[Federal Register Volume 87, Number 236 (Friday, December 9, 2022)]
[Proposed Rules]
[Pages 75551-75569]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-26731]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. FDA-2020-N-0258]
RIN 0910-AI37


Investigational New Drug Application Annual Reporting

AGENCY: Food and Drug Administration, Department of Health and Human 
Services (HHS).

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
proposing to replace its current annual reporting requirement for 
investigational new drug applications (INDs) with a new requirement: 
the annual FDA development safety update report (FDA DSUR). The 
proposed annual FDA DSUR is intended to be consistent with the format 
and content of the DSUR that is supported by the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH), which is described in FDA's ICH guidance for industry 
entitled ``E2F Development Safety Update Report'' (E2F DSUR) (August 
2011). The proposed annual FDA DSUR regulation, if finalized, would 
require an annual report that is more comprehensive and informative 
than the IND annual report currently required under FDA regulations.

DATES: Submit either electronic or written comments on the proposed 
rule by March 9, 2023. Submit comments on information collection issues 
under the Paperwork Reduction Act of 1995 (PRA) by January 9, 2023.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of March 9, 2023. Comments received 
by mail/hand delivery/courier (for written/paper submissions) will be 
considered timely if they are postmarked or the delivery service 
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2020-N-0258 for ``Investigational New Drug Application Annual 
Reporting.'' Received comments, those filed in a timely manner (see 
ADDRESSES) will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://

[[Page 75552]]

www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    Submit comments on information collection issues under the PRA to 
the Office of Management and Budget (OMB) in the following ways:
     Fax to the Office of Information and Regulatory Affairs, 
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or email to 
[email protected]. All comments should be identified with the 
title, ``Investigational New Drug Application Annual Reporting.''

FOR FURTHER INFORMATION CONTACT: 
    With regard to the proposed rule: Dat Doan, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 3334, Silver Spring, MD 20993-0002, 240-
402-8926, [email protected]; or Stephen Ripley, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-
402-7911, [email protected].
    With regard to the information collection: Domini Bean, Office of 
Operations, Food and Drug Administration, Three White Flint North 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms Used in This 
Document
III. Background
    A. Introduction
    B. Need for the Regulation
    C. FDA's Current Regulatory Framework
    D. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
    A. Scope
    B. Definitions
    C. Proposed Provisions of the FDA DSUR
VI. Proposed Effective and Compliance Dates
VII. Preliminary Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
    C. Summary of Regulatory Flexibility Analysis
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to replace the current annual reporting 
requirement under Sec.  312.33 (21 CFR 312.33), Annual reports, with a 
new requirement under Sec.  312.33, Development safety update reports. 
Current Sec.  312.33 requires sponsors that have an IND in effect to 
submit an annual report that must contain individual study information, 
which generally includes brief summaries of the status of each ongoing 
study and of each study completed during the previous year. The 
proposed annual FDA DSUR regulation would require these sponsors to 
provide an annual report that is more comprehensive and informative 
than the IND annual report currently required under FDA regulations--
such as the requirement for an integrated overall safety analysis and a 
summary of cumulative pertinent safety information. In light of the 
increasing complexity of clinical studies, requiring a DSUR that offers 
a more comprehensive and informative assessment of risk than the 
current annual report would provide an important tool for FDA and 
sponsors to identify and manage potential risks and therefore reduce 
exposure of human subjects to unnecessary risks. Furthermore, because 
FDA intends that the DSUR be consistent with the format and content of 
submission of the DSUR supported by ICH, the annual reporting process 
for sponsors would be more efficient by supporting one format for 
submission to FDA and multiple regulatory authorities in the European 
Union (EU) and other countries and regions. This action is consistent 
with FDA's overarching goal of fostering international harmonization of 
regulatory requirements to the extent appropriate and feasible. If ICH 
updates its DSUR guidelines, FDA may evaluate the proposed regulation 
to determine if any corresponding updates are necessary.

B. Summary of the Major Provisions of the Proposed Rule

    The following is a brief summary of the proposed revisions to the 
current requirements for IND annual reporting that are made by the 
proposed annual FDA DSUR regulation:
     Expands the scope to require comprehensive information and 
allow for a thorough assessment by FDA of clinical investigations 
conducted anywhere in the world on behalf of the sponsor evaluating the 
drug (proposed Sec.  312.33(a)(1)).
     Provides that a sponsor-investigator for a clinical 
investigation that is not intended to support a marketing application 
is only required to submit information obtained from that clinical 
investigation (e.g., information that is part of that sponsor-
investigator's protocol for the IND) (proposed Sec.  312.33(a)(2)).
     Requires an executive summary (proposed Sec.  312.33(c)).
     Requires a description of all actions relevant to the 
safety of the drug that were taken during the reporting period by any 
regulatory authority or by the sponsor, if known (proposed Sec.  
312.33(g)).
     Provides that the investigator brochure would serve as the 
reference safety information during the reporting period. If a sponsor 
is not required to submit an investigator brochure, the FDA-approved 
prescribing information would serve as the reference safety 
information. If the sponsor uses another source as the reference safety 
information, the regulation would require the sponsor to identify the 
reference safety information used (proposed Sec.  312.33(h)(1)).
     Requires sponsors to provide a list of all safety-related 
changes to the reference safety information, if applicable, for the 
investigational drug during the reporting period. (proposed Sec.  
312.33(h)(2)).
     Requires that the report provide the clinical trial phase, 
the date the first participant provided informed consent, a brief 
description of the clinical investigation, and a brief description of 
the dose and regimen of the investigational drug and any comparators as 
part of an inventory of clinical investigations conducted during the 
reporting period. Also expands the requirement for information on study 
subjects to include the cumulative number of subjects enrolled in all 
treatment arms of each clinical investigation (or an estimate), the 
countries or regions in which each investigation was conducted, and the 
total number of subjects planned to be enrolled in each clinical 
investigation (proposed Sec.  312.33(i)).
     Adds the requirement to include the cumulative number of 
subjects exposed to the investigational drug and comparators during 
clinical investigations that are conducted on behalf of the sponsor 
(proposed Sec.  312.33(j)).
     Adds the requirement that sponsors provide line listings 
of all serious suspected adverse reactions (as defined in Sec.  
312.32(a)) that occurred during the reporting period, including 
treatment assignment. Adds the requirement that

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the line listings of all serious suspected adverse reactions identify 
those that are unexpected (serious and unexpected suspected adverse 
reaction) as defined in Sec.  312.32(a).
     Adds the requirement to include a cumulative summary 
tabulation of serious adverse events (as defined in Sec.  312.32(a)) 
obtained from all clinical investigations conducted on behalf of the 
sponsor that occurred since the date the IND went into effect (proposed 
Sec.  312.33(k)(1)(ii)).
     Requires identifying each event omitted from the listings 
and tabulations of safety data required under proposed Sec.  
312.33(k)(1) because the event is a study endpoint or a component of a 
study endpoint (proposed Sec.  312.33(k)(2)).
     Requires a brief summary of safety and effectiveness 
findings from clinical investigations of the investigational drug 
conducted on behalf of the sponsor that are obtained during the 
reporting period (proposed Sec.  312.33(l)).
     Adds the requirement that the sponsor submit a brief 
summary of key safety findings obtained from other sources during the 
reporting period (proposed Sec.  312.33(m)).
     Requires sponsors to provide a summary of significant 
chemistry, manufacturing, and control changes, including 
microbiological changes (if applicable), made to the investigational 
drug during the reporting period, as well as a brief description of the 
safety significance of the identified changes (proposed Sec.  
312.33(n)).
     Requires a concise, integrated evaluation of all new 
clinical, nonclinical, and epidemiological safety information obtained 
about the drug by the sponsor during the reporting period relative to 
the sponsor's prior knowledge of the drug (proposed Sec.  312.33(s)).
     Requires providing a cumulative listing and brief 
description of all important known risks and potential risks associated 
with the use of the drug identified by the sponsor throughout the 
course of studies of the drug conducted on behalf of the sponsor 
(proposed Sec.  312.33(t)).
     Requires a conclusion that briefly summarizes changes to 
the sponsor's previous knowledge of the investigational drug's efficacy 
and safety resulting from information obtained during this reporting 
period, in addition to an outline of actions by the sponsor that have 
been taken during the current reporting or will be taken in the future 
to address emerging safety findings (proposed Sec.  312.33(u)).

C. Legal Authority

    FDA is issuing this proposed rule under sections 201, 301, 501, 
502, 503, 505, and 701 of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 321, 331, 351, 352, 353, 355, and 371) and under 
section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262).

D. Costs and Benefits

    The estimated benefits would result from savings in labor costs for 
sponsors who may no longer have to prepare a different type of periodic 
safety report for submission to certain other countries or regions in 
which a drug might be studied. Moreover, FDA would receive safety data 
on investigational new drugs that is more comprehensive, which would 
enhance our ability to oversee the progress and safety of clinical 
investigations. The estimate of annualized benefits over 10 years 
ranges from $47.86 million to $117.99 million with a primary value of 
$86.46 million at a 7 percent discount rate and from $49.24 million to 
$121.01 million with a primary value of $88.79 million at a 3 percent 
discount rate. The primary estimate of the present value of benefits 
over 10 years is $607.29 million at a 7 percent discount rate and 
$757.38 million at a 3 percent discount rate. Costs would arise from 
increased labor associated with preparing and submitting a periodic 
safety report that is more comprehensive to meet the proposed 
requirements. Costs to government would arise from increased FDA 
resources being used to review the more comprehensive report. The 
estimate of annualized costs over 10 years ranges from $40.43 million 
to $101.34 million at a 7 percent discount rate with a primary value of 
$61.11 million. Using a 3 percent discount rate, the annualized costs 
range from $40.89 million to $102.48 million with a primary value of 
$61.81 million. The primary estimate of the present value of costs over 
10 years is $429.20 million at a 7 percent discount rate and $527.21 
million at a 3 percent discount rate.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

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     Abbreviation/acronym                    What it means
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CBER.........................  Center for Biologics Evaluation and
                                Research.
CDER.........................  Center for Drug Evaluation and Research.
CIOMS........................  Council for International Organizations
                                of Medical Sciences.
DMC..........................  Data Monitoring Committee.
DSUR.........................  Development Safety Update Report.
E2F DSUR.....................  E2F Development Safety Update Report
                                (guidance for industry).
EU...........................  European Union.
FDA..........................  Food and Drug Administration.
FDA DSUR.....................  FDA Development Safety Update Report.
ICH..........................  International Council for Harmonisation.
IND..........................  Investigational New Drug Application.
OMB..........................  Office of Management and Budget.
PHS..........................  Public Health Service.
PRA..........................  Paperwork Reduction Act of 1995.
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III. Background

A. Introduction

    FDA is proposing to replace the current annual reporting 
requirement with a new annual reporting requirement. The proposed 
action would require IND sponsors to submit an annual FDA DSUR--a 
report that retains the general aspects of the current annual report 
but includes information that is more comprehensive and is generally 
consistent with the format and content of the E2F DSUR (available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e2f-development-safety-update-report). The proposed annual 
FDA DSUR is similar to the annual safety reporting requirements in 
certain other countries and regions in which a drug might be studied. 
Promulgation of a rule containing requirements that are similar to the 
DSUR recommendations developed by ICH (see E2F DSUR) is also consistent 
with FDA's overarching goal of fostering international

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harmonization of regulatory requirements to the extent appropriate and 
feasible. Therefore, FDA expects that some of the additional regulatory 
burden associated with preparing a report for FDA that is more 
comprehensive than previously required will be offset by the mitigation 
of the previous regulatory burden on those sponsors who submit multiple 
different reports to regulatory authorities in other countries or 
regions.

