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Familywise error control in multi-armed response-adaptive trials.

Authors
  • Robertson, D S1
  • Wason, J M S1, 2
  • 1 MRC Biostatistics Unit, University of Cambridge, IPH Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
  • 2 Institute of Health and Society, Newcastle University, Newcastle upon Tyne, NE2 4AX, UK.
Type
Published Article
Journal
Biometrics
Publisher
Wiley (Blackwell Publishing)
Publication Date
Sep 01, 2019
Volume
75
Issue
3
Pages
885–894
Identifiers
DOI: 10.1111/biom.13042
PMID: 30714095
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Response-adaptive designs allow the randomization probabilities to change during the course of a trial based on cumulated response data so that a greater proportion of patients can be allocated to the better performing treatments. A major concern over the use of response-adaptive designs in practice, particularly from a regulatory viewpoint, is controlling the type I error rate. In particular, we show that the naïve z-test can have an inflated type I error rate even after applying a Bonferroni correction. Simulation studies have often been used to demonstrate error control but do not provide a guarantee. In this article, we present adaptive testing procedures for normally distributed outcomes that ensure strong familywise error control by iteratively applying the conditional invariance principle. Our approach can be used for fully sequential and block randomized trials and for a large class of adaptive randomization rules found in the literature. We show there is a high price to pay in terms of power to guarantee familywise error control for randomization schemes with extreme allocation probabilities. However, for proposed Bayesian adaptive randomization schemes in the literature, our adaptive tests maintain or increase the power of the trial compared to the z-test. We illustrate our method using a three-armed trial in primary hypercholesterolemia. © 2019 The Authors. Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.

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