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

Yuhan Li,Hans-Jürgen Fülle,Martin Posch,Cornelia Dunger-Baldauf,Ekkehard Glimm,Peter Mesenbrink,Franz König,Elias Laurin Meyer

doi:10.1016/j.clinthera.2020.05.010

Abstract

PurposeRecent 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. MethodsWe 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. FindingsMost 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. ImplicationsMaster protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.

Highlights

Since the late 1940s, randomized controlled trials (RCTs) have served as the gold standard for establishing therapeutic efficacy.[1]
20% of all articles were published in Journal of Clinical Oncology, Statistics in Medicine, or Clinical Trials
The level of skepticism toward master protocols differs considerably, especially with respect to their appropriateness for confirmatory clinical trials, we believe the general consensus in the identified literature is that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development

Summary

Introduction

Since the late 1940s, randomized controlled trials (RCTs) have served as the gold standard for establishing therapeutic efficacy.[1] recent advances in drug discovery and biotechnology have accelerated tremendously the detection of treatment candidates. The classic 2-arm parallel-group RCTs have become one of the rate-limiting factors in drug development, and more. Because of several subgroups running in parallel, the chance of patients meeting the inclusion criteria of at least one of the subgroups is increased

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