B. Need for the Regulation

    FDA is proposing this action because of the advantages that the 
proposed annual FDA DSUR would provide over the current IND annual 
report. The advantages include: (1) enabling FDA to more efficiently 
identify and review new safety signal information; (2) creating a more 
efficient reporting process for certain sponsors by supporting a more 
comprehensive format for submission to FDA and multiple regulatory 
authorities worldwide; and (3) allowing regulatory authorities 
worldwide to have access to the same data within the same timeframes. 
For example, the DSUR includes a section that tracks knowledge about 
each specific safety issue through time, facilitating efficient 
identification and review of any new safety signal information. The 
integration of data from a development program with postmarketing data 
provides a powerful means to facilitate identification and review of 
any new safety signals. As discussed in section III.D.3, the proposed 
annual FDA DSUR will provide a more comprehensive and detailed safety 
summary than the IND annual report, which will facilitate reviewers' 
ability to efficiently identify and review new safety signal 
information.
    The proposed annual FDA DSUR would better capture and characterize 
the evolving safety profile of the investigational drug and would 
better describe new safety findings that could have an impact on the 
protection of study subjects. Simply accumulating and reporting data 
for a given time period, as required under the current IND annual 
report, without considering all previously available data from clinical 
trials and other sources, may delay identification of important risks. 
DSURs specifically include a section that tracks knowledge about each 
specific safety issue through time, facilitating efficient 
identification and review of any new safety signal information.
    Furthermore, a requirement for investigational drug reporting 
similar to the reporting done in the EU could help sponsors who need to 
satisfy annual reporting requirements in different countries and 
regions and would help prevent sponsors from sending duplicative 
information in different formats to different regulatory authorities. A 
similar annual reporting requirement would also help provide 
authorities in different countries with a common description of the 
evolving safety profile of a drug, and thus, could help ensure greater 
consistency and predictability in regulatory actions. We expect that 
the proposed annual FDA DSUR would help harmonize FDA's requirements 
for IND annual reporting with the E2F DSUR.
    We have received support for the proposed annual FDA DSUR through 
public comments submitted in response to documents published in the 
Federal Register. For example, in response to a request for public 
comment in the Federal Register of April 27, 2011 (76 FR 23520), a 
trade organization representing major biotechnology companies urged FDA 
to update its regulations to reflect current practice and to be 
consistent with the language in the E2F DSUR. (See Docket No. FDA-2011-
N-0259.) In the Federal Register of August 5, 2008 (73 FR 45462), FDA 
requested public comment on the E2F DSUR draft guidance for industry. 
In response, FDA received comments from pharmaceutical manufacturers 
and a trade association. (See Docket No. FDA-2008-D-0386.) Some 
comments proposed certain modifications to the DSUR as described in the 
draft guidance but were generally supportive of the draft guidance and 
noted that the use of the E2F DSUR would help harmonize annual 
reporting of clinical trials, thus enhancing efficiency and providing 
regulators, investigators, patients, and industry with valuable, 
consolidated safety information. Other comments expressed a preference 
for the use of the E2F DSUR to minimize discrepancies, which are, at 
the present time, common in the information different regulators 
receive. Taken together, the public comments expressed support for 
requiring a single reporting format for periodic safety reporting under 
an IND and a preference for use of the format, content, and timing of 
the E2F DSUR.

C. FDA's Current Regulatory Framework

1. IND Regulations
    The IND regulations in part 312 contain procedures and requirements 
governing the use of investigational drugs, including biological 
products that do not also meet the definition of device under the FD&C 
Act (see 21 U.S.C. 321(g) through (h), 42 U.S.C. 262(i) through (j); 
see also 21 CFR 601.21) and contain procedures and requirements for the 
submission of INDs to FDA and for FDA's review of those INDs. Under the 
IND regulations in part 312, sponsors are required to have an IND in 
effect to support the use of an investigational drug in clinical trials 
or for expanded access uses. The IND regulations also provide various 
mechanisms for continued FDA oversight of clinical investigations 
conducted under an IND. The IND annual report currently required under 
Sec.  312.33 is intended to serve as the means for reporting the status 
of studies being conducted under the IND and for providing the general 
investigational plan and safety-related changes to the investigational 
plan for the coming year. This proposed rule focuses on Sec.  312.33, 
Annual report.
2. FDA's IND Annual Report
    In the Federal Register of March 19, 1987 (52 FR 8798, as amended 
at 52 FR 23031, June 17, 1987; 63 FR 6854, February 11, 1998; and 67 FR 
9584, March 4, 2002), FDA published regulations for new drug, 
antibiotic, and biologic drug products as part of an overall revision 
of the IND regulations (known as the IND Rewrite). These regulations, 
in part, require each sponsor to submit an annual report providing an 
update on the progress of clinical investigations conducted under its 
IND. The annual report must contain individual study information, which 
generally includes brief summaries of the status of each ongoing study 
and of each study completed during the previous year. These summaries 
are required to include, among other things: (1) a brief description of 
available results of each study completed during the previous year and 
interim results of ongoing clinical investigations and (2) information 
on the number of subjects included in each study (see Sec.  312.33(a)). 
The annual report must also include summarized information about the 
clinical investigations conducted under the IND during the previous 
year, including the following, for example:
     A summary showing the most frequent and most serious 
adverse experiences (Sec.  312.33(b)(1)).
     A summary of all IND safety reports submitted during the 
previous year (Sec.  312.33(b)(2)).
     A list of preclinical studies completed or in progress 
during the previous year, including a summary of the major preclinical 
findings (Sec.  312.33(b)(6)).
     A summary of any significant manufacturing or 
microbiological

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changes made during the past year (Sec.  312.33(b)(7)).
    Since the publication of the IND Rewrite, the increasing size and 
scope of clinical investigations have created the need for information 
and analyses that are more comprehensive, as well as the need for 
information to be presented in a format that is more useful for FDA, 
clinical investigators, sponsors, and others using the data included in 
the reports. Such comprehensive analyses will assist FDA in evaluating 
the safety profile of an investigational drug during its development 
and will assist in identifying safety signals while the clinical trials 
are ongoing. Because of the increasing complexity of clinical trials, 
having periodic reporting and consistent information reported are of 
increased importance for protecting human subjects from unnecessary 
risks. Additionally, there have been concerns about differences in the 
content and objectives between the current IND annual report and the 
annual safety report that is being used in other countries, as well as 
concerns about the burden associated with preparing different periodic 
safety reports for different regulatory authorities. These concerns led 
to an international effort to develop a common periodic safety report 
that could be used globally to satisfy reporting requirements.

D. History of the Rulemaking

1. International Harmonization of Regulatory Requirements for Drug 
Development
    In the Federal Register of October 11, 1995 (60 FR 53078), FDA 
published a notice entitled ``International Harmonization, Policy on 
Standards'' that described FDA's policy for working with other 
countries to achieve greater harmonization of regulatory requirements 
and guidelines. It also described FDA's views on international 
harmonization and collaboration as a way to enhance regulatory 
effectiveness by providing more consumer protection without added 
expenditure of government resources. Harmonization and collaboration 
can also increase worldwide consumer access to safe, effective, and 
high-quality products.
    International harmonization has been facilitated through the 
development of ICH guidelines via a process of scientific consensus 
with regulatory and industry experts participating in multinational 
working groups. In 2006, the Center for Biologics Evaluation and 
Research (CBER) and the Center for Device Evaluation and Research 
(CDER) participated in a working group sponsored by the Council for 
International Organizations of Medical Sciences (CIOMS), referred to as 
CIOMS VII (Ref. 1). CIOMS is an international, nongovernmental, 
nonprofit organization established by the World Health Organization and 
the United Nations Educational, Scientific, and Cultural Organization 
that covers drug safety topics through working groups (Refs. 2 and 3). 
The CIOMS VII working group proposed that ICH develop a guideline on 
periodic reporting of safety information from clinical trials (which it 
termed the development safety update report (DSUR)) that would 
harmonize guidelines and requirements from the various regulatory 
agencies (Ref. 1).
2. Development of an International DSUR
    The CIOMS report was the starting point for the ICH initiative 
(Ref. 4). In June 2008, the draft ICH guideline for the E2F DSUR was 
approved by the ICH steering committee (Ref. 5). In the Federal 
Register of August 5, 2008, FDA announced the availability of the draft 
ICH guidance for industry (E2F DSUR) (available at https://www.regulations.gov/document?D=FDA-2008-D-0386-0002) for public 
comment, which was the guideline prepared under the auspices of the 
ICH. After consideration of the comments received on the draft guidance 
for industry, the ICH steering committee approved a final draft of the 
guideline to be adopted by the United States, Japan, and participating 
European countries entitled ``Development Safety Update Report, E2F,'' 
dated August 17, 2010 (Ref. 5). In the Federal Register of August 23, 
2011 (76 FR 52667), FDA issued this guideline as a final ICH guidance 
for industry (the E2F DSUR) that discusses the format, content, and 
timing of submission of a DSUR as developed by the ICH.
3. Overview of the Differences Between the E2F DSUR and the Current IND 
Annual Report Regulations
    The E2F DSUR provides the recommended content and format of a drug 
safety update report that sponsors can use to satisfy the EU 
requirements for annual safety reports and FDA's requirements for IND 
annual reports, despite the differences between the EU requirements and 
FDA's requirements. Specifically, the annual safety report required 
under the EU Clinical Trial Directive 2001/20EC contains significant 
differences in the purpose, content, and timing of submission compared 
to FDA's IND annual report (Refs. 6 and 7). As a result, sponsors 
developing a drug in both jurisdictions are required to submit 
different annual reports each year to each regulatory authority. For 
example, the IND annual report is intended to provide only summaries of 
clinical studies conducted under the IND and requires a narrative or 
tabular summary of the most frequent and most serious adverse 
experiences. In contrast, the EU annual safety report is intended to be 
a clinical trial safety report and requires a cumulative summary 
tabulation of all serious adverse reactions (Refs. 6 and 7). With 
regard to timing, the required date for submission of the IND annual 
report is based on the anniversary of the effective date of the IND 
under Sec.  312.40(b), whereas the date for submission of the EU annual 
safety report is the anniversary of the development international birth 
date, which is the date on which the sponsor was first authorized to 
conduct a clinical trial in any country or region (Ref. 1). The 
differences in the purpose, content, and timing of annual reporting in 
the EU and the United States result in study sponsors sending 
duplicative information to regulators, as well as regulatory 
authorities receiving inconsistent safety information.
    The E2F DSUR provides recommendations with respect to periodic 
safety reporting during clinical development, offers guidance on 
providing meaningful information to regulators, and facilitates 
consistency among sponsors and regulators (Ref. 4). The E2F DSUR 
emphasizes high-value activities, such as data interpretation, while 
ensuring that the regulatory authorities that use the E2F DSUR have 
access to the same data in similar timeframes (Ref. 4). Following are 
overarching objectives enabled by the use of the E2F DSUR:
     Examining whether the information obtained by the sponsor 
during the reporting period aligns with prior knowledge of the safety 
of the investigational drug.
     Describing new safety findings that could have an impact 
on the protection of study subjects.
     Summarizing the current understanding and management of 
identified and potential risks.
     Providing an update on the status of the clinical 
investigation/development program and study results.
    Use of the E2F DSUR provides important advantages for safety 
evaluation as compared to FDA's IND annual report. First, the E2F DSUR 
includes additional safety information to help enhance the safety of 
subjects. For example, the E2F DSUR specifically includes a description 
of significant, safety-related changes to the investigator

[[Page 75556]]

brochure and an evaluation of the significance of the identified 
changes for the safety of subjects. For some drugs, this increased 
safety reporting requirement could potentially help characterize a 
safety signal and associated risks, and lead to timely action to 
protect subjects such as earlier termination of a study or withdrawal 
of a drug from the market due to safety concerns (as mentioned 
previously). In contrast, the IND annual report is a general update on 
the progress of the investigational drug's clinical development, which 
includes a description of the revisions made to the investigator 
brochure and a copy of the new brochure, if revised, and a summary of 
all IND safety reports submitted during the year, but no additional 
analysis is conducted by the sponsor.
    Second, unlike FDA's IND annual report, the E2F DSUR contains an 
integrated safety analysis and a summary of cumulative pertinent safety 
information. Simply accumulating and reporting data for a given time 
period, without considering all previously available data from clinical 
trials and other sources, may delay identification of important risks. 
A meaningful understanding of the evolving safety profile of an 
investigational drug requires a periodic analysis of all available 
safety information, which is crucial to the ongoing assessment of risks 
to subjects of clinical trials during the clinical development of an 
investigational drug. An integrated analysis and a summary of overall 
safety risks, as contained in the E2F DSUR, would help increase the 
usefulness of the safety data and help facilitate efforts to identify 
and assess important safety risks promptly. The E2F DSUR includes 
information on cumulative patient exposure and a summary of cumulative 
serious adverse events, which would further enhance risk identification 
and assessment.
    Third, the E2F DSUR provides safety information that is more 
comprehensive than the IND annual report, which requires only summaries 
of clinical studies conducted under the IND. In contrast to the current 
IND annual report, the E2F DSUR contains safety information from all 
studies using the drug, whether conducted under an IND or not. The E2F 
DSUR also incorporates information from studies not initiated by the 
sponsor and information from other relevant sources. For example, 
safety findings from published literature and information from the 
marketing experience of the drug would be included in the E2F DSUR, but 
these findings are not required in the IND annual report. Some sponsors 
have already voluntarily submitted their IND annual reports in the E2F 
DSUR format to the FDA; the submitted E2F DSURs have provided the 
aforementioned advantages, including superior organization and more 
comprehensive information to facilitate review.
    Finally, the ability to submit a similar annual report to 
regulatory authorities in multiple countries and for all investigations 
of the drug conducted on behalf of the sponsor could provide 
significant advantages to those sponsors who submit reports to multiple 
regulatory authorities. A similar comprehensive annual report submitted 
to regulatory authorities in multiple countries could help ensure 
consistent understanding of the safety profile of a drug and could 
therefore help improve consistency and predictability of regulatory 
actions. The use of a similar annual report in multiple countries and 
for all studies conducted on behalf of the sponsor in which the 
particular drug is studied also could help ensure that regulatory 
authorities for all development programs are relying on the same 
information about the evolving safety profile of a drug.

