A multiple comparison procedure for dose-finding trials with subpopulations

DOI10.1002/BIMJ.201800111MaRDI QIDQ5120914zbMATH OpenOpenAlexWikidataFDO

Authors Marius Thomas, Björn Bornkamp, Martin Posch, Franz Koenig

Publication date 16 September 2020

Published in Biometrical Journal (Search for Journal in Brave)

Copyright license Creative Commons Attribution 4.0 International

Full work available at URL https://arxiv.org/abs/1811.09824

zbMATH Keywords

MCP-modmultiple testingsubgroup analysestargeted therapies

Mathematics Subject Classification ID

Applications of statistics to biology and medical sciences; meta analysis (62P10)

Abstract: Identifying subgroups of patients with an enhanced response to a new treatment has become an area of increased interest in the last few years. When there is knowledge about possible subpopulations with an enhanced treatment effect before the start of a trial it might be beneficial to set up a testing strategy, which tests for a significant treatment effect not only in the full population, but also in these prespecified subpopulations. In this paper we present a parametric multiple testing approach for tests in multiple populations for dose-finding trials. Our approach is based on the MCP-Mod methodology, which uses multiple comparison procedures to test for a dose-response signal, while considering multiple possible candidate dose-response shapes. Our proposed methods allow for heteroscedasticity between populations and control the FWER over tests in multiple populations and for multiple candidate models. We show in simulations, that the proposed multi-population testing approaches can increase the power to detect a significant dose-response signal over the standard single-population MCP-Mod, when the considered subpopulation has an enhanced treatment effect.

Recommendations

• Individualized dosing for multiple ordered groups of patients
• Multiple testing for dose finding
• Uniformly most powerful tests for simultaneously detecting a treatment effect in the overall population and at least one subpopulation
• Comparison of different approaches for dose response analysis
• Optimal tests of treatment effects for the overall population and two subpopulations in randomized trials, using sparse linear programming

Cited in

(4)

• Individualized dosing for multiple ordered groups of patients
• An approach to confirmatory testing of subpopulations in clinical trials
• Uniformly most powerful tests for simultaneously detecting a treatment effect in the overall population and at least one subpopulation
• Multiplicity considerations for subgroup analysis subject to consistency constraint

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