Handling Covariates in the Design of Clinical Trials

TL;DR

This paper reviews various methods for incorporating covariates into clinical trial design, highlighting conflicts between balance, efficiency, and ethics, and proposes covariate-adjusted response-adaptive procedures to optimize these aspects.

Contribution

It introduces and advocates for covariate-adjusted response-adaptive (CARA) randomization procedures that balance efficiency and ethical considerations in clinical trials.

Findings

CARA procedures can optimize both efficiency and ethics.

Balance does not always lead to increased efficiency.

Simulation studies demonstrate advantages of CARA methods.

Abstract

There has been a split in the statistics community about the need for taking covariates into account in the design phase of a clinical trial. There are many advocates of using stratification and covariate-adaptive randomization to promote balance on certain known covariates. However, balance does not always promote efficiency or ensure more patients are assigned to the better treatment. We describe these procedures, including model-based procedures, for incorporating covariates into the design of clinical trials, and give examples where balance, efficiency and ethical considerations may be in conflict. We advocate a new class of procedures, covariate-adjusted response-adaptive (CARA) randomization procedures that attempt to optimize both efficiency and ethical considerations, while maintaining randomization. We review all these procedures, present a few new simulation studies, and conclude with our philosophy.