Optimal scheduling of interim analyses in group sequential trials

Abstract

Group sequential designs (GSDs) are well established and the most commonly used adaptive design in confirmatory clinical trials with interim analyses. However, they remain underutilised, and their implementation involves unique theoretical and practical decisions that demand careful consideration to optimise efficiency. A common practice is to schedule interim analyses at equal intervals based on calendar time or accumulated data. While straightforward, this approach does not completely exploit the potential sample size savings achievable with GSDs. To address this challenge, we develop OptimInterim, an R-based tool that can determine the optimal scheduling of interim analyses to minimise the expected sample size under the alternative hypothesis while controlling overall type I and type II errors. Our method accommodates trials with continuous or binary endpoints, allows multiple interim analyses and supports a range of stopping boundaries. Through extensive simulations, we demonstrate that optimally spaced interim analyses can yield substantial savings in expected sample size compared to equally spaced interim analyses, without compromising the maximum sample size, across various endpoint types, effect sizes, error rates and stopping rules. We illustrate its practical utility with two landmark trials evaluating steroid use in septic shock. Notably, for given type I and type II error rates, the optimal scheduling is independent of endpoint types and effect sizes, ensuring broad applicability across a wide range of trial contexts. To facilitate implementation, we offer a ready-to-use reference table of optimal schedules for up to eight interim analyses under commonly used error rates and stopping rules. Access OptimInterim at https://github.com/zhangyi-he/GSD_OptimInterim.