The US Food and Drug Administration (FDA) recently released a draft guidance addressing the use of master protocols to expedite the development of oncology drugs and biologics.
Outsourcing-Pharma (OSP) caught up with Kevin Barber (KB), vice president, regulatory at the contract research organization (CRO) Rho to discuss the advantages and challenges to master protocol clinical trials.
OSP: What is a master protocol?
KB: 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, the 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.
OSP: What are the benefits of this design?
KB: 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 candidates in parallel rather than sequentially.
OSP: What are the challenges of implementing such a design?
KB: 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For example, the draft guidance notes that sponsors should have medical monitors with appropriate training and experience in the conduct of clinical trials and the indications under study,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 of failure to promptly identify adverse events.
Furthermore, the FDA acknowledges that one of the challenges for master protocols is related to assessment of safety of the investigational products 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.
The FDA also cautions that multiple study groups under a master protocol could result in overinterpretation 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.
OSP: What is one of the most important takeaways from the draft guidance?
KB: 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 the 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.
OSP: Other comments?
KB: There are additional regulatory considerations and activities for a master protocol, because sponsors should submit each master protocol as a new IND to the 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.
Trials & Tribulations is a column dedicated to exploring the key trends and challenges facing clinical trials and the greater contract research and manufacturing industry. Have a challenge you are trying to solve? Email me at Melissa.Fassbender@wrbm.com.