82_FR_4362 82 FR 4353 - Multiple Endpoints in Clinical Trials; Draft Guidance for Industry; Availability

82 FR 4353 - Multiple Endpoints in Clinical Trials; Draft Guidance for Industry; Availability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

Page Range4353-4354
FR Document2017-00695

The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled ``Multiple Endpoints in Clinical Trials.'' This draft guidance provides sponsors and review staff with the Agency's thinking about the problems posed by multiple endpoints in the analysis and interpretation of study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 Issue 9 (Friday, January 13, 2017) 
[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]


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

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Multiple Endpoints in Clinical Trials; Draft Guidance for 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.

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

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the availability of a draft guidance for industry entitled ``Multiple 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 This draft guidance provides sponsors 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

Federal Register / Vol. 82, No. 9 / Friday, January 13, 2017 / Notices 4353 these informal, Pre-RFD inquiries, FDA complete process involved with informal, Pre-RFD inquiries, who have expects the proposed Pre-RFD program preparing the Pre-RFD submission takes consulted and advised sponsors and to be utilized as a viable program in the approximately 12 hours and an industry representatives on the future and expects that the number of additional 1 hour for meetings. information collection, and who have Pre-RFDs will increase initially to This average is based upon estimates reviewed the documentation submitted. approximately 180 submissions. by FDA administrative and technical FDA estimates from past experience staff who are familiar with the Therefore, the total reporting burden with informal Pre-RFD inquiries that the information collection relating to hours is estimated to be 1,768 hours. TABLE 2—ESTIMATED ANNUAL REPORTING BURDEN 1 Total burden Hourly Total cost Number of respondents hours wage rate annualized annualized 136 ............................................................................................................................................... 13 $33.26 $58,803.68 1 There are no capital costs or operating and maintenance costs associated with this collection of information. Assuming an hourly wage plus benefit guidance for industry entitled ‘‘Multiple third party may not wish to be posted, rate of $33.26,1 the result is a cost of Endpoints in Clinical Trials.’’ This draft such as medical information, your or $432.38 per respondent. The estimated guidance provides sponsors and review anyone else’s Social Security number, or submission cost of $432.38 multiplied staff with the Agency’s thinking about confidential business information, such by 136 submissions per year equals the problems posed by multiple as a manufacturing process. Please note $58,803.68, which is the estimated endpoints in the analysis and that if you include your name, contact aggregated industry reporting cost interpretation of study results and how information, or other information that annualized. these problems can be managed in identifies you in the body of your This draft guidance also refers to clinical trials for human drugs, comments, that information will be previously approved information including drugs subject to licensing as posted on http://www.regulations.gov. collections found in FDA regulations. biological products. Most clinical trials • If you want to submit a comment The collections of information in 21 performed in drug development contain with confidential information that you CFR part 3 are approved under OMB multiple endpoints to assess the effects do not wish to be made available to the control number 0910–0523. of the drug and to document the ability public, submit the comment as a of the drug to favorably affect one or written/paper submission and in the IV. Electronic Access more disease characteristics. The manner detailed (see ‘‘Written/Paper Persons with access to the Internet purpose of this guidance is to describe Submissions’’ and ‘‘Instructions’’). may obtain the document at http://www. various strategies for grouping and fda.gov/RegulatoryInformation/ Written/Paper Submissions ordering endpoints for analysis and Guidances/ucm534661.htm. applying some well-recognized Submit written/paper submissions as Dated: January 9, 2017. statistical methods for managing follows: multiplicity within a study to control • Mail/Hand delivery/Courier (for Leslie Kux, the chance of making erroneous written/paper submissions): Division of Associate Commissioner for Policy. conclusions about a drug’s effects. Dockets Management (HFA–305), Food [FR Doc. 2017–00629 Filed 1–12–17; 8:45 am] and Drug Administration, 5630 Fishers DATES: Although you can comment on BILLING CODE 4164–01–P Lane, Rm. 1061, Rockville, MD 20852. any guidance at any time (see 21 CFR • For written/paper comments 10.115(g)(5)), to ensure that the Agency submitted to the Division of Dockets DEPARTMENT OF HEALTH AND considers your comment on this draft Management, FDA will post your HUMAN SERVICES guidance before it begins work on the comment, as well as any attachments, final version of the guidance, submit except for information submitted, Food and Drug Administration either electronic or written comments marked and identified, as confidential, [Docket No. FDA–2016–D–4460] on the draft guidance by March 14, if submitted as detailed in 2017. ‘‘Instructions.’’ Multiple Endpoints in Clinical Trials; ADDRESSES: You may submit comments Instructions: All submissions received Draft Guidance for Industry; as follows: must include the Docket No. FDA– Availability 2016–D–4460 for ‘‘Multiple Endpoints Electronic Submissions in Clinical Trials; Draft Guidance for AGENCY: Food and Drug Administration, HHS. Submit electronic comments in the Industry; Availability.’’ Received following way: comments will be placed in the docket ACTION: Notice of availability. • Federal eRulemaking Portal: http:// and, except for those submitted as SUMMARY: The Food and Drug www.regulations.gov. Follow the ‘‘Confidential Submissions,’’ publicly instructions for submitting comments. asabaliauskas on DSK3SPTVN1PROD with NOTICES Administration (FDA or Agency) is viewable at http://www.regulations.gov announcing the availability of a draft Comments submitted electronically, or at the Division of Dockets including attachments, to http:// Management between 9 a.m. and 4 p.m., 1 Wage is based on the 2015 Bureau of Labor www.regulations.gov will be posted to Monday through Friday. Statistic’s survey, National Industry Specific the docket unchanged. Because your • Confidential Submissions—To Occupational Employment and Wage Estimate, for comment will be made public, you are submit a comment with confidential standard occupational code 13–1041, compliance officer in pharmaceutical and medicine solely responsible for ensuring that your information that you do not wish to be manufacturing (http://www.bls.gov/oes/current/ comment does not include any made publicly available, submit your oes131041.htm). confidential information that you or a comments only as a written/paper VerDate Sep<11>2014 19:06 Jan 12, 2017 Jkt 241001 PO 00000 Frm 00075 Fmt 4703 Sfmt 4703 E:\FR\FM\13JAN1.SGM 13JAN1

