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The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review
Elias Laurin Meyer1, Peter Mesenbrink2, Cornelia Dunger-Baldauf3
1Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
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.
Insights
Master protocols offer flexible clinical trial designs, increasing efficiency in drug development. These innovative approaches, particularly platform trials, show great promise despite ongoing challenges.
Area of Science:
- Clinical Trials
- Drug Development
- Biostatistics
Background:
- Traditional clinical trial designs are evolving.
- Master protocols enable flexible investigation of multiple substudies within a single trial structure.
- These designs offer advantages over traditional adaptive and group sequential trials.
Purpose of the Study:
- To identify and characterize existing master protocol studies.
- To summarize relevant literature on the design and methods of master protocol trials.
- To review platform, basket, and umbrella trial designs.
Main Methods:
- A comprehensive systematic literature search was conducted.
- Articles were included regardless of statistical complexity.
- Literature was classified into reviews of planned/conducted trials, trial designs, or statistical methods.
Main Results:
- Most master protocol trials are single-arm, Phase II oncology trials using binary endpoints and frequentist rules.
- There has been an exponential increase in publications related to master protocols.
- Master protocols offer significant advantages in efficiency and flexibility for clinical drug development.
Conclusions:
- Master protocol trials, especially platform trials, have the potential to revolutionize drug development.
- Overcoming methodological and operational challenges is key to realizing the full potential of master protocols.
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