Twenty-five years of confirmatory adaptive designs: Opportunities and pitfalls

Abstract

'Multistage testing with adaptive designs' was the title of an article by Peter Bauer that appeared 1989 in the German journal Biometrie und Informatik in Medizin und Biologie. The journal does not exist anymore but the methodology found widespread interest in the scientific community over the past 25 years. The use of such multistage adaptive designs raised many controversial discussions from the beginning on, especially after the publication by Bauer and Köhne 1994 in Biometrics: Broad enthusiasm about potential applications of such designs faced critical positions regarding their statistical efficiency. Despite, or possibly because of, this controversy, the methodology and its areas of applications grew steadily over the years, with significant contributions from statisticians working in academia, industry and agencies around the world. In the meantime, such type of adaptive designs have become the subject of two major regulatory guidance documents in the US and Europe and the field is still evolving. Developments are particularly noteworthy in the most important applications of adaptive designs, including sample size reassessment, treatment selection procedures, and population enrichment designs. In this article, we summarize the developments over the past 25 years from different perspectives. We provide a historical overview of the early days, review the key methodological concepts and summarize regulatory and industry perspectives on such designs. Then, we illustrate the application of adaptive designs with three case studies, including unblinded sample size reassessment, adaptive treatment selection, and adaptive endpoint selection. We also discuss the availability of software for evaluating and performing such designs. We conclude with a critical review of how expectations from the beginning were fulfilled, and - if not - discuss potential reasons why this did not happen.