Master Protocols and the New FDA Guidance
January 15, 2019
Kevin Barber, PhD, VP, Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has lead the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products.
In September of 2018, FDA released a new FDA guidance on master protocols. So, what are master protocols, how can they benefit sponsors and patients, and what are the challenges?
Benefits of a master protocol design
Through an over-arching infrastructure, trial design, and protocol with multiple sub-studies run simultaneously, a master protocol is intended to run continuously to evaluate and assess a single investigational drug for multiple indications or patient populations, or multiple drug candidates for the same indication. Over the past several years, FDA has been encouraging sponsors of clinical development programs in areas such as oncology and pediatrics to consider using a master protocol approach to expedite and streamline mid- to late-stage drug development. If well-executed, a master protocol approach can reduce study overhead and duplication of activities, reduce patient exposure to control arms through use of a single common control arm, and most importantly, generate data to address multiple questions regarding the safety and efficacy of drug candidate(s) in parallel rather than sequentially.
Master protocol implementation challenges
Planning, executing and monitoring the simultaneous sub-studies under a master protocol require a great deal of coordination and the appropriate trial infrastructure, so a sponsor has to have sufficient resources and well-trained personnel. For example, the draft guidance notes that sponsors should have medical monitors with appropriate training and experience in the conduct of clinical trials and the indications under study, given the potential for rapid patient accrual with increased risks to patients if adverse events are not promptly identified.
Furthermore, FDA acknowledges that one of the challenges for master protocols is related to assessment of safety of the investigational product(s) under the protocol. With multiple arms assessing a single product across multiple patient populations or multiple products across a given patient population, there could be difficulty in attributing adverse events appropriately to the investigational drugs.
FDA also cautions that multiple study groups under a master protocol could result in over-interpretation of findings, such as falsely identifying a responder population based on multiple between-arm comparisons. Therefore, sponsors should take a great deal of care and consideration in the design and execution of the statistical analysis plan for a master protocol. There are additional regulatory considerations and activities for a master protocol, because sponsors should submit each master protocol as a new IND to FDA, with the master protocol as the only trial to be conducted under the IND. The requirement to submit a new IND does afford the sponsor an opportunity to request a pre-IND meeting to reach agreement on the design and conduct of the master protocol.
Although implementing a master protocol could accelerate a drug development program, a sponsor should carefully consider the potential advantages and challenges to determine whether a master protocol is appropriate. The guidance provides useful considerations and examples, but most importantly, the sponsor should follow the recommendations to meet with and gain agreement with FDA regarding key features of the master protocol design and analysis plan. This is especially critical for a master protocol intended to generate adequate safety and efficacy data to support a marketing application.