Adaptive Randomization for Master Protocols in Precision Medicine

In the era of precision medicine and with the release of FDA draft guidance (2010), innovative adaptive designs, e.g. Umbrella (or Platform), Basket trials, adaptive enrichment strategies have generated greater interests and applications in clinical trials and resulted in rapidly revolutionized methodologies, including adaptive randomization, to conduct clinical trials in the setting of biomarkers and targeted therapies, whereas the traditional paradigm of treating very large number of unselected patients is increasingly less efficient, lacks cost effectiveness and is ethically challenging. In this paper, we presented a general overview of adaptive design and master protocols strategies for clinical trials, including Bayesian and frequentist approaches. Examples were used to demonstrate the procedure for design parameters calibration and operating characteristics. In addition, for clinical trials with survival outcomes, we also introduced a nonparametric model which is robust to model of event time distribution to response-adaptive design. The operating characteristics of the proposed design and the parametric design were compared by simulation studies, including their robustness properties with respect to model misspecifications. Both advantages and disadvantages of adaptive randomization were discussed in the summary from practical perspective of clinical trials as well as illustrations by master protocol case studies.