
Sec.  11.66(a) addresses corrections of errors, or misstatement of 
facts that are found to be incorrect. Errors include, but are not 
limited to: Inadvertent, typographical errors, such as transpositions 
of numbers or characters; or inadvertent omissions of data, such as 
omission of one component of set of participant exclusion criteria. 
They also include submitted values that are demonstrably wrong, such as 
an outcome measure indicating more than 24 hours per day of a given 
value. We expect to detect some such errors during the quality review 
procedures described in section III.C.12 of this preamble and may 
identify others in the course of operating the data bank. We intend to 
inform responsible parties of errors we identify so that they may be 
corrected. Responsible parties may also detect errors when reviewing 
submitted information, or they may be alerted to potential errors by 
other parties. As indicated in proposed Sec.  11.66(a), we would 
require responsible parties to correct identified errors not later than 
15 calendar days after becoming aware of them, whether they identify 
the errors themselves, or whether we inform them of errors we have 
detected, such as through our quality assurance procedures, whichever 
is earlier.
    Second, Sec.  11.66(b) addresses corrections to information that is 
falsified or based on falsified information. Consistent with FDA's 
proposed use of the term ``falsification of data'', we consider 
``information that is falsified or based on falsified information'' to 
mean information that was created, altered, recorded, or omitted in 
such a way that the data do not represent what actually occurred in the 
clinical trial. (See 75 FR 7414, Feb. 19, 2010.) Examples of 
information that are falsified or based on falsified information 
include, but are not limited to, the following (based on examples in 75 
FR 7414, Feb. 19, 2010):
    (1) Created information that was never obtained (e.g., the values 
submitted for a primary outcome measure were made up or based on 
participant-level data that were made up; the actual enrollment value 
submitted includes subjects who did not exist or were not actually 
enrolled in the clinical trial).
    (2) Information that was altered by replacing original information 
with something different that does not accurately reflect study conduct 
or results (e.g., the value submitted for a baseline characteristic is 
changed to a less extreme deviation from normal or is based on 
individual measures of the baseline characteristic that were changed be 
less extreme deviations from normal).
    (3) Information that was recorded or obtained from a human subject 
in a way that does not accurately reflect the study protocol (e.g., a 
submitted outcome measure is based on measurements from subjects who 
were given a different dose

[[Page 69655]]

of an experimental drug than that specified in the protocol and the 
ClinicalTrials.gov record).
    (4) Omitted information that was obtained and would be appropriate 
for submission based on study design and conduct (e.g., values are not 
submitted for a secondary outcome measure for which data were collected 
during the clinical trial or the values submitted for the secondary 
outcome measure do not include outcomes that were measured on some 
subjects so the analysis yields a result that would not have been 
obtained had all data been analyzed).
    As specified in proposed Sec.  11.66(b), we would require a 
responsible party to inform the Director when a sponsor determines that 
information submitted to ClinicalTrials.gov was falsified or based on 
falsified information. The responsible party would be required to 
inform the Director about falsification at the same time as he or she 
submits corrected information or informs the Director that either 
correct information cannot be generated or previously submitted 
information is correct (i.e., the falsification did not result in 
incorrect information being submitted to ClinicalTrials.gov). If 
corrected information can be generated, we would require the 
responsible party to submit corrected information not later than 15 
calendar days after it becomes available. If it is determined that 
submitted information cannot be corrected or is correct as previously 
submitted we would require the responsible party to notify the Director 
not later than 15 days after such a determination is made. For a 
clinical trial for which corrected data cannot be generated, we would 
indicate in ClinicalTrials.gov that data for such clinical trial were 
determined to be falsified or based on falsified information and that 
corrected information is not available. Such an indication would inform 
users of ClinicalTrials.gov of the status of the information in the 
record for that clinical trial. For a clinical trial for which the 
falsification of data does not affect the information submitted to 
ClinicalTrials.gov (e.g., because underlying falsified data did not 
contribute to the analysis of outcomes), we would not include an 
indication of falsification on the ClinicalTrials.gov record. 
Information about findings of falsification might be included in 
published journal articles for which Medline citations are linked from 
the record, in FDA information that is linked from the record, or in 
other publicly available information.
    We recognize that, in some cases, after determining that submitted 
information was falsified or based on falsified information, it may 
take time for a responsible party to assess whether or not the 
information submitted to ClinicalTrials.gov was affected, determine 
whether any affected information can be corrected, and generate 
corrected information, as needed. For example, the results of the 
clinical trial may need to be reanalyzed after excluding data that have 
been falsified and the results of such reanalysis compared with 
previously submitted data. Under our proposal, a responsible party 
would be required to notify the Director of falsification only after he 
or she had assessed whether or not the falsification resulted in 
incorrect data being submitted to ClinicalTrials.gov, determined 
whether corrected information could be generated, and generated any 
needed corrections to the data. We considered, but do not include in 
this proposed rule, a requirement for a responsible party to provide 
earlier notification to the Director of a determination that 
information submitted to ClinicalTrials.gov had been falsified or was 
based on falsified information (e.g., such notification could be 
provided not later than 15 days after the determination is made). 
Following such a proposal, the responsible party would then have been 
required either to make a second notification stating whether the 
submitted information was correct as submitted or unable to be 
corrected or to submit corrected information. We invite public comment 
on the advantages and disadvantages of this alternative approach, 
including on the amount of time that might typically pass between 
determining that data have been falsified and determining whether 
submitted clinical trial information can be corrected or does not need 
correction. We specifically invite comment on the implications of the 
proposed approach in cases when that time period may be lengthy. We 
also invite comment on what, if any, information might be made make 
publicly available in ClinicalTrials.gov in these situations. We invite 
comments on all other aspects of our proposal, as well.
    Third, Sec.  11.66(c) addresses corrections necessary to address 
various other deficiencies in submitted information. Such deficiencies 
include but are 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, 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. We believe 
that requiring corrections of such information is necessary step in 
ensuring that the information contained in ClinicalTrials.gov is not 
false or misleading. We expect to identify some needed corrections 
during the quality review procedures described in section III.C.12 of 
this preamble and in the course of operating the data bank. As with 
errors, we plan to inform responsible parties of these needed 
corrections. We expect that responsible parties may also become aware 
of needed corrections through their own reviews of submitted data or 
from other parties. Proposed Sec.  11.66(c) provides that responsible 
parties who become aware of needed corrections or are informed by NIH 
of needed corrections to clinical trial information submitted under 
Sec. Sec.  11.28, 11.48, or 11.60 must submit corrected information as 
soon as possible, but not later than 15 calendar days after the date 
that they become aware of the need for correction or that NIH informs 
them of the needed correction, whichever is earlier.
    Compliance with our quality control process, including the 
requirements set forth in Sec.  11.66, does not necessarily constitute 
a legal defense to enforcement pursuant to section 301(jj) of the FD&C 
Act (21 U.S.C. 331) and 303(f) of the FD&C Act (21 U.S.C. 333(f)).

V. Response to Comments

    Because of the large number of public comments we normally receive 
on Federal Register documents, we are not able to acknowledge or 
respond to them individually. We will consider all comments we receive 
by the date and time specified in the Dates section of this preamble, 
and will respond generally to the comments in the preamble to any 
subsequent rulemaking document.

VI. Regulatory Impact Statement

    The Agency has examined the impacts of this proposed 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 (Public Law 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

[[Page 69656]]

net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). A regulatory impact analysis (RIA) 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 
proposed requirements to regulated entities is approximately $49.7 
million annually. We believe there are intangible benefits, in the form 
of increased public trust in clinical research and improvements in 
human subjects protection, clinical care, clinical research, and 
product development that may result from enhanced access to clinical 
trial results. We believe that this proposed rule is not an 
economically significant regulatory action as defined by Executive 
Order 12866. Because of the interest in this proposed 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 proposed rule. We request comments on the economic analyses 
provided in this proposed 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. Because the rule is likely to impose estimated costs of 
approximately $6,700 per applicable clinical trial on organizations 
that conduct applicable clinical trials, the Agency proposes to certify 
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.'' (See 2 U.S.C. 1352(a)) The 
current threshold after adjustment for inflation is $141 million, based 
on the Gross Domestic Price deflator for 2012. The Agency does not 
expect this proposed 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 proposed 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. The Proposed Rule

    This proposed rule would implement the provisions for the mandatory 
registration and submission of results information for applicable 
clinical trials at ClinicalTrials.gov, as required by section 402(j) of 
the PHS Act (42 U.S.C. 282(j)), added by section 801 of FDAAA. This 
proposed rule would both clarify the statutory requirements for 
submission of registration and results information, including adverse 
events information, and implement the expansion of the registry and 
results data bank by rulemaking as required by section 402(j)(3)(D) of 
the PHS Act.

B. Need for the Proposed Rule

    The Agency is promulgating this proposed 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 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 proposed rule is 
intended, in part, to implement the statutory requirements and clarify 
the Agency's interpretation of them. It clarifies the meaning of terms 
defined in 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 proposed 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 proposed 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.'' That 
section 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 
previously 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 full protocol or ``such 
information on the protocol . . . as may be necessary to help evaluate 
the results of the trial.'' This proposed rule addresses each of these 
topics and others specified in section 402(j) of the PHS Act.

C. Benefits of the Proposed Rule

    As discussed in this preamble, the overarching aim of this proposed 
rule is to provide public access to a standardized set of non-technical 
and technical information describing the conduct and results of certain 
clinical trials of FDA-regulated drugs (including biological products) 
and devices. Access to this information will benefit not only the 
general public, but also other groups of people involved in improving 
public health. These groups of people include potential and enrolled 
clinical trial participants, clinical researchers, systematic 
reviewers, disease and

[[Page 69657]]

patient advocacy groups, regulators, drug and device manufacturers, 
health care providers, patients and their family members. Access to 
information contained in the data bank is intended to enhance patient 
enrollment in clinical trials and improve the evidence-base that 
informs clinical care, enhance public health and safety, increase the 
efficiency of drug and device development processes, and improve 
clinical research practice, among other uses. It is also intended to 
build public trust in clinical research by providing public access to 
the results of such research. These benefits are intangible.

D. Costs Associated With the Proposed Rule

    The costs associated with this proposed rule consist of the time 
and effort necessary for responsible parties to comply with the 
proposed 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 submission. We do not intend this proposed rule to cause 
responsible parties to collect any information that was not already 
intended to be collected during the clinical trial (as described by the 
study protocol), nor do we intend this proposed rule to cause 
responsible parties to analyze such information in ways that were not 
intended, as described in the protocol or the associated statistical 
analysis plan. Rather, the rule specifies those elements of the 
collected results information and statistical analyses that must be 
submitted to the data bank and the format in which they must be 
submitted.
    The calculations below present our estimates of the time and cost 
associated with meeting the information submission requirements of this 
proposed 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 
(including adverse event information), (3) submitting certifications, 
extension requests and appeals to delay the results 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. We estimate the total annual cost to 
be $49,713,753. As explained below, we expect that during the first 
year after the effective date of this proposed rule, responsible 
parties will incur some additional time and cost to update clinical 
trial information that previously was submitted to the data bank for 
trials that were initiated prior to the effective date and ongoing as 
of that date. We estimate this additional, non-recurring cost to be 
$2,457,080.
    We expect that over time the cost of complying with this proposed 
rule will decline notably once a final rule is published and 
responsible parties become more familiar with the registration and 
results submission requirements as well as the data submission and 
review processes. Many data providers have developed standard operating 
procedures for data entry personnel and refined their data management 
systems to facilitate data submission. 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 once the requirements for submission 
of clinical trial information are clarified, responsible parties will 
automate portions of the data extraction and formatting processes for 
required results information, significantly reducing the burden of 
compliance with this proposed rule.

