ABSTRACT
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Disclaimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
In the last two decades, the clinical trial methodology considered or employed in regulatory applications is increasingly complex. As the potential ethical issues with use of placebo draw more awareness, use of an active control as a comparative treatment arm is increasingly stipulated for assessing the effect of a test treatment. Noninferiority trial designs have therefore been revisited. On another front, even for the placebo-controlled trial, the conventional trial design has been facing a great many of challenges that arise from possible design adaptations, following an increasing use of group sequential designs. Evidentiary standard may require consideration of more innovative trial designs and inferential frameworks for studying more than one objective or endpoint in regulatory submissions. Globalization of drug development adds a great deal of complexity to trial designs and generates issues with interpretability and applicability of a global estimate of treatment effect for each geographical region. Literature has been growing rapidly on these topics. In this chapter, we shall focus primarily on a number of emerging major challenges of the clinical trial methodology on the topics: active controlled trial designs, adaptive designs, multiple comparison considerations, and multiregional clinical trials. Because of this specific focus and multiple topics, only the references very closely related to the emerging challenges under discussion are selected for inclusion in this chapter. The readers are encouraged to read the articles cited in these selected references.