IV. Legal Authority

    FDA is issuing this proposed rule under sections 201, 301, 501, 
502, 503, 505, and 701 of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 321, 331, 351, 352, 353, 355, and 371) and under 
section 351 of the PHS Act.

V. Description of the Proposed Rule

A. Scope

    The proposed rule would revise current Sec. Sec.  312.3 and 312.33 
concerning IND annual reports. The proposed rule would require IND 
sponsors to submit an annual DSUR that is more comprehensive and 
informative than the IND Annual Report currently required under FDA 
regulations. The proposed annual FDA DSUR is intended to be consistent 
with the format and content of the E2F DSUR supported by ICH for annual 
reporting in certain other countries and regions. If finalized, this 
rule would require sponsors to submit an annual FDA DSUR in lieu of the 
IND Annual Report. A sponsor would be able to submit an annual DSUR 
containing additional information to that proposed to be required by 
the annual FDA DSUR, in the format recommended in the E2F DSUR, as long 
as the submitted DSUR complies with the requirements provided in the 
proposed annual FDA DSUR and FDA requirements for electronic 
submissions (see, e.g., section 745A(a) of the FD&C Act (21 U.S.C. 
379k-1)(a)). The proposed requirements are intended to provide 
information that is sufficiently comprehensive to facilitate FDA's 
assessment of clinical investigations conducted on behalf of the IND 
sponsor, including the sponsor of a large, multinational clinical 
development program intended to support applications for marketing 
approval of a drug in multiple countries and regions.

B. Definitions

    The proposed rule would revise Sec.  312.3 (Definitions and 
interpretations) by adding a definition for data lock point. The data 
lock point would be defined as the designated cutoff date for data to 
be included in the proposed annual FDA DSUR. The definition would 
establish a fixed data lock point that is 1 calendar day before the 
anniversary of the date the IND went into effect. We propose to require 
that a sponsor submit the annual FDA DSUR to FDA not later than 60 
calendar days after the data lock point (see proposed Sec.  312.33).

C. Proposed Provisions of the FDA DSUR

1. General
    FDA is proposing to revise current Sec.  312.33, Annual reports, by 
replacing the section with a section entitled ``Development safety 
update reports.'' Proposed Sec.  312.33 describes the scope, format, 
and content of the proposed annual FDA DSUR as well as when to submit 
the annual report. The proposed requirements are intended to be 
consistent with the content recommended in the E2F DSUR to the extent 
possible. Some of the language used in this proposed rule differs from 
that in the E2F DSUR because of minor differences in terminology and 
for consistency with other FDA requirements. We recognize that some of 
the information discussed in the proposed annual FDA DSUR may not be 
known to sponsors, which is why the proposed annual FDA DSUR only 
requires sponsors to submit the information that is known to them.
2. Scope
    Proposed Sec.  312.33(a) states that the annual FDA DSUR is 
intended to provide a thorough annual assessment of the clinical 
investigations conducted and safety information collected during the 
reporting period that is related to an investigational new drug. The 
annual FDA DSUR is intended to: (1) be sufficiently comprehensive to 
cover the entire scope of a large-scale, international development 
program

[[Page 75557]]

designed to support applications for marketing in multiple countries 
and regions and (2) capture data from all completed and ongoing 
clinical investigations conducted on behalf of the sponsor anywhere in 
the world evaluating the drug, including investigations not conducted 
under an IND (see Sec.  312.33(a)(1)). Proposed Sec.  312.33(a)(1) 
further provides that a sponsor must submit the same annual FDA DSUR 
for each IND held by the sponsor for that drug.
    Under Sec.  312.10, sponsors may request that FDA waive any 
applicable requirement in part 312. We expect that some sponsors will 
request that FDA waive the requirement under proposed Sec.  312.33 that 
they must submit the annual FDA DSUR not later than 60 calendar days 
after a data lock point established by proposed Sec.  312.3 (which is 1 
calendar day before the anniversary of the date the IND went into 
effect) to allow them to coordinate the timing of the annual FDA DSUR 
submission with the submission of reports to regulatory agencies in 
other countries or regions. We also expect that some sponsors will 
request that FDA waive the requirement under proposed Sec.  
312.33(a)(1) that a sponsor submit the same annual FDA DSUR for each 
IND held by the sponsor for the drug because of substantial differences 
in, for example, the intended uses or populations being studied under 
different INDs.
    As required under Sec.  312.10(a), a waiver request must contain 
the following: (1) an explanation of why the sponsor's compliance with 
the requirement is unnecessary or cannot be achieved, (2) a description 
of an alternative submission or course of action that satisfies the 
purpose of the requirement, or (3) other information that justifies a 
waiver. As provided under Sec.  312.10(b), FDA may grant a requested 
waiver if it finds that the sponsor's noncompliance would not pose a 
significant and unreasonable risk to human subjects of the 
investigation and that at least one of the following is met: (1) the 
sponsor's compliance with the requirement is unnecessary for the Agency 
to evaluate the application or compliance cannot be achieved, (2) the 
sponsor's proposed alternative satisfies the requirement, or (3) the 
applicant's submission otherwise justifies a waiver.
    FDA expects that the waiver criteria in Sec.  312.10(b) will likely 
be met when a sponsor submits a waiver request in accordance with Sec.  
312.10(a) for the following reasons: (1) an alternate data lock point 
would permit the sponsor to coordinate the timing of submission of an 
annual FDA DSUR with the sponsor's submission of the proposed annual 
FDA DSUR to other INDs covered by the same annual FDA DSUR (e.g., INDs 
for studies investigating other indications for a drug), (2) an 
alternate data lock point would permit the sponsor to coordinate the 
timing of submission of an annual FDA DSUR with the timing of 
submission of other reports to regulatory agencies in other countries 
and regions (e.g., to coordinate the timing of submission of an annual 
FDA DSUR with the date of first approval or authorization for 
conducting a clinical investigation in any country or region (i.e., the 
development international birth date of the drug)), or (3) an alternate 
data lock point would permit the sponsor to coordinate the timing of 
submission of an annual FDA DSUR with the timing of submission of the 
postmarketing periodic safety report required under 21 CFR 314.80(c)(2) 
or 600.80(c)(2), if a sponsor is submitting both reports to FDA (e.g., 
is conducting clinical investigations of a lawfully marketed drug or 
biological product).
    FDA expects that the waiver criteria in Sec.  312.10(b) will 
probably be met when a sponsor submits a waiver request in accordance 
with Sec.  312.10(a) to allow a sponsor to submit individual annual FDA 
DSURs for INDs that cover very different dosage forms of a drug (e.g., 
the same active ingredient for intravenous use for a life-threatening 
disease versus topical administration for a more chronic disease) on 
the basis that submission of the same annual FDA DSUR for each IND 
would not be useful to FDA because of substantial differences in, for 
example, the intended uses or populations being studied.
3. Major Differences Between the Current IND Annual Report and the 
Proposed FDA DSUR
    Table 1 shows the major differences between the current IND annual 
report and the proposed annual FDA DSUR.

Table 1--Examples of Major Differences Between the Current Regulatory Requirements for the IND Annual Report and
                            the Regulatory Requirements for the Proposed FDA DSUR \1\
----------------------------------------------------------------------------------------------------------------
                                           Current IND annual report
             Sec.   312.33                       requirements                Proposed FDA DSUR requirements
----------------------------------------------------------------------------------------------------------------
Overall safety assessment.............   Not required.........   Requires providing a concise,
                                                                         integrated evaluation of all new
                                                                         clinical, nonclinical, and
                                                                         epidemiological safety information
                                                                         obtained about the drug by the sponsor
                                                                         during the reporting period in relation
                                                                         to the safety information obtained
                                                                         during prior reporting periods
                                                                         (proposed Sec.   312.33(s)(1)) and a
                                                                         description of the balance between
                                                                         theoretical or anticipated benefits and
                                                                         cumulative identified risks related to
                                                                         use of the drug.
                                                                         Requires a description of
                                                                         changes in the benefit-risk profile
                                                                         compared to the previous DSUR, based on
                                                                         information obtained during the
                                                                         reporting period (proposed Sec.
                                                                         312.33(s)(2))
Executive summary.....................   Not required.........   Requires an executive summary
                                                                         (proposed Sec.   312.33(c))
Scope of information on clinical         Requires information    Expands the scope to require
 investigations.                         about clinical investigations   comprehensive information about
                                         of the investigational drug     clinical investigations conducted
                                         under the IND (Sec.   312.33).  anywhere in the world on behalf of the
                                                                         sponsor evaluating the drug or,
                                                                         including clinical investigations not
                                                                         conducted under an IND (proposed Sec.
                                                                         312.33(a)(1)).
Cumulative exposure...................   Not required.........   Adds the requirement to include
                                                                         the cumulative number of subjects
                                                                         exposed to the investigational drug and
                                                                         comparators during clinical
                                                                         investigations conducted on behalf of
                                                                         the sponsor and to include a tabulation
                                                                         of such exposure by age, sex, and race
                                                                         (proposed Sec.   312.33(j)).
                                                                         If the drug is lawfully
                                                                         marketed by the sponsor, the report
                                                                         must include an estimate of patients'
                                                                         cumulative exposure in any country or
                                                                         region, including an explanation of how
                                                                         that exposure was estimated (proposed
                                                                         Sec.   312.33(j)).
Study description (individual study      Requires a brief        Requires an inventory of
 information).                           summary of the status of each   ongoing and completed clinical
                                         study in progress and each      investigations conducted during the
                                         study completed during the      reporting period.
                                         previous year, including the    For each investigation in this
                                         title of each study, its        inventory, requires the protocol
                                         purpose, a brief statement      number, the title, the clinical trial
                                         identifying the patient         phase, the date the first subject
                                         population, and a statement     provided informed consent, a brief
                                         as to whether the study is      description of clinical investigation
                                         completed (Sec.                 design, and a brief description of the
                                         312.33(a)(1)).                  dose and regimen of the investigational
                                                                         drug and any comparators (proposed Sec.
                                                                           312.33(i)).

