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Covariate-adjusted response-adaptive randomization for multi-arm clinical trials using a modified forward looking Gittins index rule.

Published version
Peer-reviewed

Change log

Authors

Villar, Sofía S 
Rosenberger, William F  ORCID logo  https://orcid.org/0000-0002-6513-8006

Abstract

We introduce a non-myopic, covariate-adjusted response adaptive (CARA) allocation design for multi-armed clinical trials. The allocation scheme is a computationally tractable procedure based on the Gittins index solution to the classic multi-armed bandit problem and extends the procedure recently proposed in Villar et al. (2015). Our proposed CARA randomization procedure is defined by reformulating the bandit problem with covariates into a classic bandit problem in which there are multiple combination arms, considering every arm per each covariate category as a distinct treatment arm. We then apply a heuristically modified Gittins index rule to solve the problem and define allocation probabilities from the resulting solution. We report the efficiency, balance, and ethical performance of our approach compared to existing CARA methods using a recently published clinical trial as motivation. The net savings in terms of expected number of treatment failures is considerably larger and probably enough to make this design attractive for certain studies where known covariates are expected to be important, stratification is not desired, treatment failures have a high ethical cost, and the disease under study is rare. In a two-armed context, this patient benefit advantage comes at the expense of increased variability in the allocation proportions and a reduction in statistical power. However, in a multi-armed context, simple modifications of the proposed CARA rule can be incorporated so that an ethical advantage can be offered without sacrificing power in comparison with balanced designs.

Description

Keywords

Adaptive designs, CARA randomization, Ethics, Multi-armed bandit, Sequential allocation, Clinical Trials as Topic, Humans, Models, Statistical, Random Allocation, Therapeutics, Treatment Failure

Journal Title

Biometrics

Conference Name

Journal ISSN

0006-341X
1541-0420

Volume Title

74

Publisher

Oxford University Press (OUP)
Sponsorship
MRC (unknown)
Biometrika Trust (unknown)
This research started while the first author was visiting the Department of Statistics, George Mason University, supported by the UK Medical Research Council and the Biometrika Trust.