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A response-adaptive randomization procedure for multi-armed clinical trials with normally distributed outcomes.

Accepted version
Peer-reviewed

Type

Article

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Authors

Abstract

We propose a novel response-adaptive randomization procedure for multi-armed trials with continuous outcomes that are assumed to be normally distributed. Our proposed rule is non-myopic, and oriented toward a patient benefit objective, yet maintains computational feasibility. We derive our response-adaptive algorithm based on the Gittins index for the multi-armed bandit problem, as a modification of the method first introduced in Villar et al. (Biometrics, 71, pp. 969-978). The resulting procedure can be implemented under the assumption of both known or unknown variance. We illustrate the proposed procedure by simulations in the context of phase II cancer trials. Our results show that, in a multi-armed setting, there are efficiency and patient benefit gains of using a response-adaptive allocation procedure with a continuous endpoint instead of a binary one. These gains persist even if an anticipated low rate of missing data due to deaths, dropouts, or complete responses is imputed online through a procedure first introduced in this paper. Additionally, we discuss how there are response-adaptive designs that outperform the traditional equal randomized design both in terms of efficiency and patient benefit measures in the multi-armed trial context.

Description

Keywords

Gittins index, adaptive designs, continuous endpoint, dichotomization, missing data, unknown variance, Adaptive Clinical Trials as Topic, Algorithms, Biometry, Clinical Trials, Phase II as Topic, Computer Simulation, Endpoint Determination, Humans, Models, Statistical, Neoplasms, Patient Dropouts, Randomized Controlled Trials as Topic, Treatment Outcome

Journal Title

Biometrics

Conference Name

Journal ISSN

0006-341X
1541-0420

Volume Title

76

Publisher

Oxford University Press (OUP)

Rights

All rights reserved
Sponsorship
MRC (unknown)
Biometrika Trust (unknown)