4354 Federal Register / Vol. 82, No. 9 / Friday, January 13, 2017 / Notices submission. You should submit two Evaluation and Research, Food and sources of multiplicity, including copies total. One copy will include the Drug Administration, 10903 New multiple doses, time points, or study information you claim to be confidential Hampshire Ave., Bldg. 71, Rm. 7301, population subgroups. with a heading or cover note that states Silver Spring, MD 20993–0002, 240– Once a trial is successful ‘‘THIS DOCUMENT CONTAINS 402–7911. (demonstrates effectiveness or ‘‘wins’’ CONFIDENTIAL INFORMATION.’’ The SUPPLEMENTARY INFORMATION: on the primary endpoint(s)), there are Agency will review this copy, including many other attributes of a drug’s effects the claimed confidential information, in I. Background that may be described. Analyses that its consideration of comments. The FDA is announcing the availability of describe these other attributes of a drug second copy, which will have the a draft guidance for industry entitled can be informative and are often claimed confidential information ‘‘Multiple Endpoints in Clinical Trials.’’ included in physician labeling. Such redacted/blacked out, will be available This guidance describes various descriptive analyses are not the subject for public viewing and posted on http:// strategies for grouping and ordering of this draft guidance and are not www.regulations.gov. Submit both endpoints for analysis and applying addressed in detail. copies to the Division of Dockets some well-recognized statistical This draft guidance is being issued Management. If you do not wish your methods for managing multiplicity consistent with FDA’s good guidance name and contact information to be within a study. FDA’s International practices regulation (21 CFR 10.115). made publicly available, you can Conference on Harmonization (ICH) The draft guidance, when finalized, will provide this information on the cover guidance for industry ‘‘E9 Statistical represent the current thinking of FDA sheet and not in the body of your Principles for Clinical Trials’’ is a broad- on multiple endpoints in clinical trials. comments and you must identify this ranging guidance that includes It does not establish any rights for any information as ‘‘confidential.’’ Any discussion of multiple endpoints. This person and is not binding on FDA or the information marked as ‘‘confidential’’ draft guidance provides greater detail on public. You can use an alternative will not be disclosed except in the topic of multiple endpoints. The approach if it satisfies the requirements accordance with 21 CFR 10.20 and other issuance of this draft guidance of the applicable statutes and applicable disclosure law. For more represents partial fulfillment of an FDA regulations. information about FDA’s posting of commitment under the Food and Drug II. Electronic Access comments to public dockets, see 80 FR Administration Amendments Act of 2007. (Title I of the Food and Drug Persons with access to the Internet 56469, September 18, 2015, or access Administration Amendments Act of may obtain the draft guidance at either the information at: http://www.fda.gov/ 2007 (Pub. L. 110–85)). Under section XI http://www.fda.gov/Drugs/Guidance regulatoryinformation/dockets/ (Expediting Drug Development) of the ComplianceRegulatoryInformation/ default.htm. Prescription Drug User Fee Act Guidances/default.htm, http:// Docket: For access to the docket to (PDUFA) Performance Goals, FDA www.fda.gov/BiologicsBloodVaccines/ read background documents or the agreed to develop and publish for GuidanceComplianceRegulatory electronic and written/paper comments comment draft guidance on ‘‘Multiple Information/Guidances/default.htm, or