Multiple Endpoints in Clinical Trials; Draft Guidance for Industry; Availability, 4353-4354 [2017-00695]

Download as PDF 4353 Federal Register / Vol. 82, No. 9 / Friday, January 13, 2017 / Notices these informal, Pre-RFD inquiries, FDA expects the proposed Pre-RFD program to be utilized as a viable program in the future and expects that the number of Pre-RFDs will increase initially to approximately 180 submissions. FDA estimates from past experience with informal Pre-RFD inquiries that the complete process involved with preparing the Pre-RFD submission takes approximately 12 hours and an additional 1 hour for meetings. This average is based upon estimates by FDA administrative and technical staff who are familiar with the information collection relating to informal, Pre-RFD inquiries, who have consulted and advised sponsors and industry representatives on the information collection, and who have reviewed the documentation submitted. Therefore, the total reporting burden hours is estimated to be 1,768 hours. TABLE 2—ESTIMATED ANNUAL REPORTING BURDEN 1 Number of respondents Total burden hours annualized Hourly wage rate Total cost 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 rate of $33.26,1 the result is a cost of $432.38 per respondent. The estimated submission cost of $432.38 multiplied by 136 submissions per year equals $58,803.68, which is the estimated aggregated industry reporting cost annualized. This draft guidance also refers to previously approved information collections found in FDA regulations. The collections of information in 21 CFR part 3 are approved under OMB control number 0910–0523. IV. Electronic Access Persons with access to the Internet may obtain the document at https://www. fda.gov/RegulatoryInformation/ Guidances/ucm534661.htm. Dated: January 9, 2017. Leslie Kux, Associate Commissioner for Policy. [FR Doc. 2017–00629 Filed 1–12–17; 8:45 am] BILLING CODE 4164–01–P 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AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2016–D–4460] Multiple Endpoints in Clinical Trials; Draft Guidance for Industry; Availability AGENCY: Food and Drug Administration, HHS. asabaliauskas on DSK3SPTVN1PROD with NOTICES ACTION: Notice of availability. The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft SUMMARY: 1 Wage is based on the 2015 Bureau of Labor Statistic’s survey, National Industry Specific Occupational Employment and Wage Estimate, for standard occupational code 13–1041, compliance officer in pharmaceutical and medicine manufacturing (https://www.bls.gov/oes/current/ oes131041.htm). VerDate Sep<11>2014 19:06 Jan 12, 2017 Jkt 241001 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: 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 PO 00000 Frm 00075 Fmt 4703 Sfmt 4703 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 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): 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 https://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 E:\FR\FM\13JAN1.SGM 13JAN1 asabaliauskas on DSK3SPTVN1PROD with NOTICES 4354 Federal Register / Vol. 82, No. 9 / Friday, January 13, 2017 / Notices 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 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: https://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 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 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 VerDate Sep<11>2014 19:06 Jan 12, 2017 Jkt 241001 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 broadranging 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 https://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 PO 00000 Frm 00076 Fmt 4703 Sfmt 4703 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 https://www.fda.gov/Drugs/Guidance ComplianceRegulatoryInformation/ Guidances/default.htm, https:// www.fda.gov/BiologicsBloodVaccines/ GuidanceComplianceRegulatory Information/Guidances/default.htm, or https://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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2013–N–1496] Agency Information Collection Activities; Proposed Collection; Comment Request; Food and Drug Administration Rapid Response Surveys (Generic Clearance) AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA or Agency) is announcing an opportunity for public comment on the proposed collection of certain information by the Agency. Under the Paperwork Reduction Act of 1995 (the PRA), Federal Agencies are required to publish notice in the Federal Register concerning each SUMMARY: E:\FR\FM\13JAN1.SGM 13JAN1

Agencies

[Federal Register Volume 82, Number 9 (Friday, January 13, 2017)]
[Notices]
[Pages 4353-4354]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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: 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 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): 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 https://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 https://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: https://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 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 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
https://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 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or
https://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

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