[Federal Register Volume 88, Number 102 (Friday, May 26, 2023)]
[Notices]
[Pages 34163-34164]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-11263]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-D-0934]


Adjusting for Covariates in Randomized Clinical Trials for Drugs 
and Biological Products; 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 ``Adjusting 
for Covariates in Randomized Clinical Trials for Drugs and Biological 
Products.'' The guidance represents the current thinking of FDA on 
adjusting for covariates in randomized clinical trials for drugs and 
biological products. The guidance discusses general recommendations for 
performing covariate adjustment, recommendations for performing 
covariate adjustment using linear models, and recommendations for 
performing covariate adjusting using nonlinear models. The guidance is 
intended to facilitate covariate adjustment in the analysis of 
randomized clinical trials of drugs and biological products and to 
clarify recommendations for its use. The guidance finalizes the revised 
draft guidance entitled ``Adjusting for Covariates in Randomized 
Clinical Trials for Drugs and Biological Products'' issued on May 21, 
2021.

DATES: The announcement of the guidance is published in the Federal 
Register on May 26, 2023.

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-2019-D-0934 for ``Adjusting for Covariates in Randomized Clinical 
Trials for Drugs and Biological Products.'' 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

[[Page 34164]]

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 label to assist that office in processing 
your requests. The guidance may also be obtained 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: 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 Diane Maloney, 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 ``Adjusting for Covariates in Randomized Clinical Trials for 
Drugs and Biological Products.'' The guidance provides recommendations 
on adjusting for covariates in the analysis of randomized clinical 
trials. The guidance discusses the acceptability of covariate 
adjustment, recommendations for implementing adjusted analyses, 
prespecification, selection of covariates, change from baseline 
analyses, statistical inference, estimands, and various statistical 
models. The guidance includes comments on covariate adjusting using 
both linear and nonlinear models.
    This guidance finalizes the revised draft guidance issued on May 
21, 2021 (86 FR 27627). Changes from the draft to the final guidance 
include changes to wording and organization and updated and clarified 
recommendations on computing standard errors, stratified randomization, 
estimands, treatment by covariate interactions, and additional methods.
    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 ``Adjusting for Covariates in Randomized 
Clinical Trials for Drugs and Biological Products.'' 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 new 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 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR 312 pertaining to the submissions of 
investigational new drug applications have been approved under OMB 
control number 0910-0014.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.regulations.gov, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, 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 23, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-11263 Filed 5-25-23; 8:45 am]
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