                                 Table 2--Estimated Annual Cost of Proposed Rule
----------------------------------------------------------------------------------------------------------------
                                                            Estimated annual  Estimated annual  Incremental cost
             Provision                Proposed section(s)     cost prior to    cost under the    above pre-rule
                                                               rulemaking       proposed rule    data collection
----------------------------------------------------------------------------------------------------------------
Registration of applicable clinical  11.28(a),(b), 11.64..       $11,005,132       $11,483,616          $478,484
 trials, including updates.
Results submission for applicable    11.48, 11.64.........         6,444,954        37,828,800        31,383,846
 clinical trials, including updates.
Submission of certifications,        11.44(b), (c), (e)...           189,783           261,990            72,207
 extension requests, and appeals to
 delay results submission.
Triggered registration and results   11.60................                 0           129,260           129,260
 submission following voluntary
 submissions.
Submission of expanded access        11.28(c).............                 0            10,087            10,087
 records.
                                    ----------------------------------------------------------------------------
    Total..........................  .....................        17,639,869        49,713,753        32,073,884
----------------------------------------------------------------------------------------------------------------

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 proposed rule. Using the 
approach described below, we estimate that a total of 7,400 applicable 
clinical trials of drugs (including biological products) and devices 
per year would be subject to the registration requirement of this 
proposed 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, Jan. 4, 
2011). 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 of an applicable 
clinical trial but do not appear to have been conducted under an IND or 
IDE, e.g., because they are exempt. 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

[[Page 69658]]

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 would be subject to the registration 
requirement of this proposed rule each year.
    To calculate the burden associated with registering these 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 is one hour more than the estimate used 
in the existing OMB Paperwork Reduction Act clearance for the 
ClinicalTrials.gov data collection (77 FR 22579, Apr. 16, 2012) to 
account for the additional data elements that would be required by this 
proposed 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 would be updated 
an average of 8 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 would likely submit 
more updates during the course of the trial, we have found that many 
applicable clinical trials have a 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. Using these figures, we calculated 
the annual hour burden for updates to clinical trial registration 
information 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.
    To calculate the cost of registration, we examined May 2011 data 
from the U.S. Bureau of Labor Statistics on the average wages of 
workers in the pharmaceuticals and medical equipment industries who are 
involved typically in submitting registration information. 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 $32.33, which is equivalent to the weighted 25th percentile 
wage of a medical scientist in the pharmaceutical and medical equipment 
industries and is significantly higher than the median wage of other 
administrative staff in those sectors who sometimes submitting 
registration information to ClinicalTrials.gov. We doubled these wage 
figures (to $64.66 per hour) to account for benefits and overhead. 
Using this adjusted wage figure, we calculated an estimated total 
annual cost of registration under the proposed rule, including updates 
over the course of a clinical trial, of $11,483,616 (Table 2). This 
figure represents an incremental increase of $478,484 per year above 
the estimated cost of registration under the existing OMB Paperwork 
Reduction Act clearance for the ClinicalTrials.gov data collection.
2. Results Submission
    To estimate the burden associated with submission of clinical trial 
results information, we start from 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 submission for all applicable clinical trials that study drugs 
(including biological products) or devices that are approved, cleared, 
or licensed by FDA; the proposed regulation would require, in addition, 
the submission of clinical results information for applicable clinical 
trials of drugs (including biological products) and devices that are 
not approved, cleared, or licensed by FDA. We therefore estimate the 
burden associated with results submission for a total of 7,400 
applicable clinical trials of drugs (including biological products) and 
devices per year, recognizing that in most cases, such clinical trial 
results information would not be submitted in the same year as the 
associated clinical trial registration information but in accordance 
with the deadlines specified in proposed 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 would 
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 submission times [Ref. 45], comments made at the April 
2009 public meeting (Ref. 1), 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 their study design, number of 
outcome measures (primary and secondary), statistical analyses, and 
adverse event information. They 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 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 we propose 
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 the 25-hour estimate that was included in the most recent OMB 
Paperwork Reduction Act clearance for the ClinicalTrials.gov data 
collection and reflects the additional information that would be 
required to be submitted under this proposed rule. We expect the hour 
burden would decline as responsible parties become more familiar with 
ClinicalTrials.gov and implement procedures for streamlining data 
collection, analysis, and formatting. In the most recent OMB Paperwork 
Reduction Act clearance for the current ClinicalTrials.gov data 
collection, we

[[Page 69659]]

estimated that results information would be submitted for 1,845 
applicable clinical trials per year, which is the estimated number of 
clinical trials that would have been included in marketing applications 
for drugs, biological products, and devices that were initially 
approved, licensed, or cleared by the FDA and subject to the basic 
results reporting provisions of FDAAA. Under this proposed rule, 
results information would be required for all applicable clinical 
trials that were subject to the registration requirement (i.e., an 
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. This figure compares to an estimated 46,125 hours under 
the current information collection.
    We also estimate that, on average, each results record would be 
updated twice after the initial submission to reflect changes in data 
analysis or the submission of additional results from other pre-
specified outcome measures. We estimate that each such update would 
take 10 hours, on average. This figure is 2 hours higher than the 8-
hour estimate used in the OMB Paperwork Reduction Act clearance for the 
current ClinicalTrials.gov data collection 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 (two updates per trial), compared to 29,520 hours 
for the 1,845 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 
submission under the proposed rule of 444,000 hours, compared with 
75,645 hours under the existing information collection.
    To calculate the economic cost of clinical trial results 
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 2011 data from the U.S. Bureau of Labor 
Statistics, we use an average hourly wage rate of $42.60, which 
corresponds to the weighted median hourly wage of a medical scientist 
in the pharmaceutical and medical equipment manufacturing industries. 
We doubled this wage rate (to $85.20 per hour) to account for benefits 
and overhead. Using this adjusted wage rate, we estimate a total annual 
cost of results submission under this proposed rule, including updates, 
of $37,828,800 (Table 2). This represents an increase of $31,383,846 
per year above the estimated $6,444,954 cost of results submission 
under the current information collection.
3. Delayed Submission of Results via Certification or Extension Request
    We also have estimated the average time and cost associated with 
the submission of certifications and extension requests to delay 
results submission, consistent with proposed Sec. Sec.  11.44(b), (c), 
and (e). Responsible parties for applicable clinical trials may submit 
a certification to delay results submission provided that initial 
approval or approval of a new use is sought. We estimate that the 
number of clinical trials that would qualify for delayed submission of 
results in a given year would not exceed the estimated number of newly 
initiated applicable clinical trials per year that are conducted under 
an IND or IDE. Such clinical trials would study drugs and devices that 
are unapproved, unlicensed, or uncleared or that are approved, 
licensed, or cleared but are studied for possible new uses. While some 
responsible parties might elect to submit clinical trial results 
information 1 year after the completion date instead of delaying 
submission via a certification, for purposes of this estimate, we 
assume that they all will elect to submit a certification to delay 
results 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 as was used to estimate the 
number of applicable clinical trials subject to the registration 
requirements of this proposed rule, we estimate that certifications 
would be submitted for 5,150 trials per year. We estimate that it would 
take no more than 30 minutes for a responsible party to determine that 
a 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 through 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 $42.60. Doubling this wage rate to 
account for benefits and overhead produces an annual estimated cost of 
$219,390 per year.
    For good-cause extension requests, we estimate that approximately 
200 requests will be submitted each year. This estimate is based on 
several considerations, including the rate of submission of requests 
between September 2008 and September 2010, when some 70 extension 
requests were submitted to ClinicalTrials.gov. In many cases, 
responsible parties did not need to submit an extension request in 
order to delay results submission; many of the submitted extension 
requests indicated that the estimated completion date of the applicable 
clinical trial had changed or that the clinical trial was not an 
applicable clinical trial subject to section 402(j) of the PHS Act. We 
would not expect an extension request to be submitted in these 
situations; rather, we would expect responsible parties to update their 
estimated completion date to reflect changes in the progress of the 
trial or to use the approach described in proposed Sec.  11.22(b) and 
section IV.B.2(b) of this preamble to determine that the clinical trial 
is not an applicable clinical trial that is subject to this proposed 
rule. Excluding such unnecessary requests and considering only those 
submitted for applicable clinical trials for which the actual 
completion date had passed, we received approximately 20 requests per 
year. We expect that the number of extension requests will increase 
once a final rule is published and responsible parties have more 
clarity about the deadlines for submitting clinical trial results 
information. The estimated 200 extension requests per year represent a 
10-fold increase over the annual rate of submissions to date and would 
be equivalent to four 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 5,500). It would also represent more than 10 
percent of the applicable clinical trials that do not delay results 
submission via certification. While responsible parties may request an 
extension request even after they have filed a certification, we expect 
this would happen infrequently. Moreover, as explained in section 
IV.C.3(d) of this preamble, we expect that extensions will be granted 
in only a limited set of circumstances where ``good cause'' has been 
demonstrated. In those cases in which an extension request is denied,

[[Page 69660]]

the responsible party would 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, the number of appeals 
per year would total 50.
    We estimate that the time required gathering the information 
required for a good-cause extension request or appeal and submitting it 
to ClinicalTrials.gov would be no more than 2 hours. Using this figure, 
we estimate that the annualized hourly burden for extension requests 
and appeals would be 500 hours. We expect that requests will be 
submitted by those familiar with the results submission requirements 
and therefore use an hourly wage of $42.60. Doubling this wage rate (to 
$85.20) to account for benefits and overhead brings the annualized cost 
of extension requests to $42,600. Combining the estimated costs for 
certification and extension requests produces a total cost of $261,990 
per year (Table 2). The most recent OMB Paperwork Reduction Act 
clearance for the ClinicalTrials.gov data collection estimated that 
3,655 certifications would be submitted by responsible parties seeking 
initial approval or approval of a new-use of a drug, biological 
product, or device studied in an applicable clinical trial and that 200 
extension requests would be submitted per year. These figures would 
yield an estimated annual cost of $189,783, meaning that the 
incremental cost attributable to this rule would be $72,207 per year.
4. Triggered Submission of Clinical Trial Information Following a 
Voluntary Submission
    Proposed Sec.  11.60 implements section (402(j)(4)(A) of the PHS 
Act and indicates that if a responsible party voluntarily registers or 
submits results information for a clinical trial of an FDA-regulated 
drug or device that is not an applicable clinical trial subject to the 
mandatory clinical trial information submission requirements under the 
proposed part, 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 would include, e.g., phase 1 
trials of drugs, small feasibility studies of devices (neither of which 
are considered to be applicable clinical trials), 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 would trigger 
a requirement to submit clinical trial information for other applicable 
clinical trials that are included in the marketing application for a 
drug or device, as long as the entity submitting the marketing 
application or premarket notification is the same as the responsible 
party for those other trial 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 would 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 have been required to be registered in ClinicalTrials.gov under 
section 402(j)(2)(C) of the PHS Act and this proposed part. For 
example, the voluntary submission of information for a phase 1 trial of 
an unapproved drug would trigger the submission of information for an 
applicable clinical trial only if that phase 1 trial were included in a 
marketing application that also included an applicable clinical trial 
(e.g., a phase 2 clinical trial) that was not otherwise required to 
submit clinical trial information to ClinicalTrials.gov (e.g., because 
it completed before September 27, 2007), and if the responsible party 
of the voluntarily-submitted trial were the same as the entity 
submitting the marketing application. For these reasons, we do not 
anticipate many clinical trials that are submitted voluntarily after 
the date of enactment of FDAAA to be associated--through an FDA 
marketing application--with applicable clinical trials that pre-date 
FDAAA. 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 17,000 
clinical trials that are registered every year, on average, with 
ClinicalTrials.gov, we estimate that 9,600 are voluntary submissions 
(all but the 7,400 that are applicable clinical trials). Using this 
figure, voluntary registrations would trigger the required submission 
of clinical trials information for an estimated 96 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 (72), 
registration information only would need to be submitted; for the other 
quarter, results information would need to be submitted. For those 
clinical trials for which only registration information is required, we 
estimate that it would take 8 hours to register the clinical trial by a 
data submitter with an average hourly wage rate of $32.33 (consistent 
with the figures used for registration of applicable clinical trials). 
Doubling the wage rate to account for benefits and overhead produces an 
estimated cost of $37,244 per year. Submitted information would not 
generally need to be updated because the clinical trial would, in 
general, have reached its completion date by the time the requirement 
to submit clinical trial information is triggered and there would be 
few, if any, updates to report. For the remaining quarter of the 
triggered clinical trials (24) we estimate that the hourly burden would 
equal the 40 hours estimated for results submission for other 
applicable clinical trials plus 5 hours to account for the additional 
data elements that are specified in proposed Sec.  11.60(a)(2)(i)(B). 
Using these figures and doubling the estimated average hourly rate of 
$42.60, we estimate the annual cost of submission as $92,016. Combining 
this figure with the $37,244 figure for triggered clinical trials that 
submit only registration information, produces a total annual estimated 
cost for the submission of clinical trial information triggered by the 
voluntary submission of information under proposed Sec.  11.60 of 
$129,260 (Table 2). Because the submission of clinical trial 
information triggered by the voluntary submission of information was 
not included in the most recent OMB Paperwork Reduction Act clearance 
for the ClinicalTrials.gov data collection, the incremental cost 
attributable to this rule would be the full estimated cost of $129,260 
per year.
    We note that a number of voluntary submissions of clinical trial 
information would likely be made to ClinicalTrials.gov each year. 
Responsible parties often register clinical trials voluntarily in order 
to assist in the recruitment of subjects or so that they may publish 
any resulting scientific papers in leading peer-reviewed scientific 
journals. Because such clinical trials are not required to be

