[Federal Register Volume 86, Number 90 (Wednesday, May 12, 2021)]
[Notices]
[Pages 26047-26048]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-10066]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2017-D-6113]


E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials; International 
Council for Harmonisation; 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 ``E9(R1) 
Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials.'' The guidance was prepared 
under the auspices of the International Council for Harmonisation 
(ICH), formerly the International Conference on Harmonisation. The 
guidance clarifies, updates, and extends the guidance for industry ``E9 
Statistical Principles for Clinical Trials'' issued in September 1998 
in two main areas. Concerning estimands, it provides a framework for 
discussion of how the aims of a trial relate to the proposed 
statistical analysis. Concerning sensitivity analysis, it discusses how 
to use additional analyses to address concerns about the validity of 
assumptions underlying the main analysis. The guidance is intended to 
better align the choice of statistical methods with questions of 
regulatory importance and so to improve the reliability of decisions 
about and representations of the effects of medical products. The 
guidance replaces the draft guidance issued on October 31, 2017.

DATES: The announcement of the guidance is published in the Federal 
Register on May 12, 2021.

ADDRESSES: You may submit either electronic or written comments on 
Agency guidances 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 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-2017-D-6113 for ``E9(R1) Statistical Principles for Clinical 
Trials: Addendum: Estimands and Sensitivity Analysis 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 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

[[Page 26048]]

label to assist that office in processing your requests. The guidance 
may also be obtained by mail by calling CBER at 1-800-835-4709 or 240-
402-8010. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the guidance: Scott Goldie, Center for Drug Evaluation 
and Research, Food and Drug Administration, Bldg. 21, Rm. 3557, Silver 
Spring, MD 20993-0002, 301-796-2055, [email protected]; or 
Stephen Ripley, Center for Biologics Evaluation and Research, Food and 
Drug Administration, Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 
240-402-7911.
    Regarding the ICH: Jill Adleberg, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 6364, Silver Spring, MD 20993-0002, 301-796-5259.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials.'' The guidance 
was prepared under the auspices of ICH. ICH has the mission of 
achieving greater regulatory harmonization worldwide to ensure that 
safe, effective, high-quality medicines are developed, registered, and 
maintained in the most resource-efficient manner.
    By harmonizing the regulatory requirements in regions around the 
world, ICH guidelines have substantially reduced duplicative clinical 
studies, prevented unnecessary animal studies, standardized the 
reporting of important safety information, standardized marketing 
application submissions, and made many other improvements in the 
quality of global drug development and manufacturing and the products 
available to patients.
    The six Founding Members of the ICH are FDA; the Pharmaceutical 
Research and Manufacturers of America; the European Commission; the 
European Federation of Pharmaceutical Industries Associations; the 
Japanese Ministry of Health, Labour, and Welfare; and the Japanese 
Pharmaceutical Manufacturers Association. The Standing Members of the 
ICH Association include Health Canada and Swissmedic. Additionally, the 
Membership of ICH has expanded to include other regulatory authorities 
and industry associations from around the world (refer to https://www.ich.org/).
    ICH works by involving technical experts from both regulators and 
industry parties in detailed technical harmonization work and the 
application of a science-based approach to harmonization through a 
consensus-driven process that results in the development of ICH 
guidelines. The regulators around the world are committed to 
consistently adopting these consensus-based guidelines, realizing the 
benefits for patients and for industry.
    As a Founding Regulatory Member of ICH, FDA plays a major role in 
the development of each of the ICH guidelines, which FDA then adopts 
and issues as guidance for industry. FDA's guidance documents do not 
establish legally enforceable responsibilities. Instead, they describe 
the Agency's current thinking on a topic and should be viewed only as 
recommendations, unless specific regulatory or statutory requirements 
are cited.
    In the Federal Register of October 31, 2017 (82 FR 50433), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials.'' The notice 
gave interested persons an opportunity to submit comments by April 30, 
2018.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Assembly and endorsed by the regulatory agencies in November 2019.
    This guidance finalizes the draft guidance issued on October 31, 
2017. The guidance provides clarification on statistical principles for 
clinical trials and an update on the choice of estimand to describe a 
framework for planning, conducting, and interpreting sensitivity 
analyses of clinical trial data. The focus of the guidance is on 
statistical principles related to estimands and sensitivity analysis 
for confirmatory clinical trials. The guidance provides recommendations 
for aligning the choice of statistical methods with the goals of a 
clinical trial; on communicating the rationale for such choices to FDA; 
and on using sensitivity analysis to characterize the robustness of the 
conclusions to plausible deviations from the assumptions of the main 
analysis. Revisions made following the public comment period are 
intended to clarify content within the guidance; however, no new 
concepts are presented in the revised version.
    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 ``E9(R1) Statistical Principles for Clinical 
Trials: Addendum: Estimands and Sensitivity Analysis 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 guidance at 
https://www.regulations.gov, https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, or https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances.

    Dated: May 7, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-10066 Filed 5-11-21; 8:45 am]
BILLING CODE 4164-01-P