Randomization in clinical trials: can we eliminate bias?

Author(s): Oleksandr Sverdlov,William F Rosenberger

Randomization plays a fundamental role in clinical trials. While many m­odern clinical trials employ restricted, stratified or covariate-adaptive randomization designs that pursue balance in treatment assignments and balance across important covariates, some clinical trials call for response-adaptive or covariate-adjusted response-adaptive (CARA) randomization designs to address multiple experimental objectives primarily related to statistical efficiency and ethical considerations. In this paper, we elicit key principles of the well-conducted randomized clinical trial and explore the role of randomization and other important design tools in achieving valid and credible results. We give special attention to response-adaptive and CARA randomization designs, which have a firm theoretical basis, but are more complex and more vulnerable to operational biases than traditional randomization designs. We conclude that modern advances in information technology, rigorous planning, and adherence to the key principles of the well-conducted clinical trial should enable successful implementation of response-adaptive and CARA randomization designs in the near future.