[[Page 69661]]

registered or to submit results information under section 402(j) of the 
PHS Act, we do not include them in this cost estimate. Because such 
information is submitted voluntarily to ClinicalTrials.gov, we do 
account for voluntary submissions in the estimates for Paperwork 
Reduction Act clearance. See section VII below.
5. Expanded Access Records
    As specified in proposed Sec.  11.28(a), if expanded access is 
available under section 561 of the Federal Food, Drug, and Cosmetic Act 
to a drug that is studied in an applicable drug clinical trial, the 
responsible party must include the NCT number of an expanded access 
record with the clinical trial information submitted at the time of 
registration. If an expanded access record for the drug has not yet 
been submitted to ClinicalTrials.gov, the responsible party must create 
an expanded access record by submitting the data elements listed Sec.  
11.28(c). To determine the cost and burden associated with the creation 
of this record, we relied on information from the FDA that estimates 
that 10 treatment INDs or treatment protocols and 68 expanded access 
programs for treatment of an intermediate size patient population are 
initiated annually. These are the two types of expanded access programs 
for which the information listed in Sec.  11.28(c) must be submitted to 
ClinicalTrials.gov under this proposed rule (i.e., as explained in 
section IV.an expanded access record is not required if expanded access 
is available for treatment of an individual). 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. An expanded access record 
requires only about one-half of the data elements required for an 
applicable clinical trial (22 versus 39) and 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 therefore estimate the total hour burden 
associated with expanded access records to be 156 hours per year. 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 $32.33. Doubling this wage 
rate (to $64.66) to account for benefits and overhead results in a 
total estimated annual cost of $10,087 (Table 1). Because the 
submission of expanded access records was not included in the most 
recent OMB Paperwork Reduction Act clearance for the ClinicalTrials.gov 
data collection, the incremental cost attributable to this rule is the 
full estimated cost of $10,087 per year.
6. Non-Recurring Cost of Bringing Previously Submitted Registration 
Information Into Compliance With This Proposed Rule
    As discussed in section III.D of this preamble (``Effective 
Date''), we expect that a responsible party for any applicable clinical 
trial for which results information would be required to be submitted 
to ClinicalTrials.gov after the effective date of this rule would have 
to update any previously submitted clinical trial registration 
information by the compliance date to meet the requirements of proposed 
Sec.  11.28. The responsible party would need to submit any data 
elements specified in proposed Sec.  11.28(a)) that were not submitted 
at the time the trial was registered and make sure the entries for all 
required data elements include the complete set of information defined 
in proposed Sec.  11.10(b) (e.g., include all the specified elements of 
Study Design).
    To estimate the number of clinical trials that might require such 
updates, we searched ClinicalTrials.gov for clinical trials that were 
registered after the enactment of FDAAA (i.e., September 27, 2007) and 
appeared to meet the definition of an applicable clinical trial. We 
found nearly 3,700 such clinical trials registered each year. Of those 
clinical trials, approximately 1,800 per year had results information 
submitted to ClinicalTrials.gov and would therefore not require further 
submissions of results or updating of previously submitted registration 
information. Subtracting these 1,800 clinical trials from the 3,700 
trials that were registered each year results in an estimated 1,900 
clinical trials per year that would be subject to this one-time 
updating. We estimate that if the final rule were to go into effect 5 
years after enactment of FDAAA (e.g., December 2013), there could be as 
many as 9,500 registered applicable clinical trials for which results 
have not been submitted (i.e., 1,900 clinical trials per year 
multiplied by 5 years), although the actual number would probably be 
smaller because clinical trials that had been initiated earlier would 
be more likely to have reached their completion date prior to the 
effective date of the rule and to have submitted complete clinical 
trial results information. We estimate that the time required to update 
the registration information would be, on average, 4 hours, which is 
half the estimated time required to submit the full set of clinical 
trial registration information and reflects that fact that many 
registration data elements would already have been submitted and would 
not need updating. Applying this figure to the estimated 9,500 clinical 
trials produces an annual hour burden of 38,000 hours. Using an average 
wage of $32.33 (as for the registration calculation in 1 above) and 
doubling it to account for benefits and overhead yields an additional 
cost of $2,457,080. Note that this would be a one-time cost associated 
with updating registration information previously submitted to 
ClinicalTrials.gov, not a recurring annual cost.

E. Alternatives to the Proposed 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 statutory enumerated clinical 
trial information required for registration. This proposed 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. The preamble describes various 
alternatives considered by the Agency in exercising its authority to 
add or modify the statutory provisions and in addressing the topics it 
was required to address via regulation. It also describes alternatives 
it considered in implementing statutory provisions of the law that were 
not required specifically to be addressed by regulation. It also 
invites comments on alternative approaches.

F. 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 proposed rule would affect a number of small entities 
that conduct clinical trials of drugs and devices, 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 proposed rule are 
classified in seven separate North American Industrial Classification 
System (NAICS) categories by the Census

[[Page 69662]]

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. The Small Business Administration (SBA) 
size standards for all these industries define small entities as those 
companies with less than 500 employees, except for pharmaceutical 
preparation, for which it defines a small entity as one with less than 
750 employees. 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 2007. In each 
of these establishment size categories, large majorities of the 
establishments meet the criteria as small entities. 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. 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.
    The cost analysis presented above indicates an estimated cost of 
compliance with this proposed rule of $6,718 per applicable clinical 
trial ($49,713,753 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 2007 Census of Manufacturers, the average value of 
shipments for establishments in these industries with one to four 
employees ranged from $353,000 to $844,000. Assuming that such small 
operations had one applicable clinical trial that was required to 
submit registration or results information each year, the costs of this 
proposed rule would represent, at most, 1.9 percent of the annual value 
of shipments. For establishments with 50 to 99 employees, the costs of 
this proposed rule would represent at most 0.6 percent of the value of 
shipments, even if they were responsible for 10 applicable clinical 
trials administered annually. For establishments with 100 or more 
employees, the costs of this proposed rule would represent at most 0.24 
percent of the value of shipments even with 10 applicable clinical 
trials administered annually. These figures are well below the 
threshold of 3 to 5 percent of the total revenue for small entities 
needed to consider that this proposed rule would have a significant 
economic impact on a substantial number of small entities. The Agency 
concludes that this proposed rule would not have a significant economic 
impact on a substantial number of small entities.
    In practice, we expect the burden on small firms would be 
significantly lower than this estimate. In general the applicable 
clinical trials initiated by small firms would 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--
would 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 2007 
Census of Manufacturers indicates that there are approximately 5,600 
companies in the United States that are involved in the manufacture of 
medical devices and that almost 4,900 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 medical device manufacturers would initiate a trial subject to 
the registration and results submission requirements of this proposed 
rule in any given year (500 applicable device clinical trials per year 
divided by 5,600 firms equals 0.089 or 8.9 percent).

G. 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 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 1 year.'' 
2 U.S.C. 1532(a). The current threshold, adjusted for inflation using 
the 2012 Implicit Price Deflator for the Gross Domestic Product, is 
$141 million. As indicated above, we do not expect the direct burden of 
this proposed 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 proposed regulation would be private 
entities. As a result, we conclude that this rule will have no 
consequential effect on State, local, or tribal governments or on the 
private sector. We have determined that this proposed 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.

H. 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 
proposed rule in accordance with the principles set forth in Executive 
Order 13132 and has determined that this proposed rule does not contain 
policies that would impose any ``substantial direct compliance costs on 
State or local governments[.]'' This proposed 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

[[Page 69663]]

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.
    Following publication of this proposed rule, the Agency will 
further consult with appropriate State officials and organizations to 
review the scope of this proposed rule and to seek input on federalism 
issues. We specifically solicit comments on this proposed rule from 
representatives of State and local governments.

VII. Paperwork Reduction Act of 1995

    This proposed rule contains requirements that are subject to review 
by OMB under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) 
(PRA). Sections 11.28, 11.48, 11.60, 11.62, and 11.64 of this proposed 
rule contain information collection requirements that are subject to 
OMB approval. A revision of the existing PRA clearance for clinical 
trial registration and results submission (OMB 0925-0586) to meet the 
requirements of this proposed Part will be submitted to OMB for review.
    A description of the information collection requirements included 
in this proposed rule is provided in the Regulatory Impact Statement 
(section V) 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. The Agency 
invites 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 .
    The information collection provisions of this proposed rule will be 
submitted to OMB for review. Other organizations and individuals 
desiring to submit comments on the information collection and 
submission requirements should send their comments by February 19, 2015 
to (1) Ms. Seleda Perryman, 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 Federal 
Register.
    The estimate includes the annual hourly burden for submission, 
updating, and correction of information both for applicable clinical 
trials that are subject to this proposed rule and for the larger number 
of clinical trials for which information is submitted to 
ClinicalTrials.gov on a voluntarily 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 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 regulation follows 
the estimates presented in section V of this preamble. They differ from 
the burden estimates contained in the current OMB Paperwork Reduction 
Act clearance in several ways. For registration, we have increased from 
5,500 to 7,400 the estimate of the number of clinical trials that would 
be subject to mandatory registration under the rule. This increase 
reflects the revised estimate of the number of protocols for applicable 
clinical trials that are submitted to the FDA for under and IND or IDE. 
We also increased the estimated hour burden of registration from 7 
hours to 8 hours to reflect the additional data elements that would be 
required under this proposed rule. For results submission we have 
increased from 1,845 to 7,400 our estimate of the number of clinical 
trials that would be subject to mandatory results submission under this 
proposed rule. This proposed rule would require the submission of 
results information for all registered applicable clinical trials, 
regardless of whether or not the drug (including biological product) or 
device under study in the trial is approved, licensed, or cleared. We 
have made commensurate increases in the estimated number of clinical 
trials for which a certification to delay results 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 proposed 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 proposed Sec.  11.60. 
Finally, we have included a separate estimate of the burden associated 
with the creation of an expanded access record if a drug that is 
studied in an applicable clinical trial is available via an expanded 
access program.