[[Page 75558]]

 
Study subjects (individual study         Requires a brief        Requires an inventory of
 information).                           summary of the status of each   ongoing and completed clinical
                                         study in progress and each      investigations conducted during the
                                         study completed during the      reporting period.
                                         previous year, including the    For each investigation in this
                                         following:                      inventory, requires the cumulative
                                        --the total number of subjects   number of subjects enrolled in all
                                         initially planned for           treatment arms of the investigation (or
                                         inclusion in the study (Sec.    an estimate); a demographic breakdown
                                          312.33(a)(2)).                 of study population by age, sex, and
                                        --the number of subjects         race; and the total number of subjects
                                         entered into the study to       (if any) planned to be enrolled in the
                                         date (tabulated by age group,   clinical investigation (proposed Sec.
                                         sex, and race).                 312.33(i)).
                                        --the number whose               Requires a list of subjects who
                                         participation in the study      withdrew from a clinical investigation
                                         was completed as planned, and.  during the reporting period because of
                                        --the number who withdrew from   an adverse event (proposed Sec.
                                         the study for any reason        312.33(k)(1)(iv) and Sec.
                                         (Sec.   312.33(a)(2)).          312.33(s)(iv)).
Study results (individual study          In a brief summary of   Requires a brief summary of
 information).                           the status of each study in     safety and effectiveness findings
                                         progress and each study         obtained from clinical investigations
                                         completed during the previous   conducted on behalf of the sponsor of
                                         year, requires including a      the investigational drug during the
                                         brief description of any        reporting period, including results
                                         available study results if a    obtained from any completed trials or
                                         study has been completed or     interim analysis that resulted in a
                                         if interim results are known    decision, based on lack of efficacy, to
                                         (Sec.   312.33(a)(3)).          either stop a trial or to revise the
                                                                         information provided to subjects to
                                                                         seek informed consent (proposed Sec.
                                                                         312.33(l)).
Safety findings from other sources....   Not required.........   Adds the requirement that a
                                                                         sponsor submit a brief summary of
                                                                         relevant safety findings from other
                                                                         sources, if known, including
                                                                         noninterventional studies of the drug;
                                                                         pooled or meta-analyses of randomized
                                                                         clinical investigations of the drug;
                                                                         safety findings from marketing
                                                                         experience, if the drug is lawfully
                                                                         marketed; nonclinical studies of the
                                                                         drug; published clinical or nonclinical
                                                                         investigations of the drug not
                                                                         conducted on behalf of the sponsor; and
                                                                         published studies concerning other
                                                                         members of the pharmacological class of
                                                                         the drug.
                                                                         The brief summary would also
                                                                         include all additional significant
                                                                         safety findings about the drug that are
                                                                         obtained from other sources during the
                                                                         reporting period, if known, including
                                                                         expanded access use under part 312,
                                                                         subpart I, or a similar program
                                                                         conducted on behalf of the sponsor in
                                                                         another country or region (proposed
                                                                         Sec.   312.33(m)).
Serious adverse experiences...........   Requires a narrative    Requires a list of all serious
                                         or tabular summary showing      suspected adverse reactions as defined
                                         the most frequent and most      in Sec.   312.32(a) that occurred
                                         serious adverse experiences     during the reporting period, including
                                         by body system (Sec.            the treatment group assignment, if
                                         312.33(b)(1)).                  known, or designated as ``blinded'' if
                                                                         the blind has not been broken.
                                                                         Requires that the line listings
                                                                         identify serious and unexpected
                                                                         suspected adverse reactions as defined
                                                                         in Sec.   312.32(a) and that they also
                                                                         include study identification
                                                                         information as listed (proposed Sec.
                                                                         312.33(k)(1)(i)).
                                                                         Requires a summary list of
                                                                         serious adverse events for all clinical
                                                                         investigations conducted on behalf of
                                                                         the sponsor that occurred since the
                                                                         date the IND went into effect (proposed
                                                                         Sec.   312.33(k)(1)(ii)).
IND safety reports....................   Requires a summary of
                                         all IND safety reports
                                         submitted during the past
                                         year (Sec.   312.33(b)(2)).
Information on drug's actions.........   Requires a brief        A brief description is not
                                         description of what             required for this section because
                                         information, if any, was        information that is more detailed is
                                         obtained during the previous    required elsewhere in the proposed
                                         year's clinical and             rule.
                                         nonclinical investigations
                                         that is pertinent to an
                                         understanding of the drug's
                                         actions (such as dose
                                         response, bioavailability)
                                         (Sec.   312.33(b)(5)).
Nonclinical studies and findings......   Requires a list of      Changes the requirement to
                                         preclinical studies             focus on safety by requiring a summary
                                         (including animal studies)      of safety findings from other sources
                                         completed or in progress        for the reporting period, including
                                         during the past year and a      nonclinical in vivo and in vitro
                                         summary of the major            studies; published nonclinical studies
                                         preclinical findings (Sec.      not conducted on behalf of the sponsor;
                                         312.33(b)(6)).                  and published studies on other members
                                                                         of the pharmacological class of the
                                                                         drug (proposed Sec.   312.33(m)).
Manufacturing and microbiological        Requires a summary of   Revises the current requirement
 changes.                                any significant manufacturing   so that sponsors would be required to
                                         or microbiological changes      provide a summary of significant
                                         made during the past year       chemistry, manufacturing, and control
                                         (Sec.   312.33(b)(7)).          changes, including microbiological
                                                                         changes (if applicable), made to the
                                                                         investigational drug during the
                                                                         reporting period.
                                                                        ........................................
                                                                         Requires a brief description of
                                                                         the safety significance of the
                                                                         identified changes (proposed Sec.
                                                                         312.33(n)).
Investigator brochure changes.........   If the investigator     States that, if the sponsor
                                         brochure has been revised,      must submit an investigator brochure
                                         requires a description of the   under Sec.   312.23(a)(5), the brochure
                                         revision and a copy of the      will serve as the reference safety
                                         new brochure (Sec.              information during that reporting
                                         312.33(d)).                     period.
                                                                         If an investigator brochure is
                                                                         not required under Sec.   312.23(a)(5)
                                                                         and the drug is subject to an FDA-
                                                                         approved marketing application, the FDA-
                                                                         approved prescribing information will
                                                                         serve as the reference safety
                                                                         information during the reporting
                                                                         period.
                                                                         If neither is the case and the
                                                                         sponsor uses another source as the
                                                                         reference safety information, the
                                                                         report must identify the reference
                                                                         safety information used (e.g., coding
                                                                         dictionary version(s) used).
                                                                         Requires that the report list
                                                                         all safety-related changes to the
                                                                         reference safety information made
                                                                         during the reporting period.
Actions taken for safety reasons......   Requires a brief        Requires a description of all
                                         summary of significant          actions relevant to safety and reasons
                                         foreign marketing               for such actions taken during the
                                         developments with the drug      reporting period by the sponsor
                                         during the past year, such as   (including actions taken following a
                                         approval of marketing in any    recommendation from a DMC) or by a
                                         country or withdrawal or        regulatory authority.
                                         suspension from marketing in
                                         any country (Sec.
                                         312.33(f)).

[[Page 75559]]

 
Event otherwise omitted from safety      Not required.........   Requires identifying each event
 tabulations because it is a study                                       omitted from the listings and
 endpoint.                                                               tabulations of safety data required by
                                                                         Sec.   312.33(k)(1) because the event
                                                                         is a study endpoint or a component of a
                                                                         study endpoint (proposed Sec.
                                                                         312.33(k)(2)).
Summary of important risks............   Not required.........   Requires providing a cumulative
                                                                         listing and a brief description of all
                                                                         important known and potential risks
                                                                         associated with the drug identified by
                                                                         the sponsor during the course of
                                                                         studies of the drug conducted on behalf
                                                                         of the sponsor.
                                                                         Requires an update of the risks
                                                                         identified in a prior reporting period
                                                                         with any new risk information obtained
                                                                         during the current reporting period
                                                                         (proposed Sec.   312.33(t)).
Exceptions for sponsor-investigators..   Provides no             States that a sponsor-
                                         distinction between sponsor-    investigator for a clinical
                                         investigators and other         investigation not intended to support a
                                         sponsors (Sec.   312.33).       marketing application is required to
                                                                         submit only information obtained from
                                                                         the clinical investigation conducted by
                                                                         the sponsor-investigator (proposed Sec.
                                                                           312.33(a)(2)).
Conclusion............................   Not required.........   Requires including a conclusion
                                                                         (proposed Sec.   312.33(u)).
----------------------------------------------------------------------------------------------------------------
\1\ This table compares the regulatory requirements in current Sec.   312.33 with the new requirements in
  proposed Sec.   312.33. Although current annual reporting practices may go further than that required by the
  current regulations to be more consistent with the E2F DSUR, this table only highlights the regulatory
  requirements and not common practices.

4. FDA DSUR Content
    FDA acknowledges that the proposed content requirements of the 
annual FDA DSUR are more extensive than generally would be needed for 
reporting the status of a sponsor-investigator IND for a single 
clinical investigation that is not intended to support a marketing 
application. Therefore, we are proposing that the report for an IND 
conducted by a sponsor-investigator (as defined in Sec.  312.3) that is 
not intended to support a marketing application must contain the 
required information that is obtained from the investigation conducted 
by the sponsor-investigator (see Sec.  312.33(a)(2)). The sponsor-
investigator is required to submit only information that is obtained 
from the clinical investigation conducted by the sponsor-investigator 
(e.g., information that is part of that sponsor-investigator's protocol 
for the IND). For example, if a commercial IND sponsor provides an 
investigational drug to a sponsor-investigator to conduct an 
investigation under the sponsor-investigator's IND, it would not be 
necessary for the sponsor-investigator to submit information unrelated 
to their study (e.g., data concerning animal toxicity, drug 
manufacturing information, or safety information from investigations 
conducted under the commercial sponsor's IND) because the information 
would be submitted by the sponsor. Also, the sponsor-investigator may 
not have right of reference to the data. For these reasons, we do not 
propose requiring the sponsor-investigator to provide information in 
the annual FDA DSUR that is not obtained from the sponsor-
investigator's own clinical investigation under an IND.
    Proposed Sec.  312.33(a)(3) provides that, in Sec.  312.33, ongoing 
clinical investigations consist of all active investigations, including 
those that are on clinical hold; investigations that have not been 
terminated; and investigations for which a final study report has not 
been submitted but the investigation might otherwise be completed. The 
intent is to capture all relevant investigations conducted on behalf of 
the sponsor.
    Proposed Sec.  312.33(b) through (u) describe the content FDA 
proposes to be included in the annual FDA DSUR.
    Proposed Sec.  312.33(b) describes the content of the title page, 
including the IND number, report number (reports to be numbered 
sequentially), name of the investigational drug, reporting period, date 
of the report, and sponsor's name and address. The reporting period is 
the designated 12-month period during which information was obtained 
for the annual FDA DSUR and ending with the data lock point. This 
period would run from the previous anniversary of the date the IND went 
into effect under Sec.  312.40(b) until 1 calendar day before the 
anniversary of the date the IND went into effect unless FDA grants a 
waiver pursuant to Sec.  312.10(b) for the sponsor to designate an 
alternate date for the data lock point.
    Proposed Sec.  312.33(c) describes the content of the executive 
summary for the proposed annual FDA DSUR. Proposed Sec.  312.33(c) 
would require that the executive summary contain all of the following 
information:
     The report number and reporting period;
     A brief description of the investigational drug, including 
the therapeutic class(es), pharmacological class (if applicable), and 
mechanism of action (if known), and the indications, doses, 
formulations, and routes of administration being studied on behalf of 
the sponsor;
     The cumulative number of subjects to whom the drug has 
been administered throughout the course of studies of the drug 
conducted on behalf of the sponsor or an estimate of these subjects if 
a precise number cannot be determined (e.g., for a study that is 
currently enrolling subjects);
     A summary of the overall safety assessment required under 
proposed Sec.  312.33(s) of the main report;
     A summary of the list of important risks required under 
proposed Sec.  312.33(t) of the main report;
     A summary of actions taken for safety reasons as required 
under proposed Sec.  312.33(g);
     A list of countries and regions (if a drug product is 
approved by a region, which may be the case in the EU) in which the 
drug has been approved for marketing; and
     A summary of the conclusion as required under proposed 
Sec.  312.33(u) of the main report.
    We are proposing to require that the report contain a table of 
contents with sufficient detail to direct the annual FDA DSUR reader to 
each of the components of the report described in paragraphs (e) 
through (u) of proposed Sec.  312.33 (see proposed Sec.  312.33(d)).
    We are proposing to require a detailed introduction containing the 
following information: (1) identification of the reporting period; (2) 
a brief description of the investigational drug (including the 
therapeutic class(es), pharmacological class (if applicable), and the 
mechanism of action (if known); (3) a list of the indications, doses, 
formulations, and routes of administration being investigated; and (4) 
a list of the clinical investigations conducted on behalf of the 
sponsor that are referred to in the report (see Sec.  312.33(e)).

