Adaptive design clinical trials and trial logistics models in CNS drug development

In accordance with the spirit of the U.S. Food and Drug Administration adaptive design draft guidance document recently released, this paper enlists the critical considerations from both methodological aspects and regulatory aspects in reviewing an adaptive design proposal and discusses two general types of adaptations, sample size planning and re-estimation, and two-stage adaptive design. Literature examples of adaptive designs in central nervous system are used to highlight the principles laid out in the U.S. FDA draft guidance. Four logistics models seen in regulatory adaptive design applications are introduced. In general, complex adaptive designs require simulation studies to access the design performance. For an adequate and well-controlled clinical trial, if a Learn-and-Confirm adaptive selection approach is considered, the study-wise type I error rate should be adhered to. However, it is controversial to use the simulated type I error rate to address a strong control of the study-wise type I error rate.