Covariate-adjusted response-adaptive designs for semiparametric survival models.

Abstract

Covariate-adjusted response adaptive (CARA) designs are effective in increasing the expected number of patients receiving superior treatment in an ongoing clinical trial, given a patient's covariate profile. There has recently been extensive research on CARA designs with parametric distributional assumptions on patient responses. However, the range of applications for such designs becomes limited in real clinical trials. Sverdlov et al. have pointed out that irrespective of a specific parametric form of the survival outcomes, their proposed CARA designs based on the exponential model provide valid statistical inference, provided the final analysis is performed using the appropriate accelerated failure time (AFT) model. In real survival trials, however, the planned primary analysis is rarely conducted using an AFT model. The proposed CARA designs are developed obviating any distributional assumptions about the survival responses, relying only on the proportional hazards assumption between the two treatment arms. To meet the multiple experimental objectives of a clinical trial, the proposed designs are developed based on an optimal allocation approach. The covariate-adjusted doubly adaptive biased coin design and the covariate-adjusted efficient-randomized adaptive design are used to randomize the patients to achieve the derived targets on expectation. These expected targets are functions of the Cox regression coefficients that are estimated sequentially with the arrival of every new patient into the trial. The merits of the proposed designs are assessed using extensive simulation studies of their operating characteristics and then have been implemented to re-design a real-life confirmatory clinical trial.