Master Protocols for Drug and Biological Product Development

A new FDA guidance provides recommendations on the design and analysis of trials conducted under a master protocol as well as guidance on the submission of documentation to support regulatory review. In addition, the draft document provides an example on how to use the eCTD (electronic common technical document) for a master protocol.

Master Protocol and Master Protocol Sponsor

According to the FDA, the master protocol is a "protocol designed with multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure".

The term master protocol sponsor refers to the person or organization who takes responsibility for and initiates the master protocol. In many instances individual drugs chosen for evaluation in the master protocol will also be evaluated under separate Investigational New Drug Applications (INDs) independent of the master protocol. A sponsor responsible for the investigation of an individual drug evaluated under the separate IND is referred to as the individual drug sponsor. The master protocol sponsor and the individual drug sponsor may or may not be the same entity.

Advantages and Challenges of using a Master Protocol

The primary focus of the guidance is on randomized umbrella and platform trials that are intended to contribute to a demonstration of safety and substantial evidence of effectiveness of a drug. 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 (PMCs) or requirements (PMRs). However, the guidance does not apply to master protocols evaluating first-in-human drugs given the unique attributes from both a trial design and regulatory perspective that must be considered.

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

  • shared control arms and other shared protocol elements (e.g., visit schedule, measurement procedures),
  • shared infrastructure (e.g., recruitment efforts, network of clinical sites, central facilities, central randomization system, data management systems),
  • shared oversight (e.g., steering committee, data review committee).

A master protocol may thus be useful in settings where participant recruitment is challenging, as comparing multiple drugs to a shared placebo arm can reduce the number of trial participants on placebo relative to multiple trials comparing each drug to a placebo.

On the other hand, master protocols add a certain amount of complexity, which can increase start-up time and can lead to design challenges. Additionally, master protocols involving multiple stakeholders will require a high degree of coordination. Therefore, sponsors should carefully weigh these considerations when deciding whether a master protocol is appropriate as part of a drug development program.

For more information please see FDA's draft guidance Master Protocols for Drug and Biological Product Development.

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