             Table 3--Estimated Burden for Registration and Results 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 proposed 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

[[Page 69664]]

 
    Extension requests and appeals...             250  1.......................              2               500
    Registration triggered by                      72  1.......................              8               576
     voluntary submission.
    Results triggered by voluntary                 24  1.......................             45             1,080
     submission.
    Expanded access records..........              78  1.......................              2               156
                                      --------------------------------------------------------------------------
        SUBTOTAL.....................  ..............  ........................  ...............         626,487
Non-regulated submissions [Not
 subject to this Proposed Rule]:
    Registration.....................           9,600  1 Initial...............              8            76,800
                                                       8 Subsequent Updates....              2           153,600
    Results Information..............             350  1 Initial...............             40            14,000
                                                       2 Subsequent Updates....             10             7,000
                                      --------------------------------------------------------------------------
        SUBTOTAL.....................  ..............  ........................  ...............         251,400
                                      --------------------------------------------------------------------------
            TOTAL....................  ..............  ........................  ...............         877,887
----------------------------------------------------------------------------------------------------------------

    In order to estimate the burden for clinical trials that are not 
subject to this proposed rule, we examined ClinicalTrials.gov to 
determine how many clinical trials were registered during calendar 
years 2008 through 2011. We found that there were, on average, some 
17,000 studies registered per year, and that the number was consistent 
across the 3-year period. We therefore believe it is a reasonable 
estimate of total registrations in future years. We subtracted from 
this total 7,400 clinical trials to account for those applicable 
clinical trials that would be subject to mandatory submissions under 
this proposed rule. The remaining 9,600 clinical trials registered 
would not be subject to section 402(j) of the PHS Act, e.g., because 
they are studies of interventions not regulated by FDA, are phase 1 
studies of drugs or feasibility studies of devices, are observational 
studies, or otherwise fail to meet the definition of an applicable 
clinical trial. This figure represents a reduction (from 11,500) in the 
number of non-regulated submissions to ClinicalTrials.gov that was 
contained in our previous OMB Paperwork Reduction Act clearance. These 
clinical trials would be expected to have the same clinical trial 
registration information submitted for them as is submitted for 
applicable clinical trials that are subject to this proposed rule. We 
expect that information submitted for such clinical trials will be 
updated as frequently as for clinical trials that are subject to the 
rule. Therefore, for calculating the registration burden associated 
with voluntarily submitted 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: 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 230,400 hours, of which 
76,800 derives from the initial registration and 153,600 derives from 
updates (Table 3).
    As for results submission, we do not expect that clinical trial 
results information will be submitted for most of the clinical trials 
for which registration information is submitted voluntarily (non-
regulated). To estimate of the number of clinical trials for which 
results information would be submitted voluntarily, we reviewed the 
more than 7,000 results records that have been posted publicly at 
ClinicalTrials.gov since late 2008. Of these, about 1,050, or 350 per 
year, appear to be for studies that are unambiguously not applicable 
clinical trials, e.g., observational studies, clinical trials of 
interventions other than drugs (including biological products) and 
devices, and phase 1 clinical trials of drugs. We expect that this 
number of results submissions would continue to be made in future 
years. 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 voluntarily submitted clinical trials would be 14,000 
hours, plus 7,000 hours for updates (Table 3). Thus the total burden 
associated with the voluntary submission of clinical trial information 
is 251,400 hours, and the total annual burden for regulated and 
unregulated submissions of information would be 877,887 hours.

VIII. Congressional Review Act

    The U.S. Department of Health and Human Services has determined 
that this proposed rule is not a major rule as defined in 5 U.S.C. 804, 
and, thus, does not require review by Congress. The Congressional 
Review Act (5 U.S.C. 801-808) defines a major rule as one that the 
Administrator of the Office of Information and Regulatory Affairs of 
the Office of Management and Budget finds has resulted in or is likely 
to result in (A) an annual effect on the economy of $100,000,000 or 
more; (B) a major increase in costs or prices for consumers, individual 
industries, Federal, State, or local government agencies, or geographic 
regions; or `(C) significant adverse effects on competition, 
employment, investment, productivity, innovation, or on the ability of 
United States-based enterprises to compete with foreign-based 
enterprises in domestic and export markets. (5 U.S.C. 804).
    As described in section V of this preamble (Regulatory Impact 
Statement), we estimate that the rule will impose annual costs on 
responsible parties (i.e., sponsors of clinical trials or designated 
principal investigators) of less than $50 million. We do not believe 
such costs are significant enough to affect prices of the drugs 
(including biological products) or medical devices that eventually may 
be approved, cleared, or licensed for marketing by

[[Page 69665]]

FDA. Nor do we believe that the submission and public availability of 
clinical trial information, as required by this proposed rule, will 
have significant adverse effects on competition, employment, 
investment, productivity, or innovation in organizations that are 
subject to this proposed rule. This proposed rule contains provisions 
to delay the public posting of information that might be considered 
commercially relevant, including registration information for trials of 
previously unapproved or uncleared devices and results information for 
trials of unapproved products. In addition, this proposed rule would 
apply to all organizations, domestic and international, that are 
subject to FDA regulation (i.e., because they are conducting a trial 
under an IND or IDE or are seeking marketing approval from FDA). 
Thousands of organizations have submitted information similar to the 
clinical trial registration information proposed in this rule to 
publicly available registries, including ClinicalTrials.gov, for more 
than a decade on a voluntary basis. Many have also made results 
information publicly available, though not in a consistent manner.
    In accordance with the provisions of Executive Order 12866, this 
proposed rule was reviewed by the Office of Management and Budget.

IX. Legal Authority

These proposed 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), Pub. L. 
110-85, 121 Stat. 921-922 (42 U.S.C. 282(note)).

X. References

    1. National Library Medicine. National Institutes of Health. 
U.S. Department of Health and Human Services., ``Memorandum to File: 
Notice of Proposed Rulemaking, FDAAA, Title VIII: Clinical Trials 
Registration and Results Submission Regarding Synopsis of Selected 
Public Comments ``; August 23, 2012, available at http://www.regulations.gov/#!docketDetail;D=NIH-2009-0002.
    2. National Library Medicine. National Institutes of Health, 
``Data Element Definitions,'' U.S. Department of Health and Human 
Services; July 2007.
    3. Food and Drug Administration, ``Guidance for Industry: 
Information Program on Clinical Trials for Serious or Life-
Threatening Diseases and Conditions,'' U.S. Department of Health and 
Human Services; March 2002, available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126838.pdf.
    4. Food and Drug Administration, ``Draft Guidance for Industry: 
Information Program on Clinical Trials for Serious or Life-
Threatening Diseases and Conditions,'' U.S. Department of Health and 
Human Services; January 2004, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM077229.pdf.
    5. Steinbrook, R., ``Registration of clinical trials--voluntary 
or mandatory?,'' New England Journal of Medicine. 351(18): 1820-2, 
2004.
    6. Whittington, C. J., et al., ``Selective serotonin reuptake 
inhibitors in childhood depression: systematic review of published 
versus unpublished data,'' Lancet. 363(9418): 1341-5, 2004.
    7. Evans, T., et al., ``Registering clinical trials: an 
essential role for WHO,'' Lancet. 363(9419): 1413-4, 2004.
    8. Dickersin, K., et al., ``The Society for Clinical Trials 
supports United States legislation mandating trials registration 
position paper,'' Clinical Trials. 1(5): 417-20, 2004.
    9. American Medical Association (AMA), ``Influence of Funding 
Source on Outcome, Validity, and Reliability of Pharmaceutical 
Research,'' Council on Scientific Affairs; June 2004, available at 
http://www.ama-assn.org/ama/no-index/about-ama/14314.shtml.
    10. International Committee of Medical Journal Editors (ICMJE), 
``Obligation to Register Clinical Trials''; 2011, available at 
http://www.icmje.org/publishing_10register.html.
    11. International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA), ``Joint Position on the Disclosure of 
Sensitive Information via Clinical Trial Registries,'' September 5, 
2005, available at http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/FINAL%20Position%20For%20Delayed%20Disclosure%205%20Sept%2005R.pdf.
    12. International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA), ``Joint Position on the Disclosure of Clinical 
Trial Information via Clinical Trial Registries and Databases,'' 
Updated November 10, 2009, available at http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/EN/November_10_2009_Updated_Joint_Position_on_the_Disclosure_of_Clinical_Trial_Information_via_Clinical_Trial_Registries_and_Databases.pdf.
    13. Sim, I., et al., ``Clinical trial registration: transparency 
is the watchword,'' Lancet. 367(9523): 1631-3, 2006.
    14. European Commission, ``List of fields contained in the 
'EudraCT' clinical trials database to be made public, in accordance 
with Article 57(2) of Regulation (EC) No 726/2004 and its 
implementing guideline 2008/C168/02,'' February 4, 2009, available 
at http://ec.europa.eu/health/files/eudralex/vol-10/2009_02_04_guideline_en.pdf.
    15. European Commission, ``Annex 1: Structure of data to be 
collected for inclusion of results in EudraCT and their making 
public in the EU Clinical Trials Register,'' June 1, 2010, available 
at http://ec.europa.eu/health/files/clinicaltrials/table_en.pdf.
    16. Zarin, D. A., et al., ``Trial Registration at 
ClinicalTrials.gov between May and October 2005,'' New England 
Journal of Medicine. 353(26): 2779-87, 2005.
    17. Viergever, R. F. and Ghersi, D., ``The quality of 
registration of clinical trials,'' PLoS One. 6(2): e14701, 2011.
    18. National Library of Medicine, National Institutes of Health, 
``Draft Elaboration of Definitions of Responsible Party and 
Applicable Clinical Trial,'' U.S. Department of Health and Human 
Services; March 9, 2009, available at http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf.
    19. Helfand, M., ``Draft Report: Clinical Trials Registries/
Databases Assessment,'' Under Contract to the National Library of 
Medicine, National Institutes of Health: 467-MZ-501576-2, 2005.
    20. National Library Medicine. National Institutes of Health, 
``National Library of Medicine Board of Regents Working Group on 
Clinical Trials,'' U.S. Department of Health and Human Services; 
Last Updated November 2, 2010, available at http://www.nlm.nih.gov/od/bor/clinicaltrialswg/.
    21. National Library Medicine. National Institutes of Health, 
``NLM Board Working Group on Clinical Trials--February 11, 2008: 
Agenda and Presentations,'' U.S. Department of Health and Human 
Services; Last Updated November 2, 2010, available at http://www.nlm.nih.gov/od/bor/clinicaltrialswg/20080211/index.html.
    22. National Library Medicine. National Institutes of Health, 
``NLM Board Working Group on Clinical Trials--February 9, 2009: 
Meeting Minutes,'' U.S. Department of Health and Human Services, 
available at http://www.nlm.nih.gov/od/bor/Bor_Workinggroup_2009.pdf.
    23. International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
(ICH), ``ICH Harmonised Tripartite Guideline E3: Structure and 
Content of Study Reports,'' November 30, 1995, available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/Step4/E3_Guideline.pdf.
    24. Schulz, K. F., et al., ``CONSORT 2010 statement: updated 
guidelines for reporting parallel group randomized trials,'' Annals 
of Internal Medicine. 152(11): 726-32, 2010.
    25. Food and Drug Administration, ``Guidance for Industry and 
FDA Staff: Postmarket Surveillance Under Section 522 of the Federal 
Food, Drug and Cosmetic Act,'' U.S. Department of Health and Human 
Services; April 27, 2006, available at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm072564.pdf.
    26. Scherer, R. W., et al., ``Full publication of results 
initially presented in abstracts,'' Cochrane Database of Systematic 
Reviews. (2): MR000005, 2007.
    27. Emanuel, E. J., et al., ``What makes clinical research 
ethical?,'' Journal of the American Medical Association. 283(20): 
2701-11, 2000.
    28. European Union, ``Communication from the Commission--
Guidance on the information concerning paediatric clinical trials to 
be entered into the EU Database on Clinical Trials (EudraCT) and on 
the information to be made public by the European Medicines Agency 
(EMEA), in accordance with Article 41 of Regulation (EC) No 1901/
2006,'' Official Journal of the

[[Page 69666]]

