The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review

Purpose: Recent years have seen a change in the way that clinical trials are being conducted. There has been a rise of designs more flexible than traditional adaptive and group sequential trials which allow the investigation of multiple substudies with possibly different objectives, interventions, and subgroups conducted within an overall trial structure, summarized by the term master protocol. This review aims to identify existing master protocol studies and summarize their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods.

Methods: We conducted a comprehensive systematic search to review current literature on master protocol trials from a design and analysis perspective, focusing on platform trials and considering basket and umbrella trials. Articles were included regardless of statistical complexity and classified as reviews related to planned or conducted trials, trial designs, or statistical methods. The results of the literature search are reported, and some features of the identified articles are summarized.

Findings: Most of the trials using master protocols were designed as single-arm (n = 29/50), Phase II trials (n = 32/50) in oncology (n = 42/50) using a binary endpoint (n = 26/50) and frequentist decision rules (n = 37/50). We observed an exponential increase in publications in this domain during the last few years in both planned and conducted trials, as well as relevant methods, which we assume has not yet reached its peak. Although many operational and statistical challenges associated with such trials remain, the general consensus seems to be that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development.

Implications: Master protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.