Proceedings: DIA 2019 Global Annual Meeting

DIA GAM 2019

Community Meet-Up: Master Protocols – Application in Oncology

Freda Cooner

Joan Buenconsejo


he Community Roundtable Discussion Master Protocols: Application in Oncology was designed to discuss the applications of master protocols in oncology clinical development. Attendees shared their past experiences and opinions on this topic and discussed the benefits of master protocols as well as the difficulties that include both operational and analysis obstacles. The discussion extended to general master protocol development in different therapeutic areas. It is important to understand when and where master protocols could improve clinical development efficiency. The roundtable discussion concluded with the message that a lot of work remains to be done to fully utilize master protocols in oncology.

Key Takeaways

  • Definition: a master protocol uses a single infrastructure and is intended to simultaneously evaluate multiple investigational drugs (umbrella trial), multiple diseases or disease subtypes (basket trial), or multiple investigational drugs in a perpetual manner (platform trial) within the same trial structure.
  • Past experiences of master protocols are mostly in oncology.
  • Master protocols are practiced in early phases with binary endpoints more often than late phases with time-to-response endpoints.
  • Master protocols are complex in terms of planning, conducting, and monitoring. Especially when adaptive or seamless features are adopted.
  • More education and familiarization of master protocols are encouraged across different functions.
  • Landscape change is needed in almost all aspects; regulatory acceptance is needed.
Experience with master protocols is mostly in the area of oncology or rare diseases, but one attendee shared her experience of developing a master protocol in the respiratory area exploring combination products. It was utilized in early phase trials and resulted in an expectedly long exploration period. The decision was quickly made to eliminate most of the combination options based on rationales other than efficacy. It is typical to have combination therapies in the development program for oncology products, especially for later-line populations. How to design master protocols with different combinations and potentially different comparators therefore poses unique challenges. They are more prominent as oncology is a fast-growing therapeutic area with new targeted subgroups identified and new standard of care on the horizon constantly.

There was a long discussion about the added operational complexity in planning, monitoring, site/investigator engagement, and reporting, as well as the types of infrastructure and system needed to execute such trials. Questions were raised about the duration of this type of trials, and whether there is an end date to it. These trials may also add statistical complexities to the analysis and interpretation of results. These challenges could come from many factors, such as when recruitment is done in sequence or when a new treatment arm is added as well as from background changes in standard of care in the case of a platform trial design.

Because the master protocol is a fairly new concept and not well-understood by many, the attendees agreed that more education and examples are needed to persuade management to support its use. The design may need to be simple and perhaps applied in early phase studies. Adding adaptive and seamless features to a master protocol may be theoretically attractive; however, those features can easily make the master protocols too complex to carry out. Currently, there is appetite for such complex trial designs (including master protocol) only in the areas of rare diseases, oncology, and other life-threatening conditions with high unmet medical needs. The attendees agreed that we still have a way to go towards better understanding of the full potential of using a master protocol and of adopting these innovative trial designs.


Amy Xia, Vice President, Biostatistics, Design & Innovation, Amgen Inc. (Chair)

Yuan-Li Shen, Acting Associate Director, Office of Biostatistics, OTS, CDER, FDA

Scott M Berry, President and Senior Statistical Scientist, Berry Consultants LLC

Karen Lynn Price, Senior Research Advisor, Statistical Innovation Center, Eli Lilly and Company