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INTRODUCTION

This JAMA Guide to Statistics and Methods discusses the early stopping of clinical trials for futility due to lack of evidence supporting the desired benefit, evidence of harm, or practical issues that make successful completion unlikely.

The primary objectives of a confirmatory clinical trial, namely a clinical trial conducted with the intention of changing clinical practice or obtaining regulatory approval, are typically to demonstrate and quantify the benefit of a treatment in a specific population of patients. Occasionally, accumulating evidence makes it clear that an ongoing clinical trial is unlikely to meet its original goals. When this occurs, the trial may be stopped early for futility. Futility may result from lack of evidence supporting the desired benefit, from evidence of harm, or from practical issues that make successful completion unlikely.1

Pérez de la Ossa et al2 reported the results of RACECAT, a cluster randomized clinical trial evaluating the optimal transport strategy to a hospital for patients in nonurban areas with suspected ischemic stroke due to large vessel occlusion. The trial compared the effect of directly transporting patients to a thrombectomy-capable center (experimental strategy) vs transporting them to the closest local stroke center (control strategy). The primary end point was disability at 90 days, measured by the modified Rankin Scale (mRS). The trial design used prespecified statistical stopping rules for both efficacy and futility3 and included 2 interim analyses in which results were reviewed at planned time points during the trial, and a final analysis. The RACECAT trial was terminated for futility after the second interim analysis following a recommendation from the data and safety monitoring board (DSMB) to halt enrollment because a prespecified binding futility rule had been met.2 The rule suggested that the apparent lack of efficacy of direct transport to a thrombectomy-capable center was not likely to be reversed by completing the clinical trial.

THE CONCEPT OF FUTILITY

What Is Futility?

In the context of clinical research, futility is often used to indicate that a trial is unlikely to meet its original goal (eg, demonstrating treatment efficacy). Futility can be statistical, such as in the clinical trial by Pérez de la Ossa et al, or based on the infeasibility of successful trial completion. Statistical futility is defined as there being a low probability of a trial achieving its primary objective, should the trial be completed as planned.4,5 In contrast to statistical futility, infeasibility occurs when eligible participants cannot be recruited, funding is exhausted, or when external events (eg, an earthquake or approval of a competing therapy obviates the need for the therapy being tested) force early termination.4

Objective or statistical criteria for futility stopping should be prospectively defined in a clinical trial’s protocol or statistical analysis plan. Statistical futility rules may be binding, meaning the trial must be stopped if the ...

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