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

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.

Keywords: Adaptive designs; CARA randomization; Ethics; Multi-armed bandit; Sequential allocation.

Figure 1

The CARA FLGI rule and a probability tree of all trial histories using the Gittins index rule when K = 2, b = 2, Z = {0, 1} w.p {(1 – q), q}, and x̃₂ = [(2, 1); (1, 1); (1, 1); (2, 1)]. Bold text indicates the allocated combination arm under the Gittins index rule $\left\{a_{zk,t}^{GI}\right\}.$ Gittins index values used correspond to d = 0.99. Gittins indices that have been crossed out indicate arms that are not available for a patient given her covariate value.