FLEX-CP-DT: A Flexible Conditional Power Framework for Interim Futility Analysis in Clinical Trials with Count Endpoints and Temporal Trends

原文摘要

Many large-scale phase III trials with recurrent event endpoints include a pre-planned interim analysis to evaluate early futility. Conditional power (CP), which quantifies the probability of achieving statistical significance at the final analysis given the interim data, is a commonly used tool to support such decisions. The standard negative binomial model with an offset term, widely adopted for analyzing recurrent events, implicitly assumes that event rates and treatment effects remain constant over the study period. At the interim analysis, however, a substantial proportion of patients have incomplete follow-up, and when the treatment effect is delayed in onset or diminishes over time, the constant-rate assumption introduces systematic bias into the interim estimate and can lead to incorrect futility decisions. In this paper, we propose FLEX-CP-DT, a piecewise negative binomial framework that captures temporal trends in both event rates and treatment effects without imposing the constant-rate assumption. The framework yields a formula-based conditional power calculation that does not require resampling or trial simulation at the interim stage. Through extensive simulations spanning constant-effect and delayed-onset scenarios, we demonstrate that FLEX-CP-DT performs comparably to the standard approach when the constant-rate assumption holds and improves interim futility decision-making when it is violated. A case study calibrated to a published phase 3 bronchiectasis trial further illustrates the practical advantage of the proposed method in reducing the probability of falsely terminating an efficacious drug with delayed treatment onset.

摘要来源：arXiv