Evaluating futility of a binary clinical endpoint using early read‐outs

Interim analyses are routinely used to monitor accumulating data in clinical trials. When the objective of the interim analysis is to stop the trial if the trial is deemed futile, it must ideally be conducted as early as possible. In trials where the clinical endpoint of interest is only observed after a long follow-up, many enrolled patients may therefore have no information on the primary endpoint available at the time of the interim analysis. To facilitate earlier decision-making, one may incorporate early response data that are predictive for the primary endpoint (eg, an assessment of the primary endpoint at an earlier time) in the interim analysis. Most attention so far has been given to the development of interim test statistics that include such short-term endpoints, but not to decision procedures. Existing tests moreover perform poorly when the information is scarce, eg, due to rare events, when the cohort of patients with observed primary endpoint data is small, or when the short-term endpoint is a strong but imperfect predictor. In view of this, we develop an interim decision procedure based on the conditional power approach that utilizes the short-term and long-term binary endpoints in a framework that is expected to provide reliable inferences, even when the primary endpoint is only available for a few patients, and has the added advantage that it allows the use of historical information. The operational characteristics of the proposed procedure are evaluated for the phase III clinical trial that motivated this approach, using simulation studies.