Handling Covariates in the Design of Clinical Trials.

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 random ization 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 con clude with our philosophy.

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