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Optimizing Trial Design: Sequential, Adaptive, and Enrichment Strategies

Despite substantial progress in the prevention of cardiovascular disease and its ischemic complications, it remains the single largest killer in the United States. New treatment options are needed, particularly to respond to the challenges of an aging population and rising rates of obesity and diabetes. Development of novel therapeutic strategies for the management of acute cardiovascular disease is especially challenging. Specific problems include relatively low event rates, diverse patient populations, lack of reliable surrogate end points, and small treatment effects subject to substantial uncertainty. Because the clinical development process is enormously expensive and time consuming, there is considerable interest in statistical methods that use accumulating data from a clinical trial to inform and modify its design. Such redesign might include changes in target sample size and even changes in the target population. This article discusses developments in adaptive design of interest to cardiovascular research.

To illustrate the methods we discuss, we focus on the development of novel therapies for the management of acute coronary syndromes. However, the ideas we discuss have much wider application. We begin by discussing the traditional approach to determination of a fixed sample size for a clinical trial. We then describe group sequential designs and the benefit they provide in the conduct of trials. In the section on Adaptive Sample Size Reestimation, we discuss designs that are adaptive in the sense that they allow an adjustment of the target sample size based on the accumulating data from the trial. In the section on Adaptive Sample Size Reestimation With Enrichment, we discuss enrichment designs that shift the focus to a patient subgroup when the accumulating data suggest greatest benefit for that subgroup. Additional details about population enrichment are provided in the online-only Data Supplement.

We consider therapies intended to reduce the risk of acute ischemic complications in …