Notice2022-22882
Multiple Endpoints in Clinical Trials; Guidance for Industry; Availability
Primary source
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Published
October 21, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled "Multiple Endpoints in Clinical Trials." This guidance provides sponsors and review staff with the Agency's thinking about the problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for human drugs, including drugs subject to licensing as biological products. This guidance finalizes the draft guidance of the same title issued on January 13, 2017.
Full Text
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<title>Federal Register, Volume 87 Issue 203 (Friday, October 21, 2022)</title>
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[Federal Register Volume 87, Number 203 (Friday, October 21, 2022)]
[Notices]
[Pages 64055-64057]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-22882]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA 2016-D-4460]
Multiple Endpoints in Clinical Trials; Guidance for Industry;
Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a final guidance for industry entitled ``Multiple
Endpoints in Clinical Trials.'' This guidance provides sponsors and
review staff with the Agency's thinking about the problems posed by
multiple endpoints in the analysis and interpretation of study results
and how these problems can be managed in clinical trials for human
drugs, including drugs subject to licensing as biological products.
This guidance finalizes the draft guidance of the same title issued on
January 13, 2017.
DATES: The announcement of the guidance is published in the Federal
Register on October 21, 2022.
ADDRESSES: You may submit comments on any guidance at any time as
follows:
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
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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 2016-D-4460 for ``Multiple Endpoints in Clinical Trials.'' Received
comments 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, 240-402-7500.
<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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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, 240-402-7500.
You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single copies of this guidance to the
Division of Drug Information, Center for Drug Evaluation and Research,
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale
Building, 4th Floor, Silver Spring, MD 20993-0002 or to the Office of
Communication, Outreach and Development, Center for Biologics
Evaluation and Research (CBER), Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send
one self-addressed adhesive label to assist that office in processing
your requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.
FOR FURTHER INFORMATION CONTACT: Scott N. Goldie, Center for Drug
Evaluation and Research, Office of Biostatistics, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 21, Rm. 3557, Silver
Spring, MD 20993-0002, 301-796-2055, 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.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Multiple Endpoints in Clinical Trials.'' This guidance
describes various strategies for grouping and ordering endpoints for
analysis of a drug's effects and applying some well-recognized
statistical methods for managing multiplicity within a clinical trial
to control the chance of making erroneous conclusions about a drug's
effects. FDA's International Conference on Harmonization (ICH) guidance
for industry ``E9 Statistical Principles for Clinical Trials'' is a
broad-ranging guidance that includes discussion of multiple endpoints.
This guidance provides greater detail on the topic of multiple
endpoints.
Failure to account for multiplicity when there are several clinical
endpoints evaluated in a clinical trial can lead to false positive
conclusions regarding the effects of the drug. The regulatory concern
regarding multiplicity arises principally in the evaluation of clinical
trials intended to demonstrate effectiveness and support drug approval;
however, this issue is important throughout the drug development
process.
The focus of this guidance is control of the Type 1 error rate for
the planned primary and secondary endpoints of a clinical trial so that
the major findings are well supported. Multiplicity adjustments provide
a means for controlling the Type 1 error rate when there are multiple
analyses of the drug's effects. The issues of multiplicity and methods
to address them are illustrated in the guidance with examples of
different study endpoints. Both the issues and methods that apply to
multiple endpoints also apply to other sources of multiplicity,
including multiple doses, time points, or study population subgroups.
This guidance finalizes the draft guidance of the same title that
published January 13, 2017 (82 FR 4353). FDA considered comments
received on the draft guidance as the guidance was finalized. Changes
from the draft to the final guidance include clarifications for some of
the potential issues caused by including multiple endpoints in clinical
trials and clarifications for some of the strategies for handling these
issues. In addition, editorial changes were made to improve clarity by
reducing redundancies in the text.
This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``Multiple Endpoints in Clinical Trials.''
It does not establish any rights for any person and is not binding on
FDA or the public. You can use an alternative approach if it satisfies
the requirements of the applicable statutes and regulations.
II. Paperwork Reduction Act of 1995
While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. Therefore,
clearance by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not
required for this guidance. The previously approved collections of
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information are subject to review by OMB under the PRA. The collections
of information in 21 CFR 312.23 for the content and format of
investigational new drug applications have been approved under OMB
control number 0910-0014. The collections of information in 21 CFR part
314 for submitting applications for FDA approval to market a new drug
have been approved under OMB control number 0910-0001. The collections
of information in 21 CFR 201.56 and 201.57 for preparing and submitting
labeling have been approved under OMB control number 0910-0572.
III. Electronic Access
Persons with access to the internet may obtain the guidance at
<a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Dated: October 17, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-22882 Filed 10-20-22; 8:45 am]
BILLING CODE 4164-01-P
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