Adaptive design implementation in confirmatory trials: methods, practical considerations and case studies

Abstract

The rapidly changing drug development landscapes have brought unique challenges to sponsors in designing clinical trials in a faster and more efficient way. With the ability to accelerate development timeline, reduce redundant sample size, and select the right dose and patient population during the clinical trial, adaptive designs help to increase the probability of success of clinical trials and eventually contribute to bringing the promising drugs to patients earlier and fulfilling their unmet medical needs. Although extensive adaptive design methods have been proposed in recent years, a comprehensive review of how to implement adaptive design in the practical confirmatory trials is still lacking. In this paper, we will review the evolving history of adaptive designs, updates of newly released regulatory guidance and emerging practical adaptive designs, including but not limited to sample size re-estimation, seamless design and surrogate endpoint used in the interim analysis. Furthermore, we will discuss the current practice of adaptive design implementation by demonstrating a complex oncology seamless phase 2/3 adaptive design case study. Through this example, we will introduce the critical roles of each cross disciplinary function, communication process and important documents when adaptive designs are implemented in real-world setting.

Keywords: Adaptive design; Enrichment design; Multiplicity; Sample size re-estimation; Seamless design; Surrogate endpoint; Type I error control.