European Union. C 28: 4; February 4, 2009, available at http://ec.europa.eu/health/files/eudralex/vol-10/2009_c28_01/2009_c28_01_en.pdf.
    29. European Commission, ``Communication from the Commission 
regarding the guideline on the data fields contained in the clinical 
trials database provided for in Article 11 of Directive 2001/20/EC 
to be included in the database on medicinal products provided for in 
Article 57 of Regulation (EC) No 726/2004,'' Official Journal of the 
European Union. C168: 2; July 7, 2008, available at http://ec.europa.eu/health/files/eudralex/vol-10/2008_07/c_16820080703en00030004_en.pdf.
    30. European Commission, ``List of fields to be made public from 
EudraCT for Paediatric Clinical Trials in accordance with Article 41 
of Regulation (EC) No 1901/2006 and its implementing guideline 2009/
C28/01,'' February 4, 2009, available at http://ec.europa.eu/health/files/eudralex/vol-10/2009_02_04_guidelines_paed_en.pdf.
    31. Altman, D. G., et al., ``The revised CONSORT statement for 
reporting randomized trials: Explanation and elaboration,'' Annals 
of Internal Medicine. 134(8): 663-94, 2001.
    32. Helfand, M., ``Draft Report: Clinical Trials Databases 
Validation Assessment,'' Under Contract to the National Library of 
Medicine, National Institutes of Health: HHSN276200700354P, 2011,
    33. National Library of Medicine, National Institutes of Health, 
``Draft ClinicalTrials.gov Review of Results Submissions,'' U.S. 
Department of Health and Human Services; September 4, 2009, 
available at http://prsinfo.clinicaltrials.gov/ResultsDetailedReviewItems.pdf.
    34. Tse, T., et al., ``Reporting ``basic results'' in 
ClinicalTrials.gov,'' Chest. 136(1): 295-303, 2009.
    35. Bent, S., et al., ``Brief communication: Better ways to 
question patients about adverse medical events: a randomized, 
controlled trial,'' Annals of Internal Medicine. 144(4): 257-61, 
2006.
    36. Rief, W., et al., ``Medication-attributed adverse effects in 
placebo groups: implications for assessment of adverse effects,'' 
Archives of Internal Medicine. 166(2): 155-60, 2006.
    37. Rief, W., et al., ``Differences in adverse effect reporting 
in placebo groups in SSRI and tricyclic antidepressant trials: a 
systematic review and meta-analysis,'' Drug Safety. 32(11): 1041-56, 
2009.
    38. Ioannidis, J. P., et al., ``Better reporting of harms in 
randomized trials: an extension of the CONSORT statement,'' Annals 
of Internal Medicine. 141(10): 781-8, 2004.
    39. Office of Human Research Protections, ``Guidance on 
Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events,'' U.S. Department of Health 
and Human Services, available at http://www.hhs.gov/ohrp/policy/advevntguid.html.
    40. International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
(ICH), ``ICH E6(R1): Guideline for Good Clinical Practice,'' June 
10, 1996, available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf.
    41. Food and Drug Administration, ``Guidance for Sponsors, 
Institutional Review Boards, Clinical Investigators and FDA Staff: 
Guidance on Informed Consent for In Vitro Diagnostic Device Studies 
Using Leftover Human Specimens that are Not Individually 
Identifiable,'' U.S. Department of Health and Human Services; April 
25, 2006, available at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071265.pdf.
    42. National Library Medicine. National Institutes of Health, 
``Clinical Trial Registry Numbers in MEDLINE[supreg]/PubMed[supreg] 
Records,'' U.S. Department of Health and Human Services; Last 
Updated January 17, 2008, available at http://www.nlm.nih.gov/bsd/policy/clin_trials.html.
    43. Office of Extramural Research, National Institutes of 
Health, ``Clarification of Registration in ClinicalTrials.gov 
According to Date of Initiation and Status as an ``Ongoing'' Trial 
(NOT-OD-10-007),'' U.S. Department of Health and Human Services; 
October 23, 2009, available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-10-007.html.
    44. National Library Medicine. National Institutes of Health, 
``FDAAA-UPDATE-L Archives: Revisions made to ``Timing of 
Registration'' in NIH Fact Sheet on Registration,'' U.S. Department 
of Health and Human Services; October 27, 2009, available at https://list.nih.gov/cgi-bin/wa.exe?A2=ind0910&L=FDAAA-UPDATE-L&F=&S=&P=69.
    45. McCarthy, K. and Godlew, B. J., ``ClinicalTrials.gov: a 
questionnaire of industry experiences and perceptions,'' Drug 
Information Journal. 44: 233-241, 2010.

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.

    For the reasons stated in this preamble, the Department of Health 
and Human Services proposes to amend Title 42, Chapter I of the Code of 
Federal Regulations by adding a Part 11 to read as follows.

PART 11--CLINICAL TRIAL REGISTRATION AND RESULTS 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 form and manner must clinical trial information be 
submitted?
11.10 What definitions apply to this part?
Subpart B--Registration
Sec.
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 NIH post clinical trial registration information 
submitted under Sec.  11.28?
Subpart C--Results Submission
Sec.
11.40 Who must submit clinical trial results information?
11.42 For which applicable clinical trials must clinical trial 
results information be submitted in accordance with subpart C of 
this regulation?
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 When will NIH post submitted clinical trial results 
information?
11.54 What are the procedures for waiving of the requirements of 
this subpart?
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 
drugs and devices?
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?
11.66 What are the requirements for corrections of clinical trial 
information?

    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 http://www.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 or a 
clinical trial for which clinical trial registration information or 
clinical trial results information is

[[Page 69667]]

submitted voluntarily in accordance with Sec.  11.60.
    (b) The responsible party must communicate the identity and contact 
information of the responsible party to the Director by submitting the 
Responsible Party Contact Information data element under Sec.  
11.28(a)(4)(vii) as part of the clinical trial information submitted at 
the time of registration. Changes to Responsible Party Contact 
Information must be communicated to the Director by updating this 
information not later than 30 calendar days after the change has 
occurred, as specified in Sec.  11.64(b)(1)(ix) and Sec.  
11.64(b)(1)(x).
    (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 that is not 
a clinical trial, the responsible party is the entity whom FDA orders 
to conduct the pediatric postmarket surveillance of a device.
    (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:
    (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 providing notice of the 
designation to the principal investigator and obtaining from the 
principal investigator an acknowledgement 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 form and manner specified at 
http://prsinfo.clinicaltrials.gov.
    (3) Withdrawal of the designation of a principal investigator as 
the responsible party. (i) In the event a principal investigator who 
has been designated the responsible party becomes unable to meet all 
the requirements for being so designated under paragraph (c)(2)(i) of 
this section, the principal investigator must withdraw the designation 
in the form and manner specified at http://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.
    (ii) In the event a principal investigator who has been designated 
the responsible party is unable because of death or incapacity to 
withdraw his or her designation, 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?

    (a) General. The clinical trial information submitted by a 
responsible party under this part shall not be false or misleading in 
any particular. Submission of false and/or misleading information would 
subject the responsible party to civil, criminal, and/or administrative 
liability under U.S. law.
    (b) Certification. The responsible party must certify that, to the 
best of his or her knowledge, the information submitted is truthful and 
not misleading and that he or she is aware that the submission of false 
and/or misleading information would subject the responsible party to 
civil, criminal, and/or administrative liability under U.S. law.


Sec.  11.8  In what form and manner must clinical trial information be 
submitted?

    Information submitted under this part must be submitted 
electronically to ClinicalTrials.gov, the Internet-accessible clinical 
trial registry and results data bank established by the National 
Library of Medicine, in the form and manner specified at http://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 serious adverse event.
    Applicable clinical trial means an applicable device clinical trial 
or an applicable drug clinical trial.
    Applicable device clinical trial means: (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 Federal Food, Drug, 
and Cosmetic 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 
Federal Food, Drug, and Cosmetic Act.
    Applicable drug clinical trial means 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). In addition, a clinical trial of a 
combination product, where such combination product meets the 
definition in 21 CFR 3.2(e), shall be considered an applicable drug 
clinical trial, so 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 Federal Food, Drug, and Cosmetic Act and/or section 
351 of the Public Health Service Act and/or sections 510(k), 515, or 
520(m) of the Federal Food, Drug, and Cosmetic Act.
    Approved drug means 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.

[[Page 69668]]

    Approved or cleared device means 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.
    Arm means 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.
    Clinical trial means 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 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, the responsible party is required to submit to 
ClinicalTrials.gov under this part.
    Clinical trial registration information means the data elements 
that the responsible party is required to submit to ClinicalTrials.gov, 
as listed under Sec.  11.28.
    Clinical trial results information means 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).
    Comparison group means a grouping of human subjects in a clinical 
trial that is used in analyzing the results data collected during the 
clinical trial.
    Completion date means, 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. For a pediatric postmarket surveillance of a device that is 
not a clinical trial, completion date means the date on which the final 
report summarizing the results of the pediatric postmarket surveillance 
is submitted to FDA.
    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 baseline data), 
as reflected in the pre-specified primary or secondary outcome 
measures.
    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 the NIH to whom 
the NIH Director delegates authorities granted in 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 agreement to participate 
in a clinical trial, as indicated by the signing of the informed 
consent document(s).
    FDA-regulated device means, 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.
    FDA-regulated drug means, 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.
    Human subjects protection review board means an institutional 
review board (IRB) as defined in 21 CFR 50.3 or 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.
    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 812, or any successor regulation.
    Investigational New Drug Application (IND) has the meaning given in 
21 CFR 312.3, or any successor regulation.
    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 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. With respect to a pediatric postmarket surveillance of 
a device, 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 experimental variables on the human subjects 
in a clinical trial. See also primary outcome measure and secondary 
outcome measure.
    Pediatric postmarket surveillance of a device 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 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. A pediatric 
postmarket surveillance of a device may be, but is not always, a 
clinical trial.
    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. ``Primary 
outcome'' has the same meaning as primary outcome measure.
    Principal Investigator (PI) means the individual who is responsible 
for the 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, (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 the device.
    Secondary outcome measure means 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

[[Page 69669]]

investigation in a clinical trial. A clinical trial may have more than 
one secondary outcome measure. ``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 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 (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.
    Sponsor means either a ``sponsor'' or ``sponsor-investigator'', as 
each is defined in 21 CFR 50.3, or any successor regulation.
    (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, the maximum number of arms during any period or phase.
    (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 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.
    (vi) Single Arm Controlled. For a single-armed clinical trial only, 
whether or not the clinical trial is controlled, as specified by the 
protocol or statistical analysis plan.
    (6) Study Phase means, 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.
    (7) Study Type means the type of study for which clinical trial 
information is being submitted.
    (8) Whether the Study is a Pediatric Postmarket Surveillance of a 
Device means, 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.
    (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, 
using, if available, appropriate descriptors from the National Library 
of Medicine's Medical Subject Headings (MeSH) controlled vocabulary 
thesaurus http://www.nlm.nih.gov/mesh/, 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, https://uts.nlm.nih.gov.
    (10) Intervention Name 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), serial numbers, or chemical descriptions.
    (12) Intervention Description means, 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.
    (13) Intervention Type means, for each intervention studied in the 
clinical trial, the general type of intervention.
    (14) U.S. FDA Approval, Licensure, or Clearance Status means, 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.
    (15) Product Manufactured in the U.S. means, 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.
    (16) Study Start Date means 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.
    (17) Completion Date means 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.
    (18) Enrollment means the estimated total number of human subjects 
to be enrolled or target number of human subjects 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;

[[Page 69670]]

    (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) Gender means the biological sex 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 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.
    (25) Overall Recruitment Status means 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.''
    (26) Why Study Stopped means, 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.
    (27) Actual Enrollment means, 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.
    (28) Individual Site Status means the recruitment status of each 
participating facility in a clinical trial.
    (29) Availability of Expanded Access means, for an applicable drug 
clinical trial of a drug that is not an approved drug:
    (i) An indication of whether there is expanded access to the drug 
under section 561 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 360bbb) for those who do not qualify for enrollment in the 
applicable clinical trial.
    (ii) If expanded access is available under section 561 of the 
Federal Food, Drug, and Cosmetic Act, the NCT number of the expanded 
access record.
    (30) Name of the Sponsor means the name of the entity or the 
individual that is the sponsor of the clinical trial, as defined in 
Sec.  11.10(a).
    (31) Responsible Party, by Official Title means:
    (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.
    (32) 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.
    (33) Unique Protocol Identification Number means any unique 
identification number assigned to the protocol by the sponsor.
    (34) Secondary ID means:
    (i) Any identification number(s) other than the organization's 
unique protocol identification number or NCT number that is assigned to 
the clinical trial, including any unique clinical trial identification 
numbers assigned by other publicly available clinical trial registries. 
If the clinical trial is funded in whole or 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.
    (35) Food and Drug Administration IND or IDE Number means whether 
or not 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), or any successor regulation), if any, assigned to the 
clinical trial.
    (36) Human Subjects Protection Review Board Status means 
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;
    (37) Record Verification Date means 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.
    (38) 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.
    (39) Studies an FDA-regulated Device means a clinical trial studies 
a device subject to section 510(k), 515, or 520(m) of the Federal Food, 
Drug, and Cosmetic Act.
    (40) Studies an FDA-regulated Drug means a clinical trial 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

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 register the applicable clinical trial by submitting 
clinical trial registration information specified in Sec.  11.28 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.