[[Page 75560]]

    Section 312.33(e) in this proposed rule corresponds to section 3.1 
(Introduction) of the E2F DSUR. In comparing these sections, we note 
that section 3.1 of the E2F DSUR recommends the inclusion of certain 
information that is not included in FDA's proposed Sec.  312.33(e), 
such as information about the Development International Birth Date; a 
short summary of the scope of the clinical trials covered by the 
report; and a brief description and explanation of all information that 
has not been included in the annual FDA DSUR. FDA is not requiring this 
information under proposed Sec.  312.33(e) because the information is 
not expected to provide additional important information for FDA's 
safety evaluation of the drug.
    Proposed Sec.  312.33(e) would require information about the drug's 
therapeutic class(es) and pharmacological class (with pharmacological 
class included as part of the original IND per Sec.  312.23(a)(3)) 
because therapeutic class is important to FDA's evaluation of drugs and 
biologics, and pharmacological class is important to FDA's evaluation 
of drugs. Also, proposed Sec.  312.33(e) would require that the 
mechanism of action rather than the mode of action (the term used in 
the E2F DSUR) be included in the description of the drug because other 
FDA IND regulations already use the term mechanism of action (see, 
e.g., Sec.  312.23(a)(8)(i)). Unlike the E2F DSUR recommendations, FDA 
does not propose to require in this section information about 
population or populations being studied because FDA would receive this 
information pursuant to proposed Sec.  312.33(i). Lastly, FDA does not 
propose to require in this section a rationale for the submission of 
multiple annual FDA DSURs for the investigational drug because FDA 
proposes to require sponsors to prepare and submit a single report for 
a drug studied under multiple INDs. If a sponsor is unable to comply 
with this requirement (e.g., the sponsor would like to submit separate 
annual FDA DSURs for individual INDs), the sponsor may submit a waiver 
request in accordance with Sec.  312.10(a) that includes information 
that justifies a waiver.
    We are proposing that if the drug has been approved anywhere in the 
world, the sponsor would be required to provide a brief summary of the 
status of the approved drug, including the date of first approval, the 
indication(s), the approved dose(s), and where approved, (see proposed 
Sec.  312.33(f)). This proposed requirement is consistent with the 
content recommended in section 3.2 (Worldwide Marketing Approval 
Status) of the E2F DSUR.
    We are proposing to require that the sponsor describe all actions 
relevant to the safety of the drug that were taken by the sponsor or by 
a regulatory authority during the reporting period, if known (see 
proposed Sec.  312.33(g)). The sponsor's actions include any actions 
taken by the sponsor in response to a regulatory action or any actions 
taken by the sponsor following a recommendation from a Data Monitoring 
Committee (DMC), if one is used. Proposed Sec.  312.33(g) would also 
require the sponsor to provide the reason or reasons for each action.
    The corresponding section 3.3 (Actions Taken in the Reporting 
Period for Safety Reasons) of the E2F DSUR recommends, in addition, 
actions related to safety that have been taken by an ethics committee. 
While some countries use established ethics committees with 
responsibilities that differ from those of institutional review boards 
in the United States, FDA believes that actions taken by an ethics 
committee in another country would often be included in a report of 
actions taken by sponsors or regulatory authorities. Section 3.3 of the 
E2F DSUR includes a list of examples of significant actions taken for 
safety reasons, which is similar in concept to the list of actions in 
proposed Sec.  312.33(g). As such, FDA considers the information 
recommended in section 3.3 of the E2F DSUR to be substantially similar 
to what is called for by proposed Sec.  312.33(g). The intent of 
proposed Sec.  312.33(g) is to capture actions taken for safety reasons 
by the sponsor and by FDA in the United States and to capture analogous 
actions taken by regulatory authorities in other countries or regions. 
The intent is also to capture only actions that are significant to the 
conduct of clinical investigations under the IND, including the 
following examples of the types of actions to be reported under the 
proposed requirements:
     A clinical hold order issued under Sec.  312.42;
     Denial of authorization to initiate a clinical 
investigation or the suspension of the conduct of a clinical 
investigation involving use of the drug in another country or region 
(e.g., this includes early termination of an ongoing clinical trial 
because of safety findings or lack of efficacy);
     A requirement to cease distribution of the drug or other 
action related to the quality of the drug (e.g., recall of the drug);
     Refusal to approve any application for marketing of the 
drug (this includes voluntary withdrawal of an application);
     An action by a regulatory authority that places a 
condition or limitation on the use or development of the drug (e.g., a 
requirement to conduct long-term animal testing before beginning long-
term studies in humans, the need for a validated immunogenicity assay 
before beginning phase 3 testing, specific testing needed before 
initiating pediatric studies, the limitation on dosing pending 
additional safety data, the exclusion of a particular population from 
clinical investigations);
     A safety-related change in the protocol or in the 
investigational plan of an ongoing clinical investigation of the drug 
(e.g., change in dose, change in inclusion/exclusion criteria, 
monitoring that is new or more intensive, limit to the duration of the 
trial);
     A safety-related change in the information provided to 
human subjects in order to obtain informed consent for a clinical 
investigation of the drug;
     A safety-related formulation change to the drug;
     A safety advisory communication to investigators 
conducting studies under the IND or to healthcare professionals 
concerning use of the drug;
     An investigation of the drug that is initiated or planned 
to evaluate a safety risk associated with use of the drug;
     If the drug is lawfully marketed, each safety-related 
change to its labeling, including the prescribing information;
     If the drug is lawfully marketed, a significant 
restriction on distribution or other risk mitigation strategy (e.g., a 
risk evaluation and mitigation strategy implemented under section 505-1 
of the FD&C Act (21 U.S.C. 355-1)); and
     If the drug was lawfully marketed, withdrawal or 
suspension of marketing approval for the drug in any country or region.
    We are proposing that the investigator brochure, if required under 
Sec. Sec.  312.23(a)(5) and 312.55, will serve as the reference safety 
information to be used during the clinical investigation of the 
investigational drug. The investigator brochure in effect at the start 
of the reporting period will represent the reference safety information 
to be used by the sponsor during that reporting period. If an 
investigator brochure is not required and the drug is subject to an 
FDA-approved marketing application, we propose that the FDA-approved 
prescribing information will serve as the reference safety information. 
If an investigator brochure is not required under Sec. Sec.  
312.23(a)(5) and 312.55, the drug is not FDA-approved; and if the 
sponsor uses another source as the reference safety information, the

[[Page 75561]]

sponsor would be required to identify the reference safety information 
(e.g., coding dictionary version(s) used or the European Summary of 
Product Characteristics) (see proposed Sec.  312.33(h)(1)).
    We are also proposing to require the sponsor to provide a report 
that lists all safety-related changes to the reference safety 
information, if applicable, during the reporting period. If the 
investigator brochure is used as the reference safety information, 
changes to that information would include revisions made to the 
investigator brochure by the sponsor as described in Sec.  312.55(b) 
(see proposed Sec.  312.33(h)(2)).
    We are proposing to require the sponsor to provide an inventory of 
ongoing and completed clinical investigations of the investigational 
drug that were conducted on behalf of the sponsor during the reporting 
period (see proposed Sec.  312.33(i)). The intent is to identify the 
universe of clinical investigations that are conducted under the IND. 
For each clinical investigation identified, the sponsor would be 
required to provide the following information:
     The protocol number.
     The clinical investigation title (or abbreviated title).
     The National Clinical Trial (NCT) number, if applicable.
     The phase of the clinical investigation (i.e., 1, 2, 3, or 
postmarketing).
     The date the first subject provided informed consent.
     A brief description of the clinical investigation design 
and the dose and regimen of the investigational drug and any 
comparators.
     The cumulative number (or an estimate) of subjects 
enrolled in each treatment arm for all treatment arms of the clinical 
investigation during the reporting period.
     Countries or regions in which the clinical investigation 
was conducted. This would include any country or region with one or 
more study sites.
     A demographic breakdown of study population by age, sex, 
and race.
     The status of the clinical investigation (ongoing or 
completed).
     The total number of subjects (if any) planned to be 
enrolled in the clinical investigation.
    We are proposing that the report identify the cumulative number of 
subjects exposed to the investigational drug and comparators (placebo 
and active controls) since the date the IND went into effect (see 
proposed Sec.  312.33(j)(1)). For blinded studies, this number would be 
estimated. It would also require that such exposure be broken down by 
age, sex, and race. Proposed Sec.  312.33(j)(2) would further require 
the report to estimate patients' cumulative exposure to the marketed 
drug in each country and region in which the sponsor has lawfully 
marketed the drug since the date the IND went into effect, if any, 
accompanied by an explanation of how that exposure was estimated. The 
estimate of exposure is intended to provide context (i.e., a 
denominator) for the cumulative summary tabulations of serious adverse 
events and the overall assessment of safety.
    Proposed Sec.  312.33(k)(1) generally would require lists of safety 
data and other information from clinical investigations of the 
investigational drug conducted on behalf of the sponsor. Proposed Sec.  
312.33(k)(1) would not require information about adverse events that 
are study endpoints or components of study endpoints (e.g., mortality 
events in an outcomes trial).
    Proposed Sec.  312.33(k)(1)(i) would require line listings of 
serious suspected adverse reactions as defined in Sec.  312.32(a) that 
occurred during the reporting period, including the treatment 
associated with the serious suspected adverse reaction, as well as all 
serious suspected adverse reactions for any comparators, if known. The 
line listing would identify those serious suspected adverse reactions 
that are unexpected (serious and unexpected suspected adverse 
reactions), as defined in Sec.  312.32(a). The line listing should be 
formatted as a detailed record of the serious suspected adverse 
reactions and would also be required to include the following 
information, if applicable:
     Study title or abbreviated title.
     Subject's clinical trial identification number.
     Sponsor's adverse reaction case reference number.
     IND Safety Report reference number.
     Country in which case occurred.
     Age and sex of trial subject.
     Treatment group; identified as ``blinded'' if the blind 
has not been broken.
     Dose and dosing interval of investigational drug and, when 
relevant, dosage form and route of administration.
     Date of onset and/or time to onset from administration of 
last dose of the most serious suspected adverse reaction.
     Dates of treatment and/or best estimate of treatment 
duration of serious suspected adverse reaction.
     Outcome (e.g., resolved, fatal, improved, sequelae, 
unknown). This field must indicate the consequences of the reaction(s) 
for the trial subject, using the worst of the different outcomes for 
multiple reactions.
     Comments (e.g., causality assessment if the sponsor 
disagrees with the reporter; concomitant medications suspected to play 
a role in the reactions directly or by interaction; indication treated 
with suspect drug(s); dechallenge/rechallenge results if available).
    The study identification information included with the line listing 
of serious suspected adverse reactions required under proposed Sec.  
312.33(k)(1)(i) would facilitate FDA's evaluation of the drug's safety 
information across multiple clinical trials and INDs.
    Proposed Sec.  312.33(k)(1)(ii) would require a cumulative summary 
tabulation of serious adverse events as defined in Sec.  312.32(a) for 
all clinical investigations conducted on behalf of the sponsor since 
the date the IND went into effect under Sec.  312.40(b). This summary 
should be formatted as a table.
    Proposed Sec.  312.33(k)(1)(iii) would require a list of study 
subjects who died during the reporting period and the cause of death.
    Proposed Sec.  312.33(k)(1)(iv) would require a list of subjects 
who withdrew from a clinical investigation during the reporting period 
because of an adverse event as defined in Sec.  312.32(a), whether the 
adverse event was related to the investigational drug or not.
    The line listings and cumulative summary lists required under 
proposed Sec.  312.33(k)(1) correspond to section 3.7 (Data in Line 
Listings and Summary Tabulations) of the E2F DSUR, which includes 
slightly different information as a result of differences in 
terminology in safety reporting standards. Specifically, FDA issued a 
final ICH guidance for industry in March 1995 entitled ``E2A Clinical 
Safety Data Management: Definitions and Standards for Expedited 
Reporting'' (ICH E2A Clinical Safety Data Management guideline) 
(available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073087.pdf). The 
E2F DSUR cross-referenced definitions for serious adverse reaction, 
serious adverse event, and adverse drug reaction as defined in the ICH 
E2A Clinical Safety Data Management guideline. The ICH Clinical Safety 
Data Management guideline defines adverse drug reaction as ``All 
noxious and unintended responses to a medicinal product related to any 
dose should be considered adverse drug reactions. The phrase `responses 
to medicinal products' means that a causal relationship between a 
medicinal product and an adverse event is at least

