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Proposed Rule2022-26731

Investigational New Drug Application Annual Reporting

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Published

December 9, 2022

Issuing agencies

Health and Human Services DepartmentFood and Drug Administration

Abstract

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.

Full Text

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<title>Federal Register, Volume 87 Issue 236 (Friday, December 9, 2022)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
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:
<bullet> Fax to the Office of Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or email to
<a href="/cdn-cgi/l/email-protection#f29d9b8093ad8187909f9b81819b9d9cb29d9f90dc979d82dc959d84"><span class="__cf_email__" data-cfemail="c1aea8b3a09eb2b4a3aca8b2b2a8aeaf81aeaca3efa4aeb1efa6aeb7">[email&#160;protected]</span></a>. 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, <a href="/cdn-cgi/l/email-protection#b3f7d2c79df7dcd2ddf3d5d7d29ddbdbc09dd4dcc5"><span class="__cf_email__" data-cfemail="337752471d775c525d735557521d5b5b401d545c45">[email&#160;protected]</span></a>; 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, <a href="/cdn-cgi/l/email-protection#77240312071f121959251e071b120e37111316591f1f0459101801"><span class="__cf_email__" data-cfemail="dd8ea9b8adb5b8b3f38fb4adb1b8a49dbbb9bcf3b5b5aef3bab2ab">[email&#160;protected]</span></a>.
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,
<a href="/cdn-cgi/l/email-protection#247476657750454242644240450a4c4c570a434b52"><span class="__cf_email__" data-cfemail="baeae8fbe9cedbdcdcfadcdedb94d2d2c994ddd5cc">[email&#160;protected]</span></a>.

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:
<bullet> 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)).
<bullet> 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)).
<bullet> Requires an executive summary (proposed Sec. 312.33(c)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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

[[Page 75553]]

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).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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)).
<bullet> 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

------------------------------------------------------------------------
Abbreviation/acronym What it means
------------------------------------------------------------------------
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.
------------------------------------------------------------------------

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
<a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e2f-development-safety-update-report">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e2f-development-safety-update-report</a>). 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

[[Page 75554]]

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:
<bullet> A summary showing the most frequent and most serious
adverse experiences (Sec. 312.33(b)(1)).
<bullet> A summary of all IND safety reports submitted during the
previous year (Sec. 312.33(b)(2)).
<bullet> 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)).
<bullet> A summary of any significant manufacturing or
microbiological

[[Page 75555]]

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 <a href="https://www.regulations.gov/document?D=FDA-2008-D-0386-0002">https://www.regulations.gov/document?D=FDA-2008-D-0386-0002</a>) 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:
<bullet> Examining whether the information obtained by the sponsor
during the reporting period aligns with prior knowledge of the safety
of the investigational drug.
<bullet> Describing new safety findings that could have an impact
on the protection of study subjects.
<bullet> Summarizing the current understanding and management of
identified and potential risks.
<bullet> 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

