Skip to content

Regulatory Focus – FDA Officials: Master Protocols Needed for Precision Medicine

Regulatory Focus – FDA Officials: Master Protocols Needed for Precision Medicine

In an article published Thursday in the New England Journal of Medicine, two top officials from the US Food and Drug Administration (FDA) say that “master protocols” for studies involving multiple drugs or multiple diseases (or both) simultaneously are needed to efficiently generate evidence for precision medicines.


“The standard approach to generating this evidence—a series of clinical trials, each investigating one or two interventions in a single disease—has become ever more expensive and challenging to execute. As a result, important clinical questions go unanswered,” write Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) and Lisa LaVange, director of Office of Biostatistics within CDER.


Instead, the two argue that well-designed master protocols that look at multiple therapies in a single disease, a single therapy in multiple diseases, or multiple therapies across multiple diseases or disease subtypes, can provide answers more quickly and efficiently than traditional “stand-alone” clinical trials.


“If designed correctly, master protocols can last many years, even decades, with innovations from the laboratory translating quickly to clinical evaluation. As the targets for new drugs become more and more precise, there is no alternative but to move forward with these coordinated research efforts,” Woodcock and LaVange write.


According to the authors, master protocols offer a number of benefits, include streamlined logistics, improved data quality, collection and sharing, as well as the potential to use “innovative statistical approaches to study design and analysis.”


While master protocols have been most frequently implemented in oncology, where new treatments are increasingly developed to target specific mutations, master protocols have been implemented in other fields. For example, master protocols have been developed to evaluate drugs targeting multi-drug resistant infections and disease-modifying treatments in patients with a genetic risk for early-onset Alzheimer’s disease.


Master protocols can be built on existing trial infrastructure, or by building out a new trial network. But, in either case, the authors say that master protocols require “intensive” pretrial planning and coordination across a large number of stakeholders.


For instance, the Lung Master Protocol (Lung-MAP), which consists of multiple Phase 2 and 3 sub-studies of targeted therapies in advanced squamous non-small-cell lung cancer, involved coordination between the Friends of Cancer Research, multiple drugmakers, FDA, the National Cancer Institute, SWOG Cancer Research and the Foundation for the National Institutes of Health.


The authors also note that master protocols, especially long-running ones, should be capable of adapting to changes in the marketplace over time. During both Lung-MAP and I-SPY 2, an exploratory-phase master protocol that investigates treatments for early-stage, biomarker-defined breast cancer, protocol changes were required after new drugs replaced the standard of care in those studies.


“This occurred in Lung-MAP when [Opdivo] nivolumab was shown to have superiority over docetaxel, the standard of care selected for the biomarker-matched sub-studies,” the authors write.


But, while master protocols can be designed to adapt to such changes, they are not without cost, and can lead to a temporary halt in recruitment and require new statistical analysis plans.…