[Federal Register Volume 87, Number 203 (Friday, October 21, 2022)]
[Notices]
[Pages 64055-64057]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-22882]


-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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This guidance finalizes the draft guidance of the same title issued on 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:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that

[[Page 64056]]

identifies you in the body of your comments, that information will be 
posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA 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 https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://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, 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

[[Page 64057]]

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 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    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