Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products; Guidance for Industry; Availability, 34163-34164 [2023-11263]

Download as PDF Federal Register / Vol. 88, No. 102 / Friday, May 26, 2023 / Notices choice of worst-case size sample(s) in its submission. 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 ‘‘Non-Clinical Performance Assessment of Tissue Containment Systems Used During Power Morcellation Procedures.’’ 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 interested in obtaining a copy of the guidance may do so by downloading an electronic copy from use the document number GUI00019015 and complete title to identify the guidance you are requesting. III. 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 the following FDA regulations, guidance, and forms have been approved by OMB as listed in the following table: 21 CFR part or guidance Topic 807, subpart E .......................................................................................................... ‘‘Requests for Feedback and Meetings for Medical Device Submissions: The QSubmission Program’’. Premarket notification ............................. Q-submissions ........................................ Dated: May 23, 2023. Lauren K. Roth, Associate Commissioner for Policy. [FR Doc. 2023–11260 Filed 5–25–23; 8:45 am] BILLING CODE 4164–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES [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. 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 SUMMARY: VerDate Sep<11>2014 18:14 May 25, 2023 Jkt 259001 OMB control No. 0910–0120 0910–0756 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. 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’’). The announcement of the guidance is published in the Federal Register on May 26, 2023. 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 DATES: Food and Drug Administration ddrumheller on DSK120RN23PROD with NOTICES1 the internet. A search capability for all Center for Devices and Radiological Health guidance documents is available at https://www.fda.gov/medical-devices/ device-advice-comprehensiveregulatory-assistance/guidancedocuments-medical-devices-andradiation-emitting-products. This guidance document is also available at https://www.regulations.gov, https:// www.fda.gov/regulatory-information/ search-fda-guidance-documents. Persons unable to download an electronic copy of ‘‘Non-Clinical Performance Assessment of Tissue Containment Systems Used During Power Morcellation Procedures’’ may send an email request to CDRHGuidance@fda.hhs.gov to receive an electronic copy of the document. Please 34163 You may submit either electronic or written comments on Agency guidances at any time as follows: ADDRESSES: 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 PO 00000 Frm 00038 Fmt 4703 Sfmt 4703 E:\FR\FM\26MYN1.SGM 26MYN1 ddrumheller on DSK120RN23PROD with NOTICES1 34164 Federal Register / Vol. 88, No. 102 / Friday, May 26, 2023 / Notices 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-201509-18/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. VerDate Sep<11>2014 18:14 May 25, 2023 Jkt 259001 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 PO 00000 Frm 00039 Fmt 4703 Sfmt 4703 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/guidancecompliance-regulatory-information/ guidances-drugs, or https:// www.fda.gov/vaccines-blood-biologics/ guidance-compliance-regulatoryinformation-biologics/biologicsguidances. 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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2023–D–0625] Diabetes Mellitus: Efficacy Endpoints for Clinical Trials Investigating Antidiabetic Drugs and Biological Products; Draft Guidance for Industry; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice of availability. The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled ‘‘Diabetes Mellitus: Efficacy Endpoints for Clinical Trials Investigating Antidiabetic Drugs and Biological Products.’’ This draft guidance is intended to help sponsors develop antidiabetic drugs for adults and children with type 1 and type 2 diabetes mellitus. In this draft guidance, antidiabetic drug refers to drugs intended to improve glycemic control, including drugs intended to reduce diabetes-related hyperglycemia (i.e., antihyperglycemic drugs) and drugs intended to mitigate iatrogenic hypoglycemia associated with diabetes management. SUMMARY: Submit either electronic or written comments on the draft guidance by August 24, 2023 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance. DATES: E:\FR\FM\26MYN1.SGM 26MYN1

Agencies

[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]


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

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.

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

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]
BILLING CODE 4164-01-P
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