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A multi-stage drop-the-losers design for multi-arm clinical trials

Lookup NU author(s): Professor James WasonORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Multi-arm multi-stage trials can improve the efficiency of the drug development process when multiple new treatments are available for testing. A group-sequential approach can be used in order to design multi-arm multi-stage trials, using an extension to Dunnett’s multiple-testing procedure. The actual sample size used in such a trial is a random variable that has high variability. This can cause problems when applying for funding as the cost will also be generally highly variable. This motivates a type of design that provides the efficiency advantages of a group-sequential multi-arm multi-stage design, but has a fixed sample size. One such design is the two-stage drop-the-losers design, in which a number of experimental treatments, and a control treatment, are assessed at a prescheduled interim analysis. The best-performing experimental treatment and the control treatment then continue to a second stage. In this paper, we discuss extending this design to have more than two stages, which is shown to considerably reduce the sample size required. We also compare the resulting sample size requirements to the sample size distribution of analogous group-sequential multi-arm multi-stage designs. The sample size required for a multi-stage drop-the-losers design is usually higher than, but close to, the median sample size of a group-sequential multi-arm multi-stage trial. In many practical scenarios, the disadvantage of a slight loss in average efficiency would be overcome by the huge advantage of a fixed sample size. We assess the impact of delay between recruitment and assessment as well as unknown variance on the drop-the-losers designs.

Publication metadata

Author(s): Wason J, Stallard N, Bowden J, Jennison C

Publication type: Article

Publication status: Published

Journal: Statistical Methods in Medical Research

Year: 2017

Volume: 26

Issue: 2

Pages: 508-524

Print publication date: 02/01/2017

Online publication date: 16/09/2014

Acceptance date: 19/08/2014

Date deposited: 17/08/2017

ISSN (print): 0962-2802

ISSN (electronic): 1477-0334

Publisher: Sage


DOI: 10.1177/0962280214550759


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Funder referenceFunder name
Medical Research Council (grant numbers G0800860 and MR/J004979/1).