Japan MHLW Publishes Recommendations on the Design and Analysis of Master Protocol Trials

Post contributed by guest bloggerMiguel Kitamura of Kitamura Law.Not affiliated with Covington & Burling LLP.

Earlier this summer, the Pharmaceutical Evaluation Division of the Pharmaceutical Safety Bureau within the Japan Ministry of Health, Labor and Welfare ("MHLW") published "Points to Note" summarizing key considerations for sponsors when planning, conducting, analyzing, and evaluating master protocol clinical trials ("MPT Points").[1]

A master protocol is a comprehensive protocol designed to evaluate the multiple objectives of several drugs and diseases in a single trial. A master protocol includes execution plans for multiple sub-studies conducted concurrently. The studies under the master protocol are sometimes referred to as cohorts or sub-studies. This design has the potential to accelerate drug development, but it also raises some complexities. Over the past few years, various drug regulatory agencies throughout the world have issued documents addressing such challenges. For example, the U.S. Food and Drug Administration ("FDA") published guidance on master protocols for development of oncology drugs in March 2022,[2] and a draft guidance document on master protocol trials in the broader, non-oncology-specific context in December 2023.[3] Similarly, the European Medicines Agency ("EMA") addressed master protocol trials in version 6 of the Guideline on the Clinical Evaluation of Anticancer Medicinal Products finalized in November 2023.[4]

The MPT Points discuss the following three types of master protocols:

• Basket trials are designed to evaluate the efficacy and safety of a single drug against multiple diseases. The MPT Points state that basket trials are often used to develop drugs against multiple cancer types that share a common genetic abnormality.
• Umbrella trials are designed to evaluate the efficacy and safety of multiple drugs for the treatment of a single disease. The MPT Points state that the considerations for individually conducted single-arm and randomized controlled trials as sub-studies under umbrella trials are the same as those for traditional clinical trials.
• Platform trials are trials designed to evaluate multiple drugs for a disease or multiple diseases in an ongoing manner, with drugs entering or leaving the platform. Similar to FDA's guidance on this issue, the MPT Points recommend using only concurrent control data registered during the same period as the drug group for the primary analyses of the primary endpoint for the drug in confirmatory trials. In other words, if a drug enters the platform after some participants have been randomized to the control group, data from those control group participants are considered non-concurrent with the data from the drug group. Sponsors should exercise caution when using such nonconcurrent control data, as they may present comparability issues.

Among other content, the MPT Points offer the following additional recommendations to sponsors.

• Common infrastructure. The MPT Points recommend a common screening platform (e.g., types and methods of tests for patient enrollment), a common data management system that can handle the data obtained in a timely manner and facilitate data sharing, and a common infrastructure for monitoring, efficacy, and safety evaluations. In particular, the MPT Points encourage the use of a central institutional review board ("IRB") rather than relying on individual IRBs at each participating institution. In addition, an Independent Data Monitoring Committee ("IDMC") should be established as necessary to make decisions such as trial continuation, and addition or exclusion of drug groups.
• Communication with the Japan Pharmaceuticals and Medical Devices Agency ("PMDA"). For sponsors who plan to use the results of a master protocol trial or its sub-studies to confirm the efficacy and safety of an investigational drug, the MPT Points suggest that the sponsor consult with PMDA in advance. The MPT Points also note that if discussions about the appropriateness of the master protocol itself are necessary during the individual drug development plan discussions with the PMDA, the sponsor should submit the master protocol, sub-study protocols, statistical analysis plans, consultation materials with foreign regulatory authorities and related literature.
• Preparation Considerations. Because PMDA may request information related to sub-studies, the MPT Points explain that "it is essential to thoroughly discuss among stakeholders the sub-studies related to those intended for application, considering aspects such as the availability of this information, specific procedures, and contractual rights issues."

Notably, the MPT Points explicitly envisage that master protocol trials could be pursued with participating foreign institutions, or with Japanese institutions participating in foreign master protocol trials. However, the MPT Points do not address the impact of population differences on the acceptability of foreign clinical data (ICH E5), and if a local bridging study is needed, it may complicate the planning of a master protocol.

[1] MHLW, Considerations for the Utilization of Master Protocol Trials in Drug Development (June 2024), https://www.pmda.go.jp/files/000269475.pdf. The original Japanese version can be accessed at https://www.pmda.go.jp/files/000269222.pdf.

[2] FDA, Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics, Guidance for Industry (Mar. 2022), https://www.fda.gov/media/120721/download.

[3] FDA, Master Protocols for Drug and Biological Product Development, Draft Guidance for Industry (Dec. 2023), https://www.fda.gov/media/174976/download.

[4] EMA, Guideline on the Clinical Evaluation of Anticancer Medicinal Products Rev.6 (Nov. 2023), https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-evaluation-anticancer-medicinal-products-revision-6_en.pdf.

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