Notice2023-11263
Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products; Guidance for Industry; Availability
Primary source
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Published
May 26, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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 The guidance finalizes the revised draft guidance entitled "Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products" issued on May 21, 2021.
Full Text
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<title>Federal Register, Volume 88 Issue 102 (Friday, May 26, 2023)</title>
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[Federal Register Volume 88, Number 102 (Friday, May 26, 2023)]
[Notices]
[Pages 34163-34164]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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
<a href="https://www.regulations.gov">https://www.regulations.gov</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, <a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, or <a href="https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances">https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances</a>.
Dated: May 23, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-11263 Filed 5-25-23; 8:45 am]
BILLING CODE 4164-01-P
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