Timing and Frequency of Interim Analyses in Confirmatory Trials

Abstract

In many pivotal clinical trials, timing and frequency of interim analyses are important for ethical treatment of patients and for practical and regulatory purposes. It is often desirable to evaluate a large trial of a new treatment that has some safety risk in order to stop or modify the trial based on the emerging risk–benefit profile compared to control treatment. Statistical considerations would suggest not stopping too soon in order to avoid large Type I or Type II error or basing a decision on inadequate data. Regulators often prefer to minimize interim analyses of efficacy due to presumed bias created by early stopping and an inability to adequately evaluate important secondary efficacy endpoints, safety, or the general risk–benefit profile for the new treatment. For practical purposes, analyses must be done soon enough to have a meaningful impact on the trial. For the same reason, limiting enrollment rates and ensuring prompt collection and analysis of data are important. We discuss tradeoffs between these factors in deciding when to perform interim analyses. In addition to formal evaluations for early positive efficacy findings, there are different considerations for trials early in the development process, for safety monitoring during a trial, and for futility analyses. We consider logistical and regulatory issues throughout.