[[Page 69671]]

    (3) Determining the date of initiation for an applicable clinical 
trial. An applicable clinical trial, other than a pediatric postmarket 
surveillance of a device 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 that is not a clinical 
trial is considered to be initiated on the date on which U.S. Food and 
Drug Administration (FDA) approves the plan for conducting the 
surveillance.
    (b) Determination of applicable clinical trial. For purposes of 
this part, any clinical trial or study that, at any point in time, is 
described accurately by the data elements 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 is described accurately by the data elements listed in either 
paragraph (b)(1)(i) or (ii) of this section meets the definition of an 
applicable device clinical trial:
    (i) The study is a pediatric postmarket surveillance of a device as 
required by FDA under section 522 of the Federal Food, Drug, and 
Cosmetic Act.
    (ii) The study is a clinical trial 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) Either:
    (1) Number of Arms is two or more; or
    (2) Number of Arms is one, and the clinical trial is Single Arm 
Controlled;
    (D) The Intervention Type is other than a combination product;
    (E) The clinical trial Studies an FDA-regulated Device; and
    (F) One or more of the following applies:
    (1) At least one Facility Location is within the U.S. or one of its 
territories,
    (2) A device under investigation is a Product Manufactured in the 
U.S. or one of its territories and exported 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 that is 
described accurately by the following data elements meets the 
definition of an applicable drug clinical trial:
    (i) Study Type is interventional;
    (ii) Study Phase is other than phase 1;
    (iii) Either:
    (A) Number of Arms is two or more, or
    (B) Number of Arms is one, and the clinical trial is Single Arm 
Controlled;
    (iv) The clinical trial Studies an FDA-regulated Drug; and
    (v) One or more of the following applies:
    (A) At least one Facility Location for the clinical trial is within 
the U.S. or one of its territories,
    (B) A drug under investigation is a Product Manufactured in the 
U.S. or one of its territories and exported 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 subject to Sec.  
11.22 must submit clinical trial registration information, as specified 
in Sec.  11.28(a), 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 subject to Sec.  11.22 that is not for a serious or 
life-threatening disease or condition must submit clinical trial 
registration information 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 and is not a 
clinical trial must submit clinical trial registration information, as 
specified in Sec.  11.28(b), not later than December 26, 2007, or 21 
calendar days after the U.S. Food and Drug Administration 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 as required by Sec.  11.22, other than a pediatric 
postmarket surveillance of a device that is not a clinical trial, the 
responsible party must provide the data elements listed below in (1) 
through (4), as they are defined in Sec.  11.10(b):
    (1) Descriptive information:
    (i) Brief Title;
    (ii) Official Title;
    (iii) Brief Summary;
    (iv) Primary Purpose;
    (v) Study Design;
    (vi) Study Phase, for an applicable drug clinical trial;
    (vii) Study Type;
    (viii) Whether the Study is a Pediatric Postmarket Surveillance of 
a Device; for an applicable device clinical trial that is a Pediatric 
Postmarket Surveillance of a Device;
    (ix) Primary Disease or Condition Being Studied in the Trial, or 
the Focus of the Study;
    (x) Intervention Name, for each intervention studied;
    (xi) Other Intervention Name(s), for each intervention studied;
    (xii) Intervention Description, for each intervention studied;
    (xiii) Intervention Type, for each intervention studied;
    (xiv) Studies an FDA-Regulated Device;
    (xv) Studies an FDA-Regulated Drug;
    (xvi) U.S. FDA Approval, Licensure, or Clearance Status, for each 
intervention studied;
    (xvii) Product Manufactured in the U.S., for each intervention 
studied, if the entry for U.S. Food and Drug Administration IND or IDE 
number in Sec.  11.28(a)(4)(iii) indicates that there is no IND or IDE 
for the clinical trial, and the entry(ies) for Facility Information in 
Sec.  11.28(a)(3)(iii) include no facility locations in the United 
States or its territories.
    (xviii) Study Start Date;
    (xiv) Completion Date.
    (xx) Enrollment;
    (xxi) Primary Outcome Measure Information, for each primary outcome 
measure.
    (xxii) Secondary Outcome Measure Information, for each secondary 
outcome measure.
    (2) Recruitment information:
    (i) Eligibility Criteria;
    (ii) Gender;
    (iii) Age Limits;
    (iv) Accepts Healthy Volunteers;
    (v) Overall Recruitment Status.
    (vi) Why Study Stopped?
    (vii) Actual Enrollment.
    (viii) Individual Site Status;
    (ix) Availability of Expanded Access, for an applicable drug 
clinical trial of a drug that is not an approved drug. If expanded 
access is available under section 561 of the Federal Food, Drug, and 
Cosmetic Act, and the expanded access record for the drug has not been 
submitted in accordance with Sec.  11.28(c), the data elements listed 
Sec.  11.28(c) must also be submitted.
    (3) Location and contact information:
    (i) Name of the Sponsor;
    (ii) Responsible Party, by Official Title;
    (iii) Facility information.
    (4) Administrative data:
    (i) Unique Protocol Identification Number.
    (ii) Secondary IDs.
    (iii) Food and Drug Administration IND or IDE number.
    (iv) Human Subjects Protection Review Board Status.
    (v) Record Verification Date.

[[Page 69672]]

    (vii) Responsible Party Contact Information.
    (b) Pediatric postmarket surveillance of a device that is not a 
clinical trial. For each pediatric postmarket surveillance of a device 
that is not a clinical trial, that must be registered with 
ClinicalTrials.gov as required by Sec.  11.22, the responsible party 
must provide the information listed below in paragraphs (b)(1) through 
(3) of this section.
    (1) Descriptive information:
    (i) Brief Title. A short title of the pediatric postmarket 
surveillance of a device in language intended for the lay public. If an 
acronym or abbreviation is used to publicly identify the surveillance, 
it must be provided.
    (ii) Official Title. The title of the pediatric postmarket 
surveillance of a device, corresponding to the title of the protocol or 
the FDA-approved plan for conducting the surveillance.
    (iii) Brief Summary. A short description of the pediatric 
postmarket surveillance of a device, 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.
    (iv) Study Type. The type of study being registered. In the case of 
a pediatric postmarket surveillance of a device that is not a clinical 
trial, a study type of ``observational'' is required.
    (v) Whether the Study is a Pediatric Postmarket Surveillance of a 
Device. 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.
    (vi) 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, or the focus of 
the study, using, if available, appropriate descriptors from the 
National Library of Medicine's Medical Subject Headings (MeSH) 
controlled vocabulary thesaurus, http://www.nlm.nih.gov/mesh/, 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, 
https://uts.nlm.nih.gov.
    (vii) Intervention Name(s). A brief descriptive name used to refer 
to each intervention studied in the pediatric postmarket surveillance 
of a device. 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.
    (viii) 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), serial 
numbers, or chemical descriptions.
    (ix) Intervention Description. Details that can be made public 
about each intervention, other than the Intervention Name and Other 
Intervention Name, sufficient to distinguish it from other, similar 
interventions studied in the same or another clinical trial or 
pediatric postmarket surveillance of a device that is not a clinical 
trial.
    (x) Intervention Type. For each intervention studied in the 
pediatric postmarket surveillance of a device, the general type of 
intervention.
    (xi) Study Start Date. The date on which FDA approves the pediatric 
postmarket surveillance plan, as specified in 21 CFR 822.19(a) (or any 
successor regulation).
    (xii) Completion Date. The 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.
    (2) Location and contact information:
    (i) Name of the Sponsor.
    (ii) Responsible Party, by Official Title.
    (A) If the responsible party is an entity, the official name of the 
entity; or
    (B) If the responsible party is an individual, the official title 
and primary organizational affiliation of the individual.
    (iii) 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 can be 
addressed.
    (3) Administrative data:
    (i) Unique Protocol Identification Number. The unique 
identification number assigned to the pediatric postmarket surveillance 
of a device by the sponsor, if any.
    (ii) Secondary IDs. (A) Identification number(s) other than the 
organization's unique protocol identification number or NCT number that 
is assigned to the pediatric postmarket surveillance of a device, if 
any, including any unique identification numbers assigned by other 
publicly available registries. If the pediatric postmarket surveillance 
of a device is funded in whole or part by a U.S. Federal Government 
agency, the complete grant or contract number must be submitted as a 
Secondary ID.
    (B) For each secondary ID listed, a description of the type of 
secondary ID.
    (iii) Human Subjects Protection Review Board Status. Information to 
indicate whether a pediatric postmarket surveillance of a device has 
been approved by a human subjects protection review board or is exempt 
from (or otherwise not required to receive) 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 pediatric postmarket 
surveillance.
    (iv) Record Verification Date. The date upon which the responsible 
party last verified the clinical trial information in the entire 
ClinicalTrials.gov record for the pediatric postmarket surveillance of 
a device, 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 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 under 
section 561 of the Federal Food, Drug, and Cosmetic Act to a drug 
studied in an applicable drug clinical trial and the data elements set 
forth in paragraphs (b)(1) through (4) of this section have not been 
submitted via an expanded access record for a previously-registered 
applicable clinical trial of that drug, the responsible party must 
submit the clinical trial information specified in paragraphs (b)(1) 
through (4) of this section to ClinicalTrials.gov in the form of an 
expanded access record. If a responsible party voluntarily submits an 
expanded access record for a device, then the responsible party must 
submit the clinical trial information specified in paragraphs (b)(1) 
through (4) of this section.
    (1) Descriptive information:
    (i) Brief Title. A short title of the expanded access program 
written in language intended for the lay public. If an acronym or 
abbreviation is used

