Adaptive clinical trials: progress and challenges.
Adaptive designs promise the flexibility to redesign clinical trials at interim stages. This flexibility would provide greater efficiency in drug development. However, despite this promise, many hesitate to implement such designs. Here we explore three possible reasons for the hesitation: (i) confusion with respect to the definition of an 'adaptive design'; (ii) controversy surrounding the use of sample size re-estimation methods; and (iii) logistical barriers that must be overcome in order to use adaptive designs within existing trial frameworks.The large volume of recent work has created confusion with respect to the definition of an 'adaptive design'. Unfortunately, this has resulted in reduced usage of many acceptable methods because of guilt by association with the more controversial methods. This review attempts to clarify the differences among many common types of proposed adaptive designs. Once the differences are noted, it becomes apparent that some adaptive designs are well accepted while others remain very controversial. In fact, much of the controversy and criticism surrounding adaptive designs has focused on their use for sample size re-estimation. Hence, this review also examines the different types of adaptive designs for sample size re-estimation in order to clarify the controversy surrounding the use of these methods. Specifically, separating the controversial from good practice requires clarifying differences between adaptive designs with sample size re-estimation based on a revised treatment effect and re-estimation based only on nuisance parameters (internal pilot designs). Finally, many logistical barriers must be overcome in order to use adaptive designs within existing trial frameworks.If the promise of adaptive designs is to be achieved, it will be important to bring together large groups of individuals from funding sources and regulatory agencies to address these limitations. Very few discussions of these issues have appeared in journals that are targeted to clinical audiences. In fact, current use of adaptive designs is not really hindered by the lack of statistical methods to accommodate the adaptations. Rather, there is a need for education as to which adaptive designs are acceptable and which are not acceptable. These discussions will require the involvement of many individuals outside the statistical community. In this review, we summarize the existing methods and current controversies with the intent of providing a clarification that will enable these individuals to participate in these much-needed discussions.
Coffey
Christopher S
CS
Department of Biostatistics, School of Public Health, University of Alabama Birmingham, Birmingham, Alabama, USA.
Kairalla
John A
JA
D002986:Clinical Trials as Topic / Q000639:trends*; D017326:Clinical Trials, Phase III as Topic; D003627:Data Interpretation, Statistical; D015195:Drug Design; D006801:Humans; D010600:Pharmacology / Q000639:trends; D010865:Pilot Projects; D018401:Sample Size