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Design and analysis of umbrella trials: Where do we stand?

Published version
Peer-reviewed

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Authors

Ouma, Luke O 
Wason, James MS 
Zheng, Haiyan 
Wilson, Nina 
Grayling, Michael 

Abstract

BACKGROUND: The efficiencies that master protocol designs can bring to modern drug development have seen their increased utilization in oncology. Growing interest has also resulted in their consideration in non-oncology settings. Umbrella trials are one class of master protocol design that evaluates multiple targeted therapies in a single disease setting. Despite the existence of several reviews of master protocols, the statistical considerations of umbrella trials have received more limited attention. METHODS: We conduct a systematic review of the literature on umbrella trials, examining both the statistical methods that are available for their design and analysis, and also their use in practice. We pay particular attention to considerations for umbrella designs applied outside of oncology. FINDINGS: We identified 38 umbrella trials. To date, most umbrella trials have been conducted in early phase settings (73.7%, 28/38) and in oncology (92.1%, 35/38). The quality of statistical information available about conducted umbrella trials to date is poor; for example, it was impossible to ascertain how sample size was determined in the majority of trials (55.3%, 21/38). The literature on statistical methods for umbrella trials is currently sparse. CONCLUSIONS: Umbrella trials have potentially great utility to expedite drug development, including outside of oncology. However, to enable lessons to be effectively learned from early use of such designs, there is a need for higher-quality reporting of umbrella trials. Furthermore, if the potential of umbrella trials is to be realized, further methodological research is required.

Description

Peer reviewed: True

Keywords

adaptive design, biomarker-guided design, innovative design, master protocol, precision medicine, precision oncology, stratified medicine

Journal Title

Front Med (Lausanne)

Conference Name

Journal ISSN

2296-858X
2296-858X

Volume Title

Publisher

Frontiers Media SA
Sponsorship
Medical Research Council (MR/S014357/1)
Cancer Research UK (RCCPDF\100008)