The WIZARD Trial as a Case Study of Flexible Clinical Trial Design
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The WIZARD Trial as a Case Study of Flexible Clinical Trial Design Thonos D. Cook Department of Biostatistics and Medical Informatics, University of Wisconsin. Madison
Rebecco J. Bonier Pfizer Global Research and Development, New London, Connecticut Morion R. Fisher Department of Biostatistics and Medical Informatics, University of Wisconsin. Madison
Key Words Composite end points; Event-driven trials; Group sequential testing; Adaptive design; Conditional power Correspondence Address Thomas D. Cook, Department of Biostatistics and Medical Informatics, University of Wisconsin. 209 WARF Building, 610 Walnut Street, Madison, W153726 (e-mail: cook@ biostat. wiscxdu).
The design of a randomized, controlled, confirmatory efficacy clinical trial is influenced by multiple competing factors, including ethical, scientific, economic, and regulatory interests. Design elements, including choice of end points, study duration, and interim monitoring plans, need to be adapted to specific circumstances. The Weekly Intervention With Zithromax for Atherosclerosis and Its Related Disorders (WIZARD) study design was initialIy intended to meet the sponsor’s scientific
INTRODUCTION The design of a randomized, controlled confirmatory efficacy clinical trial is influenced by many competing factors, including ethical, scientific, economic, and regulatory interests. These interests manifest themselves in different ways from trial to trial, and standard design elements, including choice of end points, study duration, and interim monitoring plans need to be adapted to specific circumstances. The Weekly Intervention With Zithromax for Atherosclerosis and Its Related Disorders (WIZARD) trial was initially designed to meet the sponsor’sscientific goals, and the sample size was chosen to ensure that the investment was feasible. Subsequently, there were a number of protocol amendments, two of which are the focus of this article and that addressed changes in the study design intended to reflect better both the regulatory and revised scientific goals of the trial. The first of these amendments was issued after study start but prior to any analysis of study data and addressed the details of the interim monitoring plan. The second was issued just prior to the originally planned conclusion of the trial and increased the sample size, duration, and power of the trial. The design of the expanded trial was formulated by the sponsor without
goals while being subject to practical constraints. In response to changing circumstances, modifications to the study design were required. The WIZARD trial demonstrates the substantial flexibility in the design and conduct of group-sequential randomized trials not only during the design stage but also after the trial is under way, effectively satisfying evolving and competing demands while preserving the statistical and scientific validity of the study.
knowledge of interim results by treatment, while the decision to proceed with the expanded trial was based only minimally on the observed treatment difference
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