[[Page 75562]]

a reasonable possibility, i.e., the relationship cannot be ruled out.'' 
However, FDA issued a final rule entitled ``Investigational New Drug 
Safety Reporting Requirements for Human Drug and Biological Products 
and Safety Reporting Requirements for Bioavailability and 
Bioequivalence Studies in Humans'' on September 29, 2010 (75 FR 59935), 
which revised the definitions of these safety reporting terms under 
current Sec.  312.32(a). As a result, instead of using the term adverse 
drug reaction as defined in the ICH E2A Clinical Safety Data Management 
guideline, we are using suspected adverse reaction, which is defined 
under current Sec.  312.32(a). For the purposes of IND safety 
reporting, ``reasonable possibility,'' as it appears in Sec.  
312.32(a), means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. We are also 
making use of the term serious adverse event or serious suspected 
adverse reaction as defined in Sec.  312.32(a). In light of this 
revision in terminology, we are making it clear that sponsors would be 
required under proposed Sec.  312.33(k)(1)(i) to provide a line listing 
of all serious suspected adverse reactions. We note that adverse 
reactions, which are defined under current Sec.  312.32(a) as adverse 
events caused by a drug, are a subset of all suspected adverse 
reactions--for which there is reason to conclude that the drug caused 
the event--and, if serious, would be required to be included in the 
line listings for proposed Sec.  312.33(k)(1)(i).
    FDA's requirements under proposed Sec.  312.33(k)(1) for a list of 
study subjects who died during the reporting period and the cause of 
death and for a list of subjects who withdrew from the clinical 
investigation during the reporting period correspond to section 3.16 
(Region-Specific Information) of the E2F DSUR, which similarly includes 
a list of subjects who died during the reporting period, the case 
number, the assigned treatment, and the cause of death for each 
subject, as well as a list of subjects who withdrew from clinical 
investigations during the reporting period in association with an 
adverse event. The E2F DSUR states that information should include 
whether or not withdrawing from the investigation was thought to be 
drug-related.
    We are further proposing that a sponsor identify each event omitted 
from these listings or tabulations because the event is a study 
endpoint or a component of a study endpoint (see proposed Sec.  
312.33(k)(2)). This provision is intended to account for study 
endpoints in outcome studies in which death or major morbidity is the 
study endpoint (an adverse outcome) and to isolate those events from 
other reported adverse events. For example, deaths in a cancer trial in 
which overall survival is the study endpoint would be identified as 
required in proposed Sec.  312.33(k)(2) and omitted from the safety 
line listings and summary tabulations described in proposed Sec.  
312.33(k)(1). Similarly, fatal strokes that are a component of a 
composite primary study endpoint (e.g., all-cause mortality) would be 
identified as required by proposed Sec.  312.33(k)(2) and omitted from 
the listings and summary tabulations of serious adverse events 
described in proposed Sec.  312.33(k)(1).
    We are proposing that the report briefly summarize all safety and 
effectiveness findings from clinical investigations of the 
investigational drug conducted on behalf of the sponsor that are 
obtained during the reporting period (see proposed Sec.  312.33(l)). 
Statistically significant differences would be an example of such a 
finding, but in addition, clinically meaningful differences identified 
in an interim analysis that were provided to the sponsor and that led 
to a change in the protocol or population would also be required. The 
report would include data from any completed trials, interim analyses 
of ongoing trials, or long-term follow-up of subjects after exposure to 
the investigational drug in a clinical trial (e.g., for advanced 
therapies such as gene therapy, cell therapy, or tissue-engineered 
products). In certain cases, the lack of effectiveness on an endpoint 
compared to a comparator (e.g., cardiovascular events) can be a safety 
issue. Therefore, it is important to also report on studies in which 
there was a lack of effectiveness or lesser effectiveness relative to 
an active comparator, including results obtained from any completed 
trials or interim analysis that influenced a decision, based on lack of 
efficacy, to either stop a trial or to revise the documents provided to 
subjects when seeking informed consent.
    Proposed Sec.  312.33(m) is intended to ensure that all information 
that is relevant to the safety of the drug and obtained during the 
reporting period from any source is considered and analyzed in the 
report. This proposed section would require the report to briefly 
summarize the following safety information, if known:
     Noninterventional studies where participants are not 
prospectively assigned to receive a drug or other intervention per a 
protocol, including observational studies, epidemiological studies, 
registries, and active surveillance.
     Pooled or meta-analyses of randomized clinical 
investigations.
     Safety findings from marketing experience, if the drug is 
lawfully marketed in any country or region.
     Nonclinical in vivo and in vitro studies (e.g., 
carcinogenicity, reproductive toxicity, immunotoxicity studies).
     Published clinical or nonclinical investigations of the 
drug not conducted on behalf of the sponsor.
     Published studies of other members of the drug's 
pharmacological class. Section 3.13 (Literature) of the E2F DSUR 
provides for the inclusion of information from unpublished studies of 
which the sponsor has become aware during the reporting period. This 
section of the proposed rule would require information from published 
studies and does not create a requirement for sponsors to seek out 
unpublished studies that may be related to the drug.
     All additional significant safety findings about the drug 
from other sources. In addition, safety information provided by 
codevelopment partners or safety information from investigator-
initiated trials would also be captured under this bullet and is 
consistent with section 3.10 (Other Clinical Trial/Study Safety 
Information) of the E2F DSUR.
    We are proposing that the report include a summary of all 
significant chemistry, manufacturing, and control changes, including 
microbiological changes (if applicable), made to the investigational 
drug during the reporting period and briefly describe the safety 
significance of the identified changes (see proposed Sec.  312.33(n)).
    We are proposing that the report briefly describe each significant 
modification made to protocols in response to safety data on behalf of 
the sponsor for clinical investigations being conducted with the 
investigational drug that were not previously reported under Sec.  
312.30 (see proposed Sec.  312.33(o)). The intent of this proposed 
regulation is to provide awareness of significant modifications related 
to safety issues in trials being conducted in another country or region 
and not under an IND.
    We are proposing that the report contain a description of the 
general investigational plan for the coming year to replace the plan 
submitted 1 year earlier (consistent with the content of the general 
investigational plan described in Sec.  312.23(a)(3)(iv)) (see proposed 
Sec.  312.33(p)).

[[Page 75563]]

    We are providing the sponsor the option of including a log of any 
outstanding business concerning the IND for which the sponsor requests 
a reply, comment, or meeting (see proposed Sec.  312.33(q)).
    We are proposing that the report describe any potentially important 
late-breaking safety information about the investigational drug or the 
studies conducted under the IND that were identified by the sponsor 
during preparation of the annual FDA DSUR and after the data lock point 
(see proposed Sec.  312.33(r)). The types of findings or actions that 
would be required to be described under proposed Sec.  312.33(r) 
include clinically significant new adverse event reports; important 
follow-up data; clinically relevant toxicological findings; and actions 
taken for safety reasons that, if the actions had occurred before the 
data lock point, would have been described as required under proposed 
Sec.  312.33(g). This proposed section is intended to capture findings 
that would have been included in the body of the report but did not 
come to the sponsor's awareness until after the data lock point when 
the sponsor was preparing the annual FDA DSUR.
    We are proposing that the report provide an overall safety 
assessment that is a concise, integrated evaluation of all new 
clinical, nonclinical, and epidemiological safety information obtained 
by the sponsor during the reporting period relative to previous 
knowledge of the drug (see proposed Sec.  312.33(s)(1)). Proposed Sec.  
312.33(s)(1) is not intended to require a repeat of information or a 
summary of information presented in previous sections of the annual FDA 
DSUR; rather, it would require an interpretation of the information and 
its implications for the IND. This proposed section corresponds to 
section 3.18.1 (Evaluation of the Risks) of the E2F DSUR, and both 
provide relevant points to consider (if applicable) for evaluating the 
risks of the drug. The integrated evaluation required under proposed 
Sec.  312.33(s)(1) would include the following: (1) cumulative 
experience with the drug, (2) new information about the drug that was 
collected during the reporting period covered by the proposed annual 
FDA DSUR, and (3) for drugs with a marketing approval, clinically 
significant postmarketing data related to the drug. This proposed 
section of the report would explain how safety information obtained 
during the reporting period integrates with what was already known 
about the drug (e.g., what was in prior annual FDA DSURs). The 
assessment must include an evaluation of the following information 
potentially relevant to the risk associated with use of the drug:
     Findings that suggest a significant risk in humans exposed 
to the drug, with associated laboratory values and relationship to 
dose, duration, or time course of exposure, if known.
     Significant changes to the information concerning an 
adverse event that was contained in a previous report (e.g., increased 
frequency, increased severity, identification of a population at 
greater risk for this adverse event).
     Deaths that were previously included in an IND safety 
report required under Sec.  312.32.
     Subject withdrawals from a clinical investigation 
resulting from an adverse event.
     Findings that suggest a significant risk to specific 
populations (e.g., pediatric, geriatric, populations with hepatic or 
renal impairment, pregnant or lactating women, populations 
differentiated by genomic or genetic characteristics).
     Overdose, misuse, and abuse cases or findings regarding 
the potential for abuse to occur.
     Risks associated with long-term exposure (e.g., a drug 
used to treat a chronic disease).
     Risks associated with the method of administration of the 
drug (e.g., drugs administered by injection or drugs administered by 
intravenous, intrathecal, or inhalation methods might be associated 
with the risk of increased local concentrations, sterility, 
pyrogenicity, hypersensitivity, or variations in metabolism), 
diagnostic procedures related to use of the drug (e.g., an invasive 
sampling procedure), or procedures described in a study protocol.
     Evidence of clinically significant medication errors 
(i.e., any preventable event that may cause or lead to inappropriate 
medication use or patient harm while the medication is in the control 
of a healthcare provider, patient, or consumer).
     Drug interactions (e.g., drug-drug, drug-food).
     Any other risks that significantly affect the safety 
assessment of the investigational drug.
    We are proposing that the overall safety assessment also describe 
the balance between benefits, including theoretical or anticipated 
benefits, and cumulative identified risks related to use of the drug 
(see proposed Sec.  312.33(s)(2)). The assessment would also be 
required to describe all changes to the benefit-risk profile compared 
to the previous annual report, based on information obtained during the 
reporting period. Proposed Sec.  312.33(s)(2) is not intended to 
require a full benefit-risk assessment of the drug.
    We are proposing that the report contain a cumulative listing of 
all important known risks (i.e., risks established to be related to the 
use of the drug) and potential risks (i.e., risks that have a 
reasonable possibility of a relationship to the drug, but have not yet 
been established) associated with the drug that are identified by the 
sponsor during the course of studies of the drug conducted on behalf of 
the sponsor, along with a brief description of the nature of each risk 
(see proposed Sec.  312.33(t)). Such risks might include, for example, 
toxicities known to be associated with a particular molecular structure 
or drug class or concerns based on accumulating nonclinical or clinical 
data. Risks identified in a prior reporting period would be required to 
be re-evaluated annually and a description of each risk updated with 
new risk information obtained during the current reporting period. 
Risks that have been fully addressed or resolved would be required to 
remain in the summary and be briefly described (e.g., findings from 
toxicology studies or early clinical trials that were not borne out by 
later clinical data).
    Proposed Sec.  312.33(t) would require a summary of all important 
known and potential risks, whereas proposed Sec.  312.33(s) would 
provide an overall safety assessment.
    We are proposing that the report include a conclusion to briefly 
summarize the following information: (1) all changes to the sponsor's 
previous knowledge of efficacy and safety of the investigational drug 
resulting from information obtained during the reporting period, (2) an 
outline of actions that the sponsor has taken during the reporting 
period to address emerging safety findings, and (3) all additional 
actions that the sponsor will take to address emerging safety findings 
in the future (see proposed Sec.  312.33(u)).

VI. Proposed Effective and Compliance Dates

    FDA proposes that any final rule based on this proposed rule become 
effective 30 days after the final rule publishes in the Federal 
Register. FDA is proposing that the compliance date for any final rule 
based on this proposed rule be 180 days after the date of publication 
of such final rule to give sponsors sufficient time to compile the 
additional information that the proposed rule would require, if 
finalized. We request comments

[[Page 75564]]

specifically regarding the proposed compliance date.

