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FDA is announcing the availability of a draft guidance for industry entitled “Master Protocols for Drug and Biological Product Development.” The draft guidance addresses the design and analysis of trials conducted under a master protocol as well as the submission of documentation to support regulatory review.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 The considerations in this draft guidance apply to a range of therapeutic areas.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. ( printed 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.