Adaptive clinical trial design methods have garnered growing attention in the recent years, in large part due to their greater flexibility over their traditional counterparts. One such design is the so-called covariate-adjusted, response-adaptive (CARA) randomized controlled trial (RCT). In a CARA RCT, the treatment randomization schemes are allowed to depend on the patient’s pre-treatment covariates, and the investigators have the opportunity to adjust these schemes during the course of the trial based on accruing information (including previous responses), in order to meet a pre-specified optimality criterion, while preserving the validity of the trial in learning its primary study parameter.
In this article, we propose a new group-sequential CARA RCT design and corresponding analytical procedure that admits the use of flexible data-adaptive techniques. The proposed design framework can target general adaption optimality criteria that may not have a closed-form solution, thanks to a loss- based approach in defining and estimating the unknown optimal randomization scheme. Both in predicting the conditional response and in constructing the treatment randomization schemes, this framework uses loss-based data-adaptive estimation over general classes of functions (which may change with sample size). Since the randomization adaptation is response-adaptive, this innovative flexibility potentially translates into more effective adaptation towards the optimality criterion. To target the primary study parameter, the proposed analytical method provides robust inference of the parameter, despite arbitrarily mis-specified response models, under the most general settings.
Specifically, we establish that, under appropriate entropy conditions on the classes of functions, the resulting sequence of randomization schemes converges to a fixed scheme, and the proposed treatment effect estimator is consistent (even under a mis-specified response model), asymptotically Gaussian, and gives rise to valid confidence intervals of given asymptotic levels. Moreover, the limiting randomization scheme coincides with the unknown optimal randomization scheme when, simultaneously, the response model is correctly specified and the optimal scheme belongs to the limit of the user-supplied classes of randomization schemes. We illustrate the applicability of these general theoretical results with a LASSO- based CARA RCT. In this example, both the response model and the optimal treatment randomization are estimated using a sequence of LASSO logistic models that may increase with sample size. It follows immediately from our general theorems that this LASSO-based CARA RCT converges to a fixed design and yields consistent and asymptotically Gaussian effect estimates, under minimal conditions on the smoothness of the basis functions in the LASSO logistic models. We exemplify the proposed methods with a simulation study.
Zheng, Wenjing; Chambaz, Antoine; and van der Laan, Mark J., "Drawing Valid Targeted Inference When Covariate-adjusted Response-adaptive RCT Meets Data-adaptive Loss-based Estimation, With An Application To The LASSO" (July 2015). U.C. Berkeley Division of Biostatistics Working Paper Series. Working Paper 339.