Adaptive Designs: Terminology and Classification
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Vladimir Dragalin
GlaxoSmithKline
Key Words Adaptivedesign; Allocation rule; Decision rule; Sampling rule; Stopping rule
(orresponden,e Address
Vladimir Dragalin, Global Biostatistics and Programming, Wyeth Pharmaceuticals. 500 Arcola Road. Collegeville, PA 19426.
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Adaptive Designs: Terminology and Classification
INTRODUCTION Recent achievements in the methodology of adaptive designs provide new ways of drug development that have the potential to improve quality, speed, and efficiency of decision making. With introduced flexibility within trial design, this approach saves resources by identifying failures early and increases efficiency by focusing precious patient resources on treatments that have a higher probability of success. While clearly advantageous to the drug development program, this is also ethically beneficial to the patients in the trial as it restricts patient exposure to ineffective treatments. Unfortunately, as often happens with novel approaches, there has been substantial confusion over what these designs are and when they are most applicable. They are known as adaptive, sequential, flexible, self-designing, multistage. dynamic. response-driven. smart, novel designs. We propose here an integrated approach to defining and classifying adaptive designs to minimize confusion on their terminology and taxonomy across the pharmaceutical industry, its stakeholders and analysts, and regulatoryagencies. The primary purpose of this article is to describe the range of adaptive designs that are available and to promote the benefits they might bring in all phases of clinical drug devel-
In this article, we give a general definition of adaptive designs, describe their structure, and provide a classification of adaptive designs, mapping them against the drug development process.
opment. It is necessary to emphasize that these designs have much more to offer than the rigid conventional parallel group designs in clinical trials. To maintain focus within the space allotment available, we do not attempt an exhaustive literature review. Rather, we focus on key ideas and cite supportive literature as appropriate. The next section gives a general definition of adaptive designs and their structure. This is followed by classification of adaptive designs.
DEFINITION OF ADAPTIVE DESIGNS Adaptive design is defined as a multistage study design that uses accumulating data to decide how to modify aspects of the study without undermining the validity and integrity of the trial. To maintain study validity means providing correct statistical inference (such as adjusted P values, unbiased estimates and adjusted confidence intervals, etc.), ensuring consistency between different stages of the study. and minimizing operational bias. To maintain study integrity means providing convincing results to a broader scientific community; preplanning, as much as possible, based on intended adaptations; and maintaining the blind of interim analysis results. An adaptive design requires the trial to be conducted in multiple stages w
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