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.

A post hoc evaluation of a sample size re-estimation in the Secondary Prevention of Small Subcortical Strokes study

“…adaptive treatment selection), and what considerations need to be made other than statistical properties. 32 Modification of a study mid-stream potentially could require changes to the protocol, informed consent, staffing, and numerous other logistical items. Additionally, changes to the study mid-stream may have implications for the randomization scheme, the data entry system, the case report forms, and other aspects of data management.…”

Planning Clinical Trials: The Main Step in Developing New Drugs

“…Finally, for purposes of simple and unequivocal interpretation of the results of the comparison, there must be no interaction between the treatments studied and the two different periods, i.e. that the difference between the two treatments is the same whether they be administered in the first or second period [4].…”

Group Sequential and Confirmatory Adaptive Designs in Clinical Trials

“…The following example that was also reported in Bauer et al (2016) illustrates the implementation of an adaptive group sequential design with sample size reestimation in a Phase III clinical trial MUSEC (MUltiple Sclerosis and Extract of Cannabis, Trial Registration Number NCT00552604; for details see Zajicek et al 2012) that investigated a standardized oral cannabis extract (CE) for the symptomatic relief of muscle stiffness and pain in adult patients with stable multiple sclerosis (MS) and ongoing troublesome muscle stiffness. The primary outcome measure was a 11 point category rating scale (CRS) measuring patient reported change in muscle stiffness from baseline to 12 weeks of treatment.…”

“…We briefly summarize some trials with adaptive treatment selection which we take from a recent summary in Bauer et al (2016). First of all, Zeymer et al (2001) conducted an international, prospective, randomized, double-blind, placebo-controlled Phase II trial in patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation myocardial infarction applying a two-stage adaptive design.…”