VII. Preliminary Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). 
The Office of Information and Regulatory Affairs has determined that 
this proposed rule is an economically significant regulatory action as 
defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the proposed requirements are unlikely to impose a 
substantial burden on the affected small entities, we propose to 
certify that the proposed rule will not have a significant economic 
impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to 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.'' The current threshold after adjustment 
for inflation is $165 million, using the most current (2021) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

B. Summary of Costs and Benefits

    The proposed rule seeks to revise FDA's regulations for IND annual 
reporting. The proposed rule would modify the format and content of the 
IND annual report to be generally consistent with those of the annual 
DSUR standards devised by the ICH. The proposed harmonization would 
result in savings in labor costs for certain sponsors who may no longer 
have to prepare a different type of periodic safety report for 
submission to certain other countries or regions in which a drug might 
be studied. Moreover, FDA would receive safety data on investigational 
new drugs that is more comprehensive, which would enhance our ability 
to oversee the progress and safety of clinical investigations. The 
estimate of annualized benefits over 10 years ranges from $47.86 
million to $117.99 million with a primary value of $86.46 million at a 
7 percent discount rate and from $49.24 million to $121.01 million with 
a primary value of $88.79 million at a 3 percent discount rate. The 
primary estimate of the present value of benefits over 10 years is 
$607.29 million at a 7 percent discount rate and $757.38 million at a 3 
percent discount rate.
    Costs would arise from increased labor associated with preparing 
and submitting a periodic safety report that is more comprehensive to 
meet the proposed requirements. Costs to government would arise from 
increased FDA resources being used to review the more comprehensive 
report. The estimate of annualized costs over 10 years ranges from 
$40.43 million to $101.34 million at a 7 percent discount rate with a 
primary value of $61.11 million. Using a 3 percent discount rate, the 
annualized costs range from $40.89 million to $102.48 million with a 
primary value of $61.81 million. The primary estimate of the present 
value of costs over 10 years is $429.20 million at a 7 percent discount 
rate and $527.21 million at a 3 percent discount rate. The annualized 
estimates are presented in Table 2.

                             Table 2--Summary of Benefits and Costs in Millions of 2020 Dollars Over a 10-Year Time Horizon
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                           Units
                                                                           ------------------------------------
               Category                   Primary       Low        High                               Period                      Notes
                                         estimate    estimate    estimate      Year      Discount     covered
                                                                              dollars    rates (%)    (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $/year.......      $86.46      $47.86     $117.99        2020           7          10  Benefits are estimated in terms of cost
                                             88.79       49.24      121.01        2020           3          10   savings.
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7
                                                                                                 3
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................
 
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized $/year.......       61.11       40.43      101.34        2020           7          10
                                             61.81       40.89      102.48        2020           3          10
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7
                                                                                                 3
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................
 
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized Monetized $/     ..........  ..........  ..........  ..........           7
     year.                                                                                       3
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Other Annualized Monetized $/year.  ..........  ..........  ..........  ..........           7
                                                                                                 3
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.............................................................................................................
    Small Business: Annual costs per affected small entity represent a maximum of 0.61 percent of average shipments.....................................

[[Page 75565]]

 
    Wages: None.........................................................................................................................................
    Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

C. Summary of Regulatory Flexibility Analysis

    We estimate that at least 77 percent of establishments in the 
pharmaceutical preparations industry and at least 69 percent of 
establishments in the biological products industry employ fewer than 
1,250 employees and are therefore also classified as small businesses. 
Although a large number of small businesses will face costs under the 
proposed rule, the costs to these firms would be relatively small. The 
average annual cost per IND annual report as a percentage of average 
value of shipments for small entities is estimated to be between 0.00 
percent and 0.61 percent. We therefore conclude that this proposed rule 
is unlikely to have a significant impact on a substantial number of 
small entities.
    We have developed a comprehensive Preliminary Economic Analysis of 
Impacts that assesses the impacts of the proposed rule. The full 
preliminary analysis of economic impacts is available in the docket for 
this proposed rule (Ref. 8) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the PRA (44 U.S.C. 3501-3521). A 
description of these provisions is given in the Description section 
with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    FDA invites comments on these topics: (1) whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, 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.
    Title: Investigational New Drug Application Annual Reporting.
    Description: FDA is proposing to revise its requirements for annual 
reports submitted to INDs. FDA is proposing to replace the current 
annual reporting requirement with a new annual reporting requirement 
that is intended to be generally consistent with the format and content 
of submission of the annual DSUR devised by the ICH and described in 
the E2F DSUR. The proposed annual FDA DSUR would provide an annual 
report that is more comprehensive and informative than the IND annual 
report required under current Sec.  312.33. The E2F DSUR can be used to 
satisfy similar annual reporting requirements in certain other 
countries and regions in which a drug is being studied. Therefore, the 
proposed implementation of an annual reporting requirement similar to 
the E2F DSUR in place of the IND annual report format and content is 
consistent with FDA's overarching goal of fostering international 
harmonization of regulatory requirements to the extent appropriate and 
feasible. With the increasing complexity of clinical studies, DSURs 
that are more comprehensive and informative are important tools to 
identify and reduce exposure of human subjects to unnecessary risks. 
The proposed annual FDA DSUR would also help ensure FDA's ongoing 
oversight of the evolving safety and efficacy profile of the drug 
throughout the drug development process. We anticipate an additional 
regulatory burden associated with preparing the proposed annual FDA 
DSUR. However, for sponsors that currently prepare and submit the IND 
annual report to FDA and the E2F DSUR to another regulatory authority 
in another country or region, FDA expects that the burden associated 
with preparing two periodic safety reports will be reduced because the 
sponsors might no longer have to prepare two different annual safety 
reports, because the annual FDA DSUR and the E2F DSUR would be 
generally consistent in content and format.
    Description of Respondents: Sponsors of clinical investigations 
under an IND.
    In tables 4 and 5, the estimated averages for the number of 
respondents and total annual responses were obtained from CDER and CBER 
reports and data management systems.
    In the approved package for OMB control number 0910-0014, FDA 
estimated 360 burden hours to complete and submit an IND annual report. 
To complete and submit the annual FDA DSUR, FDA estimates that a 
sponsor would spend an additional 18 to 72 hours because of the more 
comprehensive information not currently required by the IND annual 
report. Thus, we estimate that sponsors will spend a total of 396 hours 
to comply with the proposed requirement. The estimated average burden 
hours per response was made by CDER and CBER individuals familiar with 
the burden associated with these reports and from estimates received 
from the pharmaceutical industry. For the total information collection 
burden for preparing and submitting an annual FDA DSUR, FDA estimates 
4,590,432 hours (3,855,456 CDER hours + 734,976 CBER hours = 
3,430,944). The estimated 4,590,432 total hours includes 4,173,120 
total hours to submit an IND annual report and 417,312 additional total 
hours to provide the additional information required in the annual FDA 
DSUR.

[[Page 75566]]



                                    Table 4--Estimated Annual Reporting Burden for Human Drugs Regulated by CDER \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                           21 CFR section                               Number of      responses per     Total annual   Average  burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sec.   312.33......................................................           2,877             3.38            9,736              396        3,855,456
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
Note: The Total Annual Responses may not sum up as a result of rounding.


                                    Table 5--Estimated Annual Reporting Burden for Human Drugs Regulated by CBER \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                           21 CFR section                               Number of      responses per     Total annual   Average  burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sec.   312.33......................................................             745             2.49            1,856              396          734,976
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
Note: The Total Annual Responses may not sum up as a result of rounding.

    This proposed rule also refers to previously approved collections 
of information found in FDA regulations. The collections of information 
in part 312 have been approved under OMB control number 0910-0014.
    In compliance with the PRA (44 U.S.C. 3407(d)), the Agency has 
submitted the information collection provisions of this proposed rule 
to OMB for review. These information collection requirements will not 
be effective until FDA publishes a final rule, OMB approves the 
information collection requirements, and the rule goes into effect. FDA 
will announce OMB approval of these requirements in the Federal 
Register.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
we conclude that the rule does not contain policies that have 
federalism implications as defined in the Executive order and, 
consequently, a federalism summary impact statement is not required.

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the rule does not contain policies that would have a 
substantial direct effect on one or more Indian Tribes, on the 
relationship between the Federal Government and Indian Tribes, or on 
the distribution of power and responsibilities between the Federal 
Government and Indian Tribes. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XII. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they are also available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. FDA has verified the website addresses as of 
the date this document publishes in the Federal Register, but websites 
are subject to change over time.

1. CIOMS, ``Development Safety Update Report (DSUR) Harmonizing the 
Format and Content for Periodic Safety Report During Clinical 
Trials: Report of CIOMS Working Group VII,'' ``Introduction and 
Overview, Rationale for the CIOMS VII Project,'' Chapter I.a, pp. 11 
and 12, Geneva 27, Switzerland, 2006.
* 2. ICH, Harmonisation for Better Health, ``Vision: Mission,'' 
accessed August 22, 2016.
* 3. ICH, ``ICH Steering Committee, Minneapolis, MN, USA,'' June 
2014 (available at https://www.ich.org/pressrelease/ich-steering-committee-minneapolis-mn-usa-june-2014), accessed January 7, 2020.
* 4. ICH, ``Final Concept Paper, E2F: Development Safety Update 
Report,'' 2006 (available at https://database.ich.org/sites/default/files/E2F_Concept_Paper.pdf), accessed January 7, 2020.
* 5. ICH, Harmonised Tripartite Guideline ``Development Safety 
Update Report, E2F, Finalised Guideline,'' August 2010 (https://database.ich.org/sites/default/files/E2F_Guideline.pdf), accessed 
January 7, 2020.
* 6. EU, ``Communication From the Commission--Detailed Guidance on 
the Collection, Verification and Presentation of Adverse Event/
Reaction Reports Arising From Clinical Trials on Medicinal Products 
for Human Use (`CT-3'),'' 2011 (available at https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2011:172:0001:0013:EN:PDF), accessed October 
22, 2022.
* 7. European Medicines Agency, ``ICH Topic E 2 C (R1) Clinical 
Safety Data Management: Periodic Safety Update Reports for Marketed 
Drugs,'' June 1997 (available at https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002780.pdf), accessed December 30, 2019.
* 8. FDA, Preliminary Regulatory Impact Analysis; Initial Regulatory 
Flexibility Analysis; Unfunded Mandates Reform Act Analysis, 
``Investigational New Drug Application Annual Reporting,'' 2019 
(available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations).

List of Subjects in 21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 312 be amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
1. The authority citation for part 312 continues to read as follows:


[[Page 75567]]


    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 
42 U.S.C. 262.

0
2. Amend Sec.  312.3(b) by alphabetically adding a definition for Data 
lock point to read as follows:


Sec.  312.3   Definitions and interpretations.

* * * * *
    (b) * * *
    Data lock point means the cutoff date for data to be included in 
the development safety update report required under Sec.  312.33. The 
data lock point is 1 calendar day before the anniversary of the date 
the IND went into effect under Sec.  312.40(b).
* * * * *
0
3. Revise Sec.  312.33 to read as follows:


Sec.  312.33   Development safety update reports.