received, go to http:// Endpoints in Clinical Trials,’’ and to http://www.regulations.gov. www.regulations.gov and insert the docket number, found in brackets in the complete the final guidance within one Dated: January 10, 2017. heading of this document, into the year of the close of the public comment Leslie Kux, ‘‘Search’’ box and follow the prompts period of the PDUFA Performance Goals Associate Commissioner for Policy. and/or go to the Division of Dockets (see http://www.fda.gov/ForIndustry/ [FR Doc. 2017–00695 Filed 1–12–17; 8:45 am] Management, 5630 Fishers Lane, Rm. UserFees/PrescriptionDrugUserFee/ BILLING CODE 4164–01–P ucm119243.htm). 1061, Rockville, MD 20852. Failure to account for multiplicity Submit written requests for single when there are several clinical copies of the draft guidance to the DEPARTMENT OF HEALTH AND endpoints evaluated in a study can lead Division of Drug Information, Center for HUMAN SERVICES to false positive conclusions regarding Drug Evaluation and Research, Food the effects of the drug. The regulatory and Drug Administration, 10001 New Food and Drug Administration concern regarding multiplicity arises Hampshire Ave., Hillandale Building, principally in the evaluation of clinical [Docket No. FDA–2013–N–1496] 4th Floor, Silver Spring, MD 20993– trials intended to demonstrate 0002; or the Office of Communication, effectiveness and support drug Agency Information Collection Outreach and Development, Center for approval; however, this issue is Activities; Proposed Collection; Biologics Evaluation and Research, important throughout the drug Comment Request; Food and Drug Food and Drug Administration, 10903 development process. Administration Rapid Response New Hampshire Ave., Bldg. 71, Rm. The focus of this draft guidance is Surveys (Generic Clearance) 3128, Silver Spring, MD 20993–0002. control of the Type 1 error rate for the AGENCY: Food and Drug Administration, Send one self-addressed adhesive label planned primary and secondary HHS. to assist that office in processing your endpoints of a clinical trial so that the requests. See the SUPPLEMENTARY ACTION: Notice. major findings are well supported. INFORMATION section for electronic Multiplicity adjustments provide a SUMMARY: The Food and Drug asabaliauskas on DSK3SPTVN1PROD with NOTICES access to the draft guidance document. means for controlling Type 1 error when Administration (FDA or Agency) is FOR FURTHER INFORMATION CONTACT: there are multiple analyses of the drug’s announcing an opportunity for public Scott Goldie, Center for Drug Evaluation effects. The issues of multiplicity and comment on the proposed collection of and Research, Food and Drug methods to address them are illustrated certain information by the Agency. Administration, 10903 New Hampshire in the draft guidance with examples of Under the Paperwork Reduction Act of Ave., Bldg. 21, Rm. 3557, Silver Spring, different study endpoints. Both the 1995 (the PRA), Federal Agencies are MD 20993–0002, 301–796–2055; or issues and methods that apply to required to publish notice in the Stephen Ripley, Center for Biologics multiple endpoints also apply to other Federal Register concerning each VerDate Sep<11>2014 19:06 Jan 12, 2017 Jkt 241001 PO 00000 Frm 00076 Fmt 4703 Sfmt 4703 E:\FR\FM\13JAN1.SGM 13JAN1


Document Created: 2017-01-13 02:44:45
Document Modified: 2017-01-13 02:44:45
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionNotices
ActionNotice of availability.
DatesAlthough 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.
ContactScott 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.
FR Citation82 FR 4353 
2025 Federal Register | Disclaimer | Privacy Policy
USC | CFR | eCFR