82 FR 4353 - Multiple Endpoints in Clinical Trials; Draft Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 82, Issue 9 (January 13, 2017)

The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled ``Multiple Endpoints in Clinical Trials.'' This draft guidance provides sponsors and review staff with the Agency's thinking about the problems posed by multiple endpoints in the analysis and interpretation of study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. Most clinical trials performed in drug development contain multiple endpoints to assess the effects of the drug and to document the ability of the drug to favorably affect one or more disease characteristics. The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis and applying some well- recognized statistical methods for managing multiplicity within a study to control the chance of making erroneous conclusions about a drug's effects.

[Federal Register Volume 82, Number 9 (Friday, January 13, 2017)]
[Notices]
[Pages 4353-4354]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2017-00695]


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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Multiple Endpoints in Clinical Trials; Draft Guidance for 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the availability of a draft guidance for industry entitled ``Multiple 
Endpoints in Clinical Trials.'' This draft guidance provides sponsors 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. 
Most clinical trials performed in drug development contain multiple 
endpoints to assess the effects of the drug and to document the ability 
of the drug to favorably affect one or more disease characteristics. 
The purpose of this guidance is to describe various strategies for 
grouping and ordering endpoints for analysis and applying some well-
recognized statistical methods for managing multiplicity within a study 
to control the chance of making erroneous conclusions about a drug's 
effects.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on this 
draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by March 14, 2017.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://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): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, 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; Draft 
Guidance for Industry; Availability.'' Received comments will be placed 
in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at http://www.regulations.gov or at 
the Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper

[[Page 4354]]

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 http://www.regulations.gov. Submit both copies to the Division of Dockets 
Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
    Submit written requests for single copies of the draft 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 the 
Office of Communication, Outreach and Development, Center for Biologics 
Evaluation and Research, 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 draft guidance document.

FOR FURTHER INFORMATION CONTACT: Scott Goldie, Center for Drug 
Evaluation and Research, 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 draft guidance for industry 
entitled ``Multiple Endpoints in Clinical Trials.'' This guidance 
describes various strategies for grouping and ordering endpoints for 
analysis and applying some well-recognized statistical methods for 
managing multiplicity within a study. 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 draft guidance provides greater 
detail on the topic of multiple endpoints. The issuance of this draft 
guidance represents partial fulfillment of an FDA commitment under the 
Food and Drug Administration Amendments Act of 2007. (Title I of the 
Food and Drug Administration Amendments Act of 2007 (Pub. L. 110-85)). 
Under section XI (Expediting Drug Development) of the Prescription Drug 
User Fee Act (PDUFA) Performance Goals, FDA agreed to develop and 
publish for comment draft guidance on ``Multiple Endpoints in Clinical 
Trials,'' and to complete the final guidance within one year of the 
close of the public comment period of the PDUFA Performance Goals (see 
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm).
    Failure to account for multiplicity when there are several clinical 
endpoints evaluated in a study 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 draft 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 Type 1 error when there are 
multiple analyses of the drug's effects. The issues of multiplicity and 
methods to address them are illustrated in the draft 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.
    Once a trial is successful (demonstrates effectiveness or ``wins'' 
on the primary endpoint(s)), there are many other attributes of a 
drug's effects that may be described. Analyses that describe these 
other attributes of a drug can be informative and are often included in 
physician labeling. Such descriptive analyses are not the subject of 
this draft guidance and are not addressed in detail.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent 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. Electronic Access

    Persons with access to the Internet may obtain the draft guidance 
at either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
http://www.regulations.gov.

    Dated: January 10, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-00695 Filed 1-12-17; 8:45 am]
 BILLING CODE 4164-01-P