  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.
