A response-adaptive multi-arm design for continuous endpoints based on a weighted information measure

Abstract

Multi-arm trials are gaining interest in practice given the statistical and logistical advantages that they can offer. The standard approach is to use a fixed (throughout the trial) allocation ratio, but there is a call for making it adaptive and skewing the allocation of patients towards better performing arms. However, among other challenges, it is well-known that these approaches might suffer from lower statistical power. We present a response-adaptive design for continuous endpoints which explicitly allows to control the trade-off between the number of patients allocated to the 'optimal' arm and the statistical power. Such a balance is achieved through the calibration of a tuning parameter, and we explore various strategies to effectively select it. The proposed criterion is based on a context-dependent information measure which gives a greater weight to those treatment arms which have characteristics close to a pre-specified clinical target. We also introduce a simulation-based hypothesis testing procedure which focuses on selecting the target arm, discussing strategies to effectively control the type-I error rate. The potential advantage of the proposed criterion over currently used alternatives is evaluated in simulations, and its practical implementation is illustrated in the context of early Phase IIa proof-of-concept oncology clinical trials.