[[Page 69673]]

publicly to identify the program, it must be provided.
    (ii) Official Title. The title of the expanded access program, 
corresponding to the title of the program permitted by FDA.
    (iii) Brief Summary. A short description of the expanded access 
program, including the procedure for requesting the treatment.
    (iv) Study Type. The type of study that is being registered, in 
this case an ``expanded access program.''
    (v) Primary Disease or Condition. The name(s) of the disease(s) or 
condition(s) for which expanded access to the drug is offered, using, 
if available, appropriate descriptors from the National Library of 
Medicine's Medical Subject Headings (MeSH) controlled vocabulary 
thesaurus http://www.nlm.nih.gov/mesh/, 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, https://uts.nlm.nih.gov.
    (vi) Intervention Name(s). A brief descriptive name used to refer 
to the drug that is available through the expanded access program. 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), serial 
numbers, or chemical descriptions.
    (viii) Intervention Description. Details that can be made public 
about each intervention, other than the Intervention Name or Other 
Intervention Name, sufficient to distinguish it from other, similar 
interventions available through other expanded access programs or 
clinical trials.
    (ix) Intervention Type. For each intervention available through the 
expanded access program, the general type of intervention.
    (2) Recruitment information:
    (i) Eligibility Criteria. A limited list of criteria for 
determining who is eligible to receive treatment in the expanded access 
program, provided in terms of inclusion and exclusion criteria and 
suitable for assisting potential patients in identifying expanded 
access programs of interest.
    (ii) Gender. The biological sex of the patients who may receive 
treatment in the expanded access program.
    (iii) Age Limits. The minimum and maximum age of patients who may 
receive treatment in the expanded access program, provided in relevant 
units of time.
    (iv) Expanded Access Status. The status of availability of the 
investigational drug through the expanded access program.
    (3) Location and Contact Information:
    (i) Name of the Sponsor.
    (ii) Responsible Party, by Official Title.
    (A) If the responsible party entering the clinical trial 
information into the expanded access record is an entity, the official 
name of the entity; or
    (B) If the responsible party entering the clinical trial 
information into the expanded access record is an individual, the 
official title and primary organizational affiliation of the 
individual.
    (iii) Contact Information. The name or official title, toll-free 
telephone number, and email address of a person to whom questions 
concerning the expanded access program can be addressed.
    (4) Administrative data. (i) Unique Protocol Identification Number. 
Any unique identification number assigned to the expanded access 
program by the sponsor.
    (ii) Secondary IDs.(A) Any identification number(s) other than the 
organization's unique protocol identification number or the NCT number 
that is assigned to the expanded access program, including any unique 
identification numbers 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) Food and Drug Administration IND Number. The IND number for 
the expanded access program, which must include each of the following 
elements:
    (A) Name or abbreviation of the FDA center with whom the IND is 
filed (i.e., CDER, CBER);
    (B) IND number assigned by the FDA center; and
    (C) IND serial number (as defined in 21 CFR 312.23(e), or any 
successor regulation), if any, assigned to the expanded access program.
    (iv) Record Verification Date. The date upon which the responsible 
party last verified the clinical trial information in the entire 
ClinicalTrials.gov record for the expanded access program, 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 NIH post clinical trial registration 
information submitted under Sec.  11.28?

    (a) Applicable drug clinical trial. NIH will post publicly at 
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 in accordance with Sec.  11.24 of this part.
    (b) Applicable device clinical trial. (1) For an applicable device 
clinical trial of a device that previously was approved or cleared, NIH 
will post publicly at ClinicalTrials.gov 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 Sec.  11.52 of this part.
    (2) 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.

Subpart C--Results 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 in accordance with subpart C of this 
regulation?

    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 submission of clinical

[[Page 69674]]

trial registration information is required under Sec.  11.22 and that 
meets one of the following criteria:
    (a) The completion date of the clinical trial is on or after the 
effective date of this rule; or
    (b) The completion date of the clinical trial 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.  11.44  When must clinical trial results information be submitted 
for applicable clinical trials subject to Sec.  11.42?

    (a) Standard submission deadlines (1) In general, clinical trial 
results information specified in Sec.  11.48 must be submitted no later 
than 1 year after the completion date, except as otherwise provided in 
this section.
    (2) Submitting clinical trial results information following initial 
approval, licensure, or clearance. Except as otherwise provided in 
Sec. Sec.  11.44(b), (c), (d) or (e), for any applicable clinical trial 
of an FDA-regulated drug or device that is not approved, licensed, or 
cleared as of the completion date and that receives initial FDA 
approval, licensure, or clearance thereafter, clinical trial results 
information specified in Sec.  11.48(a) must be submitted by the 
earlier of the following:
    (i) The submission deadline specified in Sec.  11.44(a)(1); or
    (ii) The date that is 30 calendar days after FDA approves, 
licenses, or clears the drug or device for any indication studied in 
the applicable clinical trial.
    (b) Delayed submission of results with certification if seeking 
approval, licensure, or clearance of a new use. (1) If, prior to the 
results submission deadline specified under paragraph (a)(1) of this 
section, the responsible party submits to ClinicalTrials.gov a 
certification that an applicable clinical trial involves an FDA-
regulated drug or device 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 or device) has been filed or will be filed within 1 year 
with FDA, the deadline for submitting complete clinical trial results 
information will be 30 calendar days after the earliest of the 
following events:
    (i) FDA approves, licenses, or clears the drug or device 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 or device 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 
complete clinical trial results information 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 or device 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 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.
    (c) Delayed submission of results with certification if seeking 
initial approval, licensure or clearance of a drug or device. (1) If, 
prior to the submission deadline specified under paragraph (a)(1) of 
this section, a responsible party submits to ClinicalTrials.gov a 
certification that an applicable clinical trial studies an FDA-
regulated drug or device that was not approved, licensed, or cleared by 
FDA for any use before the 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 or device under study, the deadline for 
submitting complete clinical trial results information will be 30 
calendar days after the earlier of the date on which:
    (i) FDA approves, licenses, or clears the drug or device for any 
indication that is studied in the applicable clinical trial;
    (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 
complete clinical trial results information 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. (1) If required clinical trial 
results information specified in Sec.  11.48 has not been collected for 
a secondary outcome measure by the completion date, the responsible 
party must submit clinical trial results information for that secondary 
outcome measure by the later of:
    (i) 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, or
    (ii) If a certification to delay results submission has been 
submitted under paragraph (b) or (c) of this section, the date on which 
results information for the primary outcome measures are due pursuant 
to paragraph (b) or (c) of this section.
    (2) If clinical trial results information was submitted for the 
primary outcome measure(s) prior to the effective date of the rule but 
data collection for all of the secondary outcome measure(s) is not 
completed until on or after the effective date of the rule, clinical 
trial results information for all primary and secondary outcome 
measures must be submitted in accordance with Sec.  11.48 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 such secondary outcome measure(s), whether the clinical trial was 
concluded according to the pre-specified protocol or was terminated.
    (e) Extensions. (1) Requesting a good-cause extension of the 
results submission deadline. A responsible party may request a good-
cause extension of the deadline for submitting clinical trial results 
information to ClinicalTrials.gov subject to paragraphs (e)(1)(i) and 
(ii) of this section. A responsible party may request more than one 
good-cause extension for the same applicable clinical trial and may 
request a good-cause extension of a delayed results submission deadline 
established by the submission of a

[[Page 69675]]

certification as described in paragraph (b) or (c) of this section.
    (i) The responsible party must submit a request for a good-cause 
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), or (f) of this section.
    (ii) A request for a good-cause extension must contain the 
following elements:
    (A) Description of the reason(s) why clinical trial results 
information cannot be provided according to the deadline, with 
sufficient detail to allow 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 NIH will provide a 
written response electronically to the responsible party indicating 
whether or not the requested extension has been granted, and the 
responsible party must either submit clinical trial results information 
not later than the deadline established by paragraphs (e)(2)(i) or (ii) 
of this section, as applicable, or appeal the denial in accordance with 
paragraph (e)(3) of this section.
    (i) If the good-cause 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 good-cause extension request is denied, the responsible 
party must either appeal in accordance with paragraph (e)(3) of this 
section or submit complete clinical trial results information by the 
later of the original submission deadline specified in paragraph (a), 
(b), (c), (d), or (f) of this section, as applicable, or 15 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 in the form of a 
written letter to the Director not later than 15 calendar days after 
the date on which the electronic notification of grant or denial of the 
request is sent to the responsible party.
    (ii) An appeal letter must contain an explanation of the reason(s) 
why the initial decision to deny an extension request or to grant an 
extension request with a shorter deadline than requested should be 
overturned or revised.
    (iii) The Director will provide an electronic notification to the 
responsible party indicating whether or not 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 an appeal of a denied extension request, 
the responsible party must submit clinical trial results information by 
the later of the original submission deadline specified in paragraph 
(a), (b), (c), (d) or (f) of this section, or 15 calendar days after 
the electronic notification of the denial upon 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 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 15 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 that is not a 
clinical trial. For each pediatric postmarket surveillance of a device 
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) not later than 30 calendar days after the date on which 
the final report of the approved pediatric postmarket surveillance of a 
device as specified in 21 CFR 822.38 (or any successor regulation) 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 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 affecting the number of human subjects enrolled in the clinical 
trial but not assigned to an arm, if any.
    (iii) Participant Data. The number of human subjects 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) Overall Number of Baseline Participants. The total number of 
human subjects for whom baseline characteristics were measured, by arm 
or comparison group, and overall.
    (iii) Baseline Measure Information. 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 are used in the analysis of outcome measures 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 in submitting the results;
    (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;
    (C) 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 who participated in the clinical trial.
    (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

[[Page 69676]]

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 which 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 differs from the number of human subjects 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 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) Outcome Measure Reporting Status. Whether data for the outcome 
measure are included in the present submission and, if not, the 
anticipated submission date;
    (F) Measure Type. For each outcome measure for which data are 
collected, the type of data to be submitted (number or measure of 
central tendency) and, if a measure of central tendency, the related 
measure of dispersion or precision;
    (G) 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 
statistical analyses, if any, including any statistical analysis that 
is:
    (A) Pre-specified in the protocol and/or statistical analysis plan 
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. Submitted Statistical Analysis 
information must include:
    (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 test, a 
description of the analysis that includes, at minimum, the power 
calculation and non-inferiority margin;
    (2) Statistical Test of Hypothesis: The p-value and the procedure 
used for the statistical analysis;
    (3) Method of Estimation: The estimation parameter, estimated 
value, and confidence interval.
    (4) Adverse event information. (i) Information 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 frequency of each event by arm or comparison group; 
and
    (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.
    (ii) Information for each table specified in paragraph (a)(4)(i) of 
this section must include the following elements:
    (A) Adverse Event Arm/Comparison 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, by Arm or Comparison Group. The overall 
number of human subjects affected, by arm or comparison group, by one 
or more
    (1) Serious adverse event(s), or
    (2) Adverse event(s) other than serious adverse events that exceed 
a frequency of 5 percent within any arm of the clinical trial.
    (C) Total Number at Risk, by Arm or Comparison Group. The overall 
number of human subjects included in the assessment, by arm or 
comparison group, for
    (1) Serious adverse events, or
    (2) Adverse event(s) other than serious adverse events that exceed 
a frequency of 5 percent within any arm of the clinical trial.
    (D) Total Number Affected, by Organ System. For each organ system 
that has one or more adverse events listed in either the table of 
serious adverse events or the table of adverse events other than 
serious adverse events that exceed a frequency of 5 percent within any 
arm of the clinical trial, the overall number of human subjects 
affected, by arm or comparison group, within each table.
    (E) Total Number at Risk, by Organ System. For each organ system 
that has one or more adverse events listed in either the table of 
serious adverse events or the table of adverse events other than 
serious adverse events that exceed a frequency of 5 percent within any 
arm of the clinical trial, the overall number of human subjects at risk 
for the adverse event, by arm or comparison group.
    (F) Adverse Event Information. 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:
    (1) Descriptive term for the adverse event; and
    (2) Organ system associated with the adverse event.
    (G) Adverse Event Data. For each type of adverse event listed in 
accordance with paragraph (a)(4)(ii)(F) of this section:
    (1) Number of human subjects affected by such adverse event;
    (2) Number of human subjects at risk for such adverse event;
    (H) Additional Adverse Event Description. If the adverse event 
information collected in the applicable 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.
    (iii) Information submitted by organ system must be grouped 
according to the organ system classification established in 
ClinicalTrials.gov.
    (5) 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 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

[[Page 69677]]

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 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.
    (6) Additional clinical trial results information for applicable 
device clinical trials of unapproved or uncleared devices. (i) For an 
applicable device clinical trial of an unapproved or uncleared device, 
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; Other Intervention Name; Intervention 
Description; Intervention Type; U.S. FDA Approval, Licensure, or 
Clearance Status; Study Start Date; Completion Date; Enrollment; 
Primary Outcome Measure Information, as previously submitted to 
ClinicalTrials.gov; Secondary Outcome Measure Information as previously 
submitted to ClinicalTrials.gov; Eligibility Criteria; Gender; Age 
Limits; Accepts Healthy Volunteers; Overall Recruitment Status; Why 
Study Stopped; Actual Enrollment; 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 IDs; Human Subjects Protection Review 
Board Status; and Record Verification Date.
    (ii) The responsible party shall submit the results information 
specified in paragraph (a)(6)(i) of this section by submitting an 
affirmation that the information previously submitted to 
ClinicalTrials.gov for the data elements listed in paragraph (a)(6)(i) 
of this section have been updated in accordance with Sec.  11.64(c) and 
are to be included as clinical trial results information.
    (b) Pediatric postmarket surveillance of a device that is not a 
clinical trial. For each pediatric postmarket surveillance of a device 
that is not a clinical trial, the responsible party must submit a copy 
of any written final report that is submitted to FDA as specified in 21 
CFR 822.38 (or any successor regulation). The final written report must 
be in a common electronic document format specified at http://prsinfo.clinicaltrials.gov. The responsible party must redact names, 
addresses, and other personally identifiable information or commercial 
confidential information contained in the final written report prior to 
submission to NIH. Redacted information may not include any information 
specified in Sec. Sec.  11.28(a) or 11.48(a) of this part.