    Not later than 60 calendar days after the data lock point, a 
sponsor must submit to FDA a development safety update report (DSUR) as 
described in paragraphs (a) through (u) of this section.
    (a) Scope. The DSUR is intended to provide a thorough annual 
assessment of clinical investigations conducted and safety information 
collected during the reporting period that are related to an 
investigational new drug.
    (1) A sponsor must submit an annual DSUR that contains the 
information required to be submitted under paragraphs (b) through (u) 
of this section for all ongoing or completed clinical investigations 
conducted anywhere in the world on behalf of the sponsor evaluating the 
drug, including clinical investigations not conducted under an 
investigational new drug application (IND), unless otherwise specified 
in this section. The sponsor must submit the same DSUR for each IND 
held by the sponsor for any dosage form of the drug.
    (2) A sponsor-investigator for a clinical investigation not 
intended to support a marketing application must provide information 
required under this section that is obtained from the clinical 
investigation conducted by the sponsor-investigator, but the sponsor-
investigator is not required to submit information that is not obtained 
from the clinical investigation conducted by the sponsor-investigator.
    (3) For the purposes of this section, ongoing clinical 
investigations consist of active clinical investigations, clinical 
investigations that are on clinical hold under Sec.  312.42, clinical 
investigations that have not been terminated, and clinical 
investigations for which a final study report has not been submitted 
but the clinical investigation might otherwise be completed.
    (b) Title page. The title page of the DSUR must contain the IND 
number, DSUR number (numbered sequentially), name of the 
investigational drug, reporting period, date of the DSUR, and sponsor's 
name and address.
    (c) Executive summary. The executive summary must contain all of 
the following information:
    (1) The DSUR number and reporting period.
    (2) A brief description of the investigational drug (including the 
therapeutic class, pharmacological class (if applicable), and mechanism 
of action (if known)) and the indication(s), dose(s), formulation(s), 
and route(s) of administration being studied.
    (3) The cumulative number of subjects to whom the drug has been 
administered throughout the course of clinical investigations of the 
drug conducted on behalf of the sponsor or, if a precise number cannot 
be determined, an estimate.
    (4) A summary of the overall safety assessment required in 
paragraph (s) of this section.
    (5) A summary of the list of important risks required in paragraph 
(t) of this section.
    (6) A summary of actions taken for safety reasons as required in 
paragraph (g) of this section.
    (7) A list of countries and regions in which the drug has been 
approved for marketing.
    (8) A summary of the conclusion required in paragraph (u) of this 
section.
    (d) Table of contents. The DSUR must contain a table of contents 
that is sufficiently detailed to direct the reader to the components of 
the DSUR as described in paragraphs (e) through (u) of this section.
    (e) Introduction. The introduction must:
    (1) Identify the reporting period;
    (2) Briefly describe the investigational drug, including the 
therapeutic class, pharmacological class (if applicable), and mechanism 
of action (if known);
    (3) List the indication(s), dose(s), formulation(s), and route(s) 
of administration being investigated; and
    (4) List the clinical investigation(s) conducted on behalf of the 
sponsor that are referred to in the DSUR.
    (f) Worldwide marketing authorizations and applications. If the 
drug has been approved for marketing anywhere in the world, the DSUR 
must provide a brief summary of the status of the approved drug, 
including date of first approval, indication(s), dose(s), and countries 
or regions in which it is approved.
    (g) Actions taken for safety reasons. The DSUR must describe all 
actions relevant to the safety of the drug that were taken during the 
reporting period by a regulatory authority or by the sponsor, if known. 
For each action taken, the reason(s) the action was taken must be 
provided, if known. Actions taken by the sponsor include those actions 
taken in response to a regulatory action and those actions taken 
following a recommendation from a data monitoring committee. Actions 
relevant to the safety of the drug include, but are not limited to, any 
of the following:
    (1) A clinical hold order issued under Sec.  312.42;
    (2) Denial of authorization to initiate a clinical investigation, 
or the suspension of the conduct of a clinical investigation of the 
drug in another country or region;
    (3) A requirement to cease distribution of the drug or other action 
related to the quality of the drug;
    (4) Refusal to approve any application for marketing of the drug;
    (5) An action that places a condition or limitation on the use or 
development of the drug;
    (6) A safety-related change in the protocol or investigational plan 
of an ongoing clinical investigation of the drug;
    (7) A safety-related change in the information provided to human 
subjects in order to obtain informed consent for a clinical 
investigation of the drug;
    (8) A safety-related formulation change to the drug;
    (9) A safety advisory communication to investigators conducting 
clinical investigations under the IND or to healthcare professionals 
concerning use of the drug;
    (10) A clinical investigation of the drug that is initiated or 
planned to evaluate a risk associated with use of the drug;
    (11) If the drug is lawfully marketed, a safety-related change to 
its labeling, including the prescribing information;
    (12) If the drug is lawfully marketed, a significant restriction on 
distribution or other risk mitigation strategy, including a risk 
evaluation and mitigation strategy (REMS) required under section 505-1 
of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355-1); and
    (13) If the drug was lawfully marketed in the past, withdrawal or 
suspension of marketing approval for the drug.
    (h) Reference safety information. (1) If required under Sec. Sec.  
312.23(a)(5) and 312.55, the investigator brochure in effect at the 
start of a reporting period will serve as the reference safety 
information for that reporting period. If an investigator brochure is 
not required under Sec. Sec.  312.23(a)(5) and 312.55 and

[[Page 75568]]

the drug is subject to an FDA-approved marketing application, the FDA-
approved prescribing information will serve as the reference safety 
information during the reporting period. If an investigator brochure is 
not required under Sec. Sec.  312.23(a)(5) and 312.55 and the drug is 
not subject to an FDA-approved marketing application, the sponsor must 
use another source as the reference safety information. The sponsor 
must identify the reference safety information used during the 
reporting period.
    (2) The DSUR must list all safety-related changes to the reference 
safety information, made during the reporting period.
    (i) Inventory of clinical investigations conducted during the 
reporting period. For each ongoing and completed clinical investigation 
of the investigational drug conducted on behalf of the sponsor during 
the reporting period, the DSUR must provide the following:
    (1) The protocol number;
    (2) The clinical investigation title (or abbreviated title);
    (3) The NCT number, if applicable;
    (4) The phase of the clinical investigation (i.e., 1, 2, 3, or 
postmarketing);
    (5) The date the first subject provided informed consent;
    (6) A brief description of the clinical investigation design and 
the dose and regimen of the investigational drug and any comparators;
    (7) The cumulative number (or an estimate) of subjects enrolled in 
each treatment arm for all treatment arms of the clinical 
investigation;
    (8) Countries or regions in which the clinical investigation was 
conducted;
    (9) A demographic breakdown of study population by age, sex, and 
race;
    (10) The status of the clinical investigation (i.e., ongoing or 
completed); and
    (11) The number of subjects (if any) planned to be enrolled in the 
clinical investigation.
    (j) Cumulative exposure. (1) The DSUR must provide the cumulative 
number (or an estimate) of subjects exposed to the investigational drug 
and comparators during clinical investigations conducted on behalf of 
the sponsor since the date the IND went into effect. The DSUR must 
provide a tabulation of exposed subjects by age, sex, and race.
    (2) If the drug is lawfully marketed by the sponsor, the DSUR must 
provide an estimate of patients' cumulative exposure to the drug in 
each country and region in which the sponsor has marketed the drug 
since the date the IND went into effect, including an explanation of 
how that exposure was estimated.
    (k) Safety data tabulations and line listings. (1) The DSUR must 
provide the following safety data from clinical investigations of the 
investigational drug that are conducted on behalf of the sponsor, with 
the exception of adverse events that are study endpoints or components 
of study endpoints:
    (i) Line listings of all serious suspected adverse reactions as 
defined in Sec.  312.32(a) that occurred during the reporting period, 
as well as all serious suspected adverse reactions for any comparators, 
if known. The line listings must identify those serious suspected 
adverse reactions that are unexpected (serious and unexpected suspected 
adverse reaction) as defined in Sec.  312.32(a) and must also include 
the following information, if applicable:
    (A) Clinical investigation identification information (e.g., number 
or name).
    (B) Subject's clinical investigation identification number.
    (C) Sponsor's adverse reaction case reference number.
    (D) IND Safety Report reference number.
    (E) Country in which case occurred.
    (F) Age and sex of subject.
    (G) Treatment group; identified as ``blinded'' if the blind has not 
been broken.
    (H) Dose and dosing interval of investigational drug and, when 
relevant, dosage form and route of administration.
    (I) Date of onset and/or time to onset from administration of last 
dose of the most serious suspected adverse reaction.
    (J) Date(s) of treatment and/or best estimate of treatment 
duration.
    (K) The DSUR must indicate the consequences of the reaction(s) for 
the subject, using the worst of the different outcomes for multiple 
reactions.
    (L) Comments.
    (ii) A cumulative summary tabulation of serious adverse events (as 
defined in Sec.  312.32(a)) obtained from all clinical investigations 
conducted on behalf of the sponsor that occurred since the date the IND 
went into effect under Sec.  312.40(b).
    (iii) A list of subjects who died during the reporting period and 
the cause of death for each subject.
    (iv) A list of subjects who withdrew from a clinical investigation 
during the reporting period because of an adverse event (as defined in 
Sec.  312.32(a)), whether the adverse event was related to the 
investigational drug or not.
    (2) The DSUR must identify each event omitted from the information 
reported pursuant to paragraph (k)(1) of this section because the event 
is a study endpoint or a component of a study endpoint.
    (l) Results from clinical investigations. The DSUR must briefly 
summarize all safety and effectiveness findings from clinical 
investigations of the investigational drug that are conducted on behalf 
of the sponsor and obtained during the reporting period, including 
results obtained from any completed clinical investigations or interim 
analysis that resulted in a decision, based on lack of efficacy, to 
either stop a clinical investigation or to revise the information 
provided to subjects when seeking to obtain informed consent.
    (m) Other safety findings. The DSUR must briefly summarize the 
following information obtained during the reporting period, if known:
    (1) Noninterventional studies of the drug, including observational 
studies; epidemiological studies; registries; and active surveillance.
    (2) Pooled analyses or meta-analyses of randomized clinical 
investigations of the drug.
    (3) Safety findings from marketing experience if the drug is 
lawfully marketed.
    (4) Nonclinical in vivo and in vitro studies of the drug.
    (5) Published clinical or nonclinical investigations of the drug 
not conducted on behalf of the sponsor.
    (6) Published studies of other members of the pharmacological class 
of the drug.
    (7) All additional significant safety findings about the drug from 
other sources.
    (n) Significant chemistry, manufacturing, and control changes, 
including microbiological changes (if applicable). The DSUR must 
include a summary of significant chemistry, manufacturing, and control 
changes, including microbiological changes (if applicable), made during 
the reporting period to the investigational drug and must briefly 
describe the safety significance of the identified changes.
    (o) Protocol modifications. The DSUR must briefly describe each 
significant modification made on behalf of the sponsor to protocols for 
phase I clinical investigations being conducted with the drug that were 
not previously reported under Sec.  312.30.
    (p) Investigational plan. The DSUR must contain a description of 
the general investigational plan for the coming year to replace the 
plan submitted 1 year earlier. The description of the general 
investigational plan must contain the

[[Page 75569]]

information described in Sec.  312.23(a)(3)(iv).
    (q) Log of outstanding business. The DSUR may, at the option of the 
sponsor, include a log of any outstanding business concerning the IND 
for which the sponsor has requested a reply, comment, or meeting.
    (r) Late-breaking information. The DSUR must describe any 
potentially important safety information about the investigational drug 
or the clinical investigations conducted under the IND that was 
identified by the sponsor during preparation of the DSUR and after the 
data lock point.
    (s) Overall safety assessment. (1) The DSUR must provide an overall 
safety assessment that is a concise, integrated evaluation of all new 
clinical, nonclinical, and epidemiological safety information obtained 
about the drug by the sponsor during the reporting period relative to 
the sponsor's prior knowledge of the drug, including knowledge obtained 
by the sponsor during any prior reporting periods. The assessment must 
include an evaluation of the risks associated with use of the drug that 
includes an interpretation of new safety information relative to the 
safety information that was previously obtained by the sponsor. The 
overall safety assessment must include the following items:
    (i) Findings that suggest a significant risk in humans exposed to 
the drug, with any associated laboratory values, and relationship to 
dose, duration, or time course of exposure, if known.
    (ii) Significant changes in information concerning adverse events 
that were identified in a previous DSUR.
    (iii) Deaths that were previously included in an IND safety report 
required in Sec.  312.32.
    (iv) Subjects who withdrew from a clinical investigation because of 
an adverse event.
    (v) Findings that suggest a significant risk to specific 
populations.
    (vi) Drug overdose, misuse, and abuse cases or findings regarding 
the potential for abuse to occur.
    (vii) Risks associated with long-term exposure.
    (viii) Risks associated with the method of administration of the 
drug, diagnostic procedures related to use of the drug, or other 
procedures described in a protocol.
    (ix) Evidence of clinically significant medication errors.
    (x) Drug interactions.
    (xi) Any other risks that significantly affect the safety 
assessment of the drug.
    (2) The overall safety assessment must describe the balance between 
benefits, including theoretical or anticipated benefits, and cumulative 
identified risks related to use of the drug. The overall safety 
assessment must also describe changes to the benefit-risk profile 
compared to the previous DSUR, based on information obtained during the 
reporting period.
    (t) Summary of important risks. The DSUR must provide a cumulative 
listing, along with a brief description, of all the important known 
risks and potential risks associated with use of the drug identified by 
the sponsor during the course of clinical and nonclinical 
investigations of the drug conducted on behalf of the sponsor. The 
listing must include a description of each risk. Risks identified by 
the sponsor in a prior reporting period must be re-evaluated annually, 
and their descriptions must be updated with any new risk information 
obtained during the reporting period.
    (u) Conclusion. The DSUR must briefly summarize the following 
information:
    (1) All changes to the sponsor's previous knowledge of the 
investigational drug's efficacy and safety resulting from information 
obtained during this reporting period.
    (2) An outline of actions that have been taken by the sponsor 
during the current reporting period to address emerging safety 
findings.
    (3) All additional actions that will be taken in the future by the 
sponsor to address emerging safety findings, to the extent known.

    Dated: November 29, 2022.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2022-26731 Filed 12-8-22; 8:45 am]
BILLING CODE 4164-01-P