AI 中文总结
FLEX-CP-DT是捕捉事件率和治疗效果时间趋势的分段负二项框架，可准确开展计数终点临床试验的中期无效性分析，能减少错误终止有效药物的概率。
AI 中文摘要
许多具有复发事件终点的大型III期临床试验会开展预先计划的中期分析，以评估早期无效性。条件功效（CP）是给定中期数据时，量化最终分析达到统计学显著性的概率，是支持此类决策的常用工具。广泛用于分析复发事件的带偏移项的标准负二项模型，隐含假设事件发生率和治疗效果在研究期间保持恒定。但在中期分析时，相当一部分患者的随访不完整，且当治疗效果起效延迟或随时间减弱时，恒定率假设会给中期估计引入系统偏差，可能导致错误的无效性决策。本文提出FLEX-CP-DT，这是一种分段负二项框架，可捕捉事件发生率和治疗效果的时间趋势，无需施加恒定率假设。该框架能得到基于公式的条件功效计算，无需在中期阶段进行重采样或试验模拟。通过涵盖恒定效果和延迟起效场景的大量模拟，我们证明，当恒定率假设成立时，FLEX-CP-DT的表现与标准方法相当；当该假设被违反时，它能改进中期无效性决策。一项基于已发表的III期支气管扩张试验校准的案例研究，进一步说明了该方法在降低错误终止具有延迟治疗起效的有效药物概率方面的实际优势。
英文摘要
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.