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............. <bullet> Not required......... <bullet> 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.
<bullet> 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..................... <bullet> Not required......... <bullet> Requires an executive summary
(proposed Sec. 312.33(c))
Scope of information on clinical <bullet> Requires information <bullet> 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................... <bullet> Not required......... <bullet> 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)).
<bullet> 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 <bullet> Requires a brief <bullet> 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 <bullet> 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 <bullet> Requires a brief <bullet> 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 <bullet> 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 <bullet> 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 <bullet> In a brief summary of <bullet> 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.... <bullet> Not required......... <bullet> 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.
<bullet> 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........... <bullet> Requires a narrative <bullet> 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.
<bullet> 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)).
<bullet> 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.................... <bullet> Requires a summary of
all IND safety reports
submitted during the past
year (Sec. 312.33(b)(2)).
Information on drug's actions......... <bullet> Requires a brief <bullet> 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...... <bullet> Requires a list of <bullet> 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 <bullet> Requires a summary of <bullet> 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.
........................................
<bullet> Requires a brief description of
the safety significance of the
identified changes (proposed Sec.
312.33(n)).
Investigator brochure changes......... <bullet> If the investigator <bullet> 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.
<bullet> 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.
<bullet> 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).
<bullet> Requires that the report list
all safety-related changes to the
reference safety information made
during the reporting period.
Actions taken for safety reasons...... <bullet> Requires a brief <bullet> 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 <bullet> Not required......... <bullet> 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............ <bullet> Not required......... <bullet> 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.
<bullet> 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.. <bullet> Provides no <bullet> 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............................ <bullet> Not required......... <bullet> 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:
<bullet> The report number and reporting period;
<bullet> 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;
<bullet> 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);
<bullet> A summary of the overall safety assessment required under
proposed Sec. 312.33(s) of the main report;
<bullet> A summary of the list of important risks required under
proposed Sec. 312.33(t) of the main report;
<bullet> A summary of actions taken for safety reasons as required
under proposed Sec. 312.33(g);
<bullet> 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
<bullet> 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:
<bullet> A clinical hold order issued under Sec. 312.42;
<bullet> 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);
<bullet> A requirement to cease distribution of the drug or other
action related to the quality of the drug (e.g., recall of the drug);
<bullet> Refusal to approve any application for marketing of the
drug (this includes voluntary withdrawal of an application);
<bullet> 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);
<bullet> 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);
<bullet> A safety-related change in the information provided to
human subjects in order to obtain informed consent for a clinical
investigation of the drug;
<bullet> A safety-related formulation change to the drug;
<bullet> A safety advisory communication to investigators
conducting studies under the IND or to healthcare professionals
concerning use of the drug;
<bullet> An investigation of the drug that is initiated or planned
to evaluate a safety risk associated with use of the drug;
<bullet> If the drug is lawfully marketed, each safety-related
change to its labeling, including the prescribing information;
<bullet> 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
<bullet> 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:
<bullet> The protocol number.
<bullet> The clinical investigation title (or abbreviated title).
<bullet> The National Clinical Trial (NCT) number, if applicable.
<bullet> The phase of the clinical investigation (i.e., 1, 2, 3, or
postmarketing).
<bullet> The date the first subject provided informed consent.
<bullet> A brief description of the clinical investigation design
and the dose and regimen of the investigational drug and any
comparators.
<bullet> 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.
<bullet> Countries or regions in which the clinical investigation
was conducted. This would include any country or region with one or
more study sites.
<bullet> A demographic breakdown of study population by age, sex,
and race.
<bullet> The status of the clinical investigation (ongoing or
completed).
<bullet> 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:
<bullet> Study title or abbreviated title.
<bullet> Subject's clinical trial identification number.
<bullet> Sponsor's adverse reaction case reference number.
<bullet> IND Safety Report reference number.
<bullet> Country in which case occurred.
<bullet> Age and sex of trial subject.
<bullet> Treatment group; identified as ``blinded'' if the blind
has not been broken.
<bullet> Dose and dosing interval of investigational drug and, when
relevant, dosage form and route of administration.
<bullet> Date of onset and/or time to onset from administration of
last dose of the most serious suspected adverse reaction.
<bullet> Dates of treatment and/or best estimate of treatment
duration of serious suspected adverse reaction.
<bullet> 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.
<bullet> 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 <a href="https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073087.pdf">https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073087.pdf</a>). 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:
<bullet> 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.
<bullet> Pooled or meta-analyses of randomized clinical
investigations.
<bullet> Safety findings from marketing experience, if the drug is
lawfully marketed in any country or region.
<bullet> Nonclinical in vivo and in vitro studies (e.g.,
carcinogenicity, reproductive toxicity, immunotoxicity studies).
<bullet> Published clinical or nonclinical investigations of the
drug not conducted on behalf of the sponsor.
<bullet> 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.
<bullet> 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:
<bullet> 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.
<bullet> 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).
<bullet> Deaths that were previously included in an IND safety
report required under Sec. 312.32.
<bullet> Subject withdrawals from a clinical investigation
resulting from an adverse event.
<bullet> 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).
<bullet> Overdose, misuse, and abuse cases or findings regarding
the potential for abuse to occur.
<bullet> Risks associated with long-term exposure (e.g., a drug
used to treat a chronic disease).
<bullet> 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.
<bullet> 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).
<bullet> Drug interactions (e.g., drug-drug, drug-food).
<bullet> 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 <a href="https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations">https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations</a>.

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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 <a href="https://www.ich.org/pressrelease/ich-steering-committee-minneapolis-mn-usa-june-2014">https://www.ich.org/pressrelease/ich-steering-committee-minneapolis-mn-usa-june-2014</a>), accessed January 7, 2020.
* 4. ICH, ``Final Concept Paper, E2F: Development Safety Update
Report,'' 2006 (available at <a href="https://database.ich.org/sites/default/files/E2F_Concept_Paper.pdf">https://database.ich.org/sites/default/files/E2F_Concept_Paper.pdf</a>), accessed January 7, 2020.
* 5. ICH, Harmonised Tripartite Guideline ``Development Safety
Update Report, E2F, Finalised Guideline,'' August 2010 (<a href="https://database.ich.org/sites/default/files/E2F_Guideline.pdf">https://database.ich.org/sites/default/files/E2F_Guideline.pdf</a>), 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 <a href="https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2011:172:0001:0013:EN:PDF">https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2011:172:0001:0013:EN:PDF</a>), 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 <a href="https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002780.pdf">https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002780.pdf</a>), 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 <a href="https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations">https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations</a>).

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

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