Abstract
In an era of precision medicine, as advanced technology such as molecular profiling at individual patient level has been developed and become increasingly accessible and affordable, biomarker-driven trials have been received a lot of attention and are expected to receive more attention in order to integrate clinical practice with clinical research. Biomarkers play a critical role to identify patients who are expected to get benefit from a treatment, and it is important to effectively incorporate the biomarkers into clinical trials to understand the biomarker-treatment relationship and increase the efficiency. We investigate incorporating biomarkers in adaptive randomization to identify patients who would respond better to the treatment and optimize the treatment allocation. The covariate-adjusted variants of the existing response-adaptive randomization are used to implement biomarker-driven randomization, and the performance of the biomarker-driven randomization is compared with the existing randomization methods, such as traditional fixed randomization with equal probability and response-adaptive randomization without incorporating biomarkers, under the group sequential design allowing early stopping due to superiority and futility. Various scenarios are taken into account to see the impact of the biomarker-driven randomization in the simulation study. It shows that the overall type I error rate is likely to be inflated by the effect of prognostic biomarkers. Several suggestions and considerations for the challenges are discussed to maintain the type I error rate at the nominal level.