
[Federal Register Volume 88, Number 245 (Friday, December 22, 2023)]
[Notices]
[Pages 88623-88625]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-28210]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-D-5259]


Master Protocols for Drug and Biological Product Development; 
Draft Guidance for Industry; Availability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the availability of a draft guidance for industry entitled ``Master 
Protocols for Drug and Biological Product Development.'' The draft 
guidance addresses the design and analysis of trials conducted under a 
master protocol as well as the submission of documentation to support 
regulatory review. The primary focus is on randomized umbrella and 
platform trials that are intended to contribute to a demonstration of 
safety and substantial evidence of effectiveness. The considerations in 
this guidance apply to a range of therapeutic areas. The draft guidance 
is intended to clarify the Agency's thinking on the use of master 
protocols in drug and biological product development, which was 
previously addressed in FDA's guidance entitled ``COVID-19: Master 
Protocols Evaluating Drugs and Biological

[[Page 88624]]

Products for Treatment or Prevention.'' FDA is also announcing the 
withdrawal of the guidance entitled ``COVID-19: Master Protocols 
Evaluating Drugs and Biological Products for Treatment or Prevention.''

DATES: Submit either electronic or written comments on the draft 
guidance by February 20, 2024 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance 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-2023-D-5259 for ``Master Protocols for Drug and Biological Product 
Development.'' 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 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 (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. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft 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 Anne Taylor, 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 ``Master Protocols for Drug and Biological Product 
Development.'' The draft guidance addresses the design and analysis of 
trials conducted under a master protocol as well as the submission of 
documentation to support regulatory review. The primary focus of this 
guidance is on randomized umbrella and platform trials that are 
intended to contribute to a demonstration of safety and substantial 
evidence of effectiveness. The concepts discussed may also be useful to 
consider for early-phase or exploratory umbrella and platform trials as 
well as those conducted to satisfy post-marketing commitments or 
requirements. The considerations in this draft guidance apply to a 
range of therapeutic areas.
    Well-designed and -conducted trials using master protocols can 
accelerate drug development by maximizing the amount of information 
obtained from the research effort. Compared with stand-alone trials 
under separate protocols, a master protocol may offer certain 
advantages by leveraging a shared control arm and other shared protocol 
elements (e.g., visit schedule, measurement procedures), shared 
infrastructure (e.g., network of clinical sites, central facilities, 
central randomization system, data management systems), and shared 
oversight (e.g., steering committee, data review committee). At the 
same time, master protocols add elements of complexity, which can 
increase startup time and can lead to design challenges such as 
ensuring adequate blinding to treatment assignment. Additionally, 
master protocols involving multiple stakeholders will require a high 
degree of coordination.

[[Page 88625]]

