Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs
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Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs Thomas Burnett1* , Pavel Mozgunov1 , Philip Pallmann2 , Sofia S. Villar3 , Graham M. Wheeler4 and Thomas Jaki1,3 Abstract Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies. Keywords: Novel designs, Innovative trials, Efficient methods, Enrichment designs, Multi-arm multi-stage platform trials
What are adaptive designs? In a traditional clinical trial, the design is fixed in advance, the study is carried out, and the data analysed after completion [1]. In contrast, adaptive designs pre-plan possible modifications on the basis of the data accumulating over the course of the trial as part of the trial protocol [2]. We consider designs that allow for modifications of the trial such as the sample size, the number of treatments, or the allocation ratio to different arms. We do not consider options such as stopping early due to failure to meet operational criteria or excessive safety events, although adaptive designs for some of these do also exist [3]. Adaptive design methodology has been around for more *Correspondence: [email protected] Department of Mathematics and Statistics, Lancaster University, Fylde College, Lancaster, LA1 4YF, UK Full list of author information is available at the end of the article 1
than 25 years [4], with some methods such as group sequential designs being even older [5]. It is crucial that the adaptive nature of a design does not undermine the trial’s integrity and validity [6]. By integrity of a trial, we mean that the data have not been used in such a way as to substantially alter the result, while the validity of the results requires that the study answers the original research questions appropriately. Adaptive designs require procedures to ensure that data is collected, analysed, and stored in an appropriate manner at every stage of the trial, with specialised statistical metho
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