Sec.  11.52  When will NIH post submitted clinical trial results 
information?

    The Director 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.


Sec.  11.54  What are the procedures for waiving of the requirements of 
this subpart?

    (a) Waiver request.
    (1) A responsible party may request a waiver from any applicable 
requirement(s) of this subpart by submitting a waiver request in the 
form of a written letter to the Secretary or delegate prior to the 
deadline specified in Sec.  11.42(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 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 15 calendar days after the 
notification of the denial is sent to the responsible party.
    (b) Appealing a denied waiver request
    (1) A responsible party may appeal a denied waiver request by 
submitting a letter in writing to the Secretary or delegate not later 
than 15 calendar days after the date on which the letter in paragraph 
(a)(iii) of this section denying the request is transmitted.
    (2) The responsible party is not required to comply with any 
requirements of this subpart for which the 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 15 calendar days after the written notice of the denial upon appeal 
is sent by the Secretary.
    (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 part of a waiver 
is granted.

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 drugs 
and devices?

    (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) Clinical trials to which this section applies. The requirements 
of this section apply to the following types of clinical trials:
    (i) A clinical trial of an FDA-regulated drug or device that is not 
an applicable clinical trial, and
    (ii) An applicable clinical trial that is not required to submit 
clinical trial registration information under Sec.  11.22(a).
    (2) Conditions for voluntary submission of certain clinical trials. 
The following conditions must be met by a responsible party who 
voluntarily submits clinical trial information for a clinical trial 
that is described in paragraph (a)(1) of this section.
    (i) The responsible party must submit the information in (A) or (B) 
for the clinical trial being submitted voluntarily.
    (A) If the responsible party voluntarily registers a clinical 
trial, the responsible party must submit complete clinical trial 
registration information specified in Sec.  11.28(a). The responsible 
party may, but is not required to, submit

[[Page 69678]]

complete clinical trial results information in Sec.  11.48(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 Sec.  11.48(a), as well as the data elements listed below, 
as those the data elements are defined in Sec.  11.10(b) and apply to 
the clinical trial and the interventions studied: Brief Title; Official 
Title; Brief Summary; Primary Purpose; Study Design; Study Phase, for a 
clinical trial of a drug; Study Type; Whether the Study is a Pediatric 
Postmarket Surveillance of a Device; Primary Disease or Condition Being 
Studied in the Trial; or the Focus of the Study; Intervention Name, for 
each intervention studied; Other Intervention Name, for each 
intervention studied; Intervention Description, for each intervention 
studied; Intervention Type, for each intervention studied; U.S. FDA 
Approval, Licensure, or Clearance Status, for each intervention 
studied; Product Manufactured in the U.S., for each intervention 
studied; Studies an FDA-regulated Device; Studies an FDA-regulated 
Drug; Study Start Date; Completion Date; Enrollment; Eligibility 
Criteria; Gender; Age Limits; Accepts Healthy Volunteers; Overall 
Recruitment Status; Why Study Stopped; Actual Enrollment; Availability 
of Expanded Access; Name of the Sponsor; Responsible Party by Official 
Title; Facility Name and Facility Location, for each participating 
facility; Unique Protocol Identification Number; Secondary IDs; Food 
and Drug Administration IND or IDE Number; Human Subjects Protection 
Review Board Status; Record Verification Date; and Responsible Party 
Contact Information.
    (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 or device under sections 505, 510(k), 515, or 
520(m) of the Federal Food, Drug, and Cosmetic Act or section 351 of 
the Public Health Service Act 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 or section 351 of the Public Health Service Act 
in an application or premarket notification for approval, licensure, or 
clearance to market the drug or device for the use studied in the 
clinical trial specified in paragraph (a)(1) of this section; and
    (B) The manufacturer of the drug or device 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 Sec.  
11.28(a), then 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 Sec.  11.28(a).
    (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 Sec.  
11.60(a)(2)(i)(B), then 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 Sec.  11.60(a)(2)(i)(B).
    (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 Sec.  
11.28(a) and the clinical trial results information specified in Sec.  
11.48(a), then the information to be submitted in accordance with 
paragraph (a)(2)(ii) of this section must consist of the clinical trial 
registration information specified in Sec.  11.28(a) and the clinical 
trial results information specified in Sec.  11.48(a).
    (iv) Submission deadlines:
    (A) Secondary outcome measure(s) for voluntarily-submitted clinical 
trials under paragraph (a) of this section. If data collection for the 
secondary outcome measure(s) for a voluntarily-submitted clinical trial 
under paragraph (a) of this section, which submission consists of 
clinical trial results information, is not completed by the completion 
date of the voluntarily-submitted clinical trial, then clinical trial 
results information for the secondary outcome measure(s) 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.
    (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 or device under 
section 351 of the Public Health Service Act or sections 505, 510(k), 
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act 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.
    (v) All submissions of clinical trial information under paragraph 
(a) of this section are subject to the update requirements specified in 
Sec.  11.64 and the corrections requirements specified in Sec.  11.66.
    (b) Statement to accompany applicable clinical trials submitted 
under paragraph (a) of this section. Each applicable clinical trial for 
which clinical trial information is submitted under paragraph (a) of 
this section and posted at ClinicalTrials.gov will include the 
statement ``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 or

[[Page 69679]]

device that has a 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 or device that is unapproved, 
unlicensed, or uncleared.
    (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 clinical trial registration 
information specified in Sec.  11.28(a) and clinical trial results 
information specified in Sec.  11.48(a) to ClinicalTrials.gov 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 
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 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?

    (a) General. (1) Except as provided in paragraphs (b) and (c) of 
this section, the responsible party for an applicable clinical trial or 
other clinical trial must submit updates to reflect changes to 
previously-submitted clinical trial information not less than once 
every 12 months, unless there are no changes to the clinical trial 
information during the preceding 12-month period.
    (2) Updates to the estimated Completion Date must be submitted not 
less than once every 12 months, unless there is no change to the 
estimated date during the preceding 12-month period.
    (3) A responsible party must continue to submit updates as 
specified in this section until the date on which 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.
    (b) Items Requiring More Rapid Updates. (1) A responsible party 
must submit updates to reflect changes to the following clinical trial 
information data elements not later than 30 calendar days after the 
change has occurred:
    (i) 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.
    (ii) 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.
    (iii) Availability of Expanded Access. (A) If expanded access to a 
drug becomes available after a clinical trial of that drug has been 
registered, the responsible party must, not later than 30 calendar days 
after expanded access becomes available, update the Availability of 
Expanded Access data element for that clinical trial and, unless an 
expanded access record has already been created as required by Sec.  
11.28(a)(2)(ix), submit the data elements listed in Sec.  11.28(c) to 
create an expanded access record.
    (B) Upon receipt of an NCT number for an expanded access record 
created for a clinical trial under Sec.  11.28(a)(2)(ix), the 
responsible party must update the Availability of Expanded Access data 
element by entering in the clinical trial record the NCT number of the 
expanded access record no later than 30 calendar days after the date on 
which the responsible party receives such NCT number.
    (C) Upon termination of an expanded access program, the responsible 
party must, not later than 30 calendar days after the date of 
termination, update the Availability of Expanded Access data element to 
indicate that expanded access is no longer available.
    (iv) 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 access to an investigational drug or investigational 
device under section 561 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 360bbb).
    (v) Overall Recruitment Status must be updated not later than 30 
calendar days after any change in overall recruitment status. At the 
time Overall Recruitment Status is changed, the responsible party must 
also make the following updates, as applicable:
    (A) If Overall Recruitment Status is changed to ``suspended,'' 
``terminated,'' or ``withdrawn,'' the Why Study Stopped data element 
must be submitted.
    (B) If Overall Recruitment Status is changed to ``terminated'' or 
``active, not recruiting,'' the Actual Enrollment data element must be 
submitted.
    (vi) Individual Site Status must be updated not later than 30 
calendar days after a change in status of any individual site.
    (vii) Human Subjects Protection Review Board Status must be updated 
not later than 30 calendar days after a change in status.
    (viii) Completion Date must be updated not later than 30 calendar 
days after the clinical trial reaches its actual completion date;
    (ix) 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;
    (x) Responsible Party Contact Information must be updated not later 
than 30 calendar days after a change in the responsible party or the 
contact information of the responsible party;
    (2) Updates to the U.S. FDA Approval, Licensure, or Clearance 
Status data element must be submitted not later than 15 calendar days 
after a change in status has occurred.
    (3) If a protocol is amended in such a manner that changes are 
communicated to human subjects in the clinical trial, updates to 
relevant clinical trial information data elements must be submitted no 
later than 30 calendar days after the protocol amendment is approved by 
a human subjects protection review board.
    (4) Record Verification Date 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.
    (c) Irrespective of update requirements established in paragraphs 
(a) and (b) of this section, upon submission of clinical trial results 
information for an applicable clinical trial or other clinical trial, a 
responsible party must submit updates to the clinical trial 
registration information submitted previously to ClinicalTrials.gov for 
that applicable clinical trial or other clinical trial, unless there 
are no changes to the clinical trial registration information.
    (d) Public availability of updates.
    (1) Updates to clinical trial registration information and clinical

[[Page 69680]]

trial results information will be posted in accordance with Sec.  11.35 
and Sec.  11.52, respectively.
    (2) 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 the updates do not result in the 
removal of any information from the original submission or any 
preceding update.


Sec.  11.66  What are the requirements for corrections of clinical 
trial information?

    (a) Correction of errors. A responsible party who becomes aware of 
errors in any clinical trial information submitted under this part or 
is informed by NIH that such clinical trial information contains errors 
shall correct such errors not later than 15 calendar days after the 
date on which the responsible party becomes aware of the errors or on 
which NIH informs the responsible party of the errors, whichever is 
earlier.
    (b) Correction of falsified data. A responsible party who becomes 
aware that clinical trial information submitted under this part was 
falsified or based on falsified information, shall notify the Director 
that such information was determined to be falsified or based on 
falsified information and either:
    (1) Submit corrected clinical trial information not later than 15 
calendar days after corrected information becomes available; or
    (2) Notify the Director not later than 15 calendar days after 
determining that such information cannot be corrected or is correct as 
submitted.
    (c) Other corrections of clinical trial information. A responsible 
party who becomes aware or is informed by NIH that corrections other 
than those specified in paragraphs (a) or (b) of this section are 
needed to any clinical trial information submitted under this part, 
shall correct such clinical trial information as soon as possible, but 
not later than 15 calendar days after the date on which the responsible 
party becomes aware, or is informed by NIH that such clinical trial 
information is in need of correction, whichever is earlier.

    Dated: October 7, 2014.
Francis S. Collins,
Director, National Institutes of Health.
    Approved: October 28, 2014.
Sylvia Mathews Burwell,
Secretary.
[FR Doc. 2014-26197 Filed 11-19-14; 11:15 am]
BILLING CODE 4140-01-P