    FDA provided recommendations on master protocols for COVID-19 drug 
and biological products in the guidance entitled ``COVID-19: Master 
Protocols Evaluating Drugs and Biological Products for Treatment or 
Prevention,'' which posted May 2021 and was announced in the Federal 
Register on June 24, 2021 (86 FR 33309) (hereafter ``2021 COVID-19 
Master Protocols Guidance''). FDA issued the guidance to communicate 
its policy for the duration of the COVID-19 public health emergency 
(PHE) declared by the Secretary of Health and Human Services (HHS) on 
January 31, 2020, including any renewals made by the HHS Secretary in 
accordance with section 319(a)(2) of the Public Health Service Act (42 
U.S.C. 247d(a)(2)). Furthermore, in the Federal Register of March 13, 
2023 (88 FR 15417), FDA listed the guidance documents that will no 
longer be effective with the expiration of the PHE declaration, 
guidances that FDA was revising to continue in effect for 180 days 
after the expiration of the PHE declaration to provide a period for 
stakeholder transition and then would no longer be in effect, and 
guidances that FDA was revising to continue in effect for 180 days 
after the expiration of the PHE declaration during which time FDA 
planned to further revise the guidances. The 2021 COVID-19 Master 
Protocols Guidance is included in the latter category. The 2021 COVID-
19 Master Protocols Guidance was revised to remain in effect for 180 
days post expiration of the PHE declaration, and then revised again to 
remain in effect until March 7, 2024, so that FDA could further revise 
the 2021 guidance.
    FDA is issuing this draft guidance because many of the issues 
addressed in the 2021 guidance arise outside the context of the COVID-
19 PHE. The recommendations in this draft guidance apply to a range of 
therapeutic areas, not just COVID-19. The draft guidance also provides 
a more comprehensive discussion of many of the design and analysis 
topics covered in the 2021 COVID-19 Master Protocols Guidance. For 
example, the draft guidance provides more detailed considerations 
related to randomization, the choice of control group, informed 
consent, blinding to treatment assignment, adaptive design, 
multiplicity, comparisons between drugs, and the evaluation of drug 
safety. The draft guidance also expands on considerations for trial 
oversight, data sharing, dissemination of information, and submissions 
to support regulatory review. The draft guidance, when finalized, will 
represent the Agency's current thinking on the use of master protocols 
in drug and biological product development.
    FDA is issuing this guidance to satisfy, in part, a mandate under 
section 3607(b)(2)(C-F) of the Food and Drug Omnibus Reform Act of 2022 
(FDORA). Consistent with the FDORA mandate, this guidance discusses 
recommendations for clinical trials to streamline logistics and 
facilitate the efficient collection and analysis of data, as well as 
important principles for the evaluation of effectiveness, 
recommendations for communication between sponsors and FDA, and 
considerations related to ensuring participant safety and data 
integrity in such trials.
    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 ``Master 
Protocols for Drug and Biological Product Development.'' 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.
    FDA is also announcing that the 2021 COVID-19 Master Protocols 
Guidance will be withdrawn upon publication of this draft guidance. FDA 
has determined that the 2021 COVID-19 Master Protocols Guidance is no 
longer needed because this new draft is available and its 
recommendations, when finalized, will be applicable outside the context 
of the COVID-19 PHE.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. The 
previously approved collections of information are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction 
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information 
in 21 CFR part 312 for the submission of investigational new drug 
applications (INDs), including protocols, protocol amendments, and 
information amendments, have been approved under OMB control number 
0910-0014. The information collections for new drug application (NDA) 
regulations (including abbreviated new drug applications (ANDAs)) (21 
CFR part 314) and related guidances are approved under OMB control 
number 0910-0001, and our biological licensing applications (BLA) 
regulations (21 CFR part 601) are approved under OMB control number 
0910-0338. The collections of information in 21 CFR parts 50 and 56 for 
the protection of human subjects and institutional review boards have 
been approved under OMB control number 0910-0130. The collections of 
information related to the protection of human subjects under 45 CFR 
part 46 and to IRB recordkeeping under 45 CFR 46.115 have been approved 
under OMB control number 0990-0260. The collections of information in 
21 CFR part 11, Electronic Records; Electronic Signatures, have been 
approved under OMB control number 0910-0303. The information collection 
requirements in FDA's guidance for industry entitled ``Establishment 
and Operation of Clinical Trial Data Monitoring Committees'' have been 
approved under OMB control number 0910-0581. The information collection 
requirements in FDA's guidance for industry entitled ``Oversight of 
Clinical Investigations--A Risk-Based Approach to Monitoring'' and 
FDA's final guidance for industry entitled ``A Risk-Based Approach to 
Monitoring of Clinical Investigations'' have been approved under OMB 
control number 0910-0733. The information collections in FDA's guidance 
for industry entitled ``Expedited Programs for Serious Conditions--
Drugs and Biologics'' have been approved under OMB control number 0910-
0765.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: December 18, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-28210 Filed 12-21-23; 8:45 am]
BILLING CODE 4164-01-P


