The US Food and Drug Administration (FDA) has issued new guidance describing its current recommendations with respect to master protocols for the evaluation of drugs and biologics to treat or prevent COVID-19. While somewhat belated, this guidance may shed light on FDA’s approach to master protocols for other disease states/products.
The guidance, COVID-19: Master Protocols Evaluating Drugs and Biological Products for Treatment or Prevention Guidance for Industry, addresses the design, conduct, and statistical considerations of master protocols used for the development of COVID-19 drugs. A master protocol is a protocol designed with multiple sub-studies that evaluate one or more investigational drugs in one or more disease subtypes, with one or more objectives, all within the same overarching trial structure. Master protocols can be umbrella trials that evaluate multiple therapies for a single disease, platform trials that perpetually evaluate multiple therapies for a single disease (e.g., therapies are added and removed from the trial using a “decision algorithm”), or basket trials that evaluate a single investigational product in multiple disease states. Master protocols help accelerate drug development by maximizing the amount of information gathered from trials while also decreasing subject enrollment needs. While FDA states that master protocols can play an important role in a public health emergency, they also have potential applications for rare diseases or diseases with significant unmet needs.
FDA’s guidance provides factors to consider when determining whether to conduct a master protocol or stand-alone trial, as well as context-specific recommendations for master protocols, such as those evaluating multiple drugs or using multiple intervention-specific endpoints, those incorporating proposals for complex adaptive or Bayesian designs, and those that are event-driven, umbrella, or platform trials. The guidance also emphasizes the importance of early interactions with FDA to discuss the use of novel protocol designs.
One particularly interesting guidance point is FDA’s discussion regarding the appropriate active comparator arm. FDA notes, “In the COVID-19 setting, a high potential exists for confounding when comparisons are made to participants who were not concurrently randomized because of changes over time such as changes in the standard of care including background treatments and supportive care . . . .” This is not the first time that FDA has discussed the importance of using standard of care (SOC) control arms. In its 2018 draft guidance on the use of master protocols in oncology, FDA also recommended that control arms be the current SOC, to allow the results to be “interpretable in the context of U.S. medical practice.” This, however, presents a challenge in a fast-moving therapeutic field such as oncology or COVID-19.
FDA’s oncology guidance stated that if there is a change in SOC, sponsors should suspend enrollment until the new SOC can be added as a control. However, given the time and cost of conducting a trial, this may not be feasible, especially in the rare disease space. Notably, while the most recent COVID-19 guidance discusses the importance of concurrent enrollment because of concerns related to changing SOC, it does not make specific mention of the need to suspend trials when SOC does change. Whether this indicates a change in FDA’s thinking is unclear. Hopefully, FDA will revisit the topic of master protocol design in the future, given the demonstrated promise of this study design.