Designing multi-arm multi-stage clinical trials using a risk-benefit criterion for treatment selection

Jaki, Thomas and Hampson, Lisa (2016) Designing multi-arm multi-stage clinical trials using a risk-benefit criterion for treatment selection. Statistics in Medicine, 35 (4). pp. 522-533. ISSN 0277-6715

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Multi-arm clinical trials that compare several active treatments to a common control have been proposed as an efficient means of making an informed decision about which of several treatments should be evaluated further in a confirmatory study. Additional efficiency is gained by incorporating interim analyses and in particular, seamless Phase II/III designs have been the focus of recent research. Common to much of this work is the constraint that selection and formal testing should be based on a single efficacy endpoint, despite the fact that in practice, safety considerations will often play a central role in determining selection decisions. Here we develop a multi-arm multistage design for a trial with an efficacy and safety endpoint. The safety endpoint is explicitly considered in the formulation of the problem, selection of experimental arm and hypothesis testing. The design extends group-sequential ideas and considers the scenario where a minimal safety requirement is to be fulfilled and the treatment yielding the best combined safety and efficacy trade-off satisfying this constraint is selected for further testing. The treatment with the best trade-off is selected at the first interim analysis while the whole trial is allowed to comprise of J analyses. We show that the design controls the familywise error rate in the strong sense and illustrate the method through an example and simulation. We find that the design is robust to misspecification of the correlation between the endpoints and requires similar numbers of subjects to a trial based on efficacy alone for moderately correlated endpoints.

Item Type:
Journal Article
Journal or Publication Title:
Statistics in Medicine
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© 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords:
?? familywise error rate multi-arm multi-stage (mams)multiple endpointssafetytreatment selectionepidemiologystatistics and probability ??
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Deposited On:
06 Nov 2015 10:10
Last Modified:
18 Dec 2023 01:31