Multi-objective optimal designs in comparative clinical trials with covariates: the reinforced doubly-adaptive biased coin design

The present paper deals with the problem of allocating patients to two competing treatments in the presence of covariates or prognostic factors in order to achieve a good trade-off among ethical concerns, inferential precision and randomness in the treatment allocations. In particular we suggest a multipurpose design methodology that combines efficiency and ethical gain when the linear homoscedastic model with both treatment/covariate interactions and interactions among covariates is adopted. The ensuing compound optimal allocations of the treatments depend on the covariates and their distribution on the population of interest, as well as on the unknown parameters of the model. Therefore, we introduce the reinforced doubly-adaptive biased coin design, namely a general class of covariate-adjusted responseadaptive procedures that includes both continuous and discontinuous randomization functions, aimed to target any desired allocation proportion. The properties of this proposal are described both theoretically and through simulations.