PDF(Pubmed)
Abstract：
Cancer immunotherapy trials are frequently characterized by delayed treatment effects such that the proportional hazards assumption is violated and the log-rank test suffers a substantial loss of statistical power. To increase the efficacy of the trial design, a variety of weighted log-rank tests have been proposed for fixed sample and group sequential trial designs. However, in such a group sequential design, it is often not recommended for futility interim monitoring due to possible delayed treatment effect which could result a high false-negative rate. To resolve this problem, we propose a group sequential design using a piecewise weighted log-rank test which provides an event-driven approach based on number of events after the delayed time. That is, the interim looks will not be conducted until the planned number of events observed after the delay time. Thus, it avoids the possibility of false-negative rate due to the delayed treatment effect. Furthermore, with an event-driven approach, the proposed group sequential design is robust against the underlying survival, accrual and censoring distributions. The group sequential designs using Fleming-Harrington-(ρ,γ) weighted log-rank test and a new weighted log-rank test are also discussed.
摘要：
癌症免疫疗法试验的特征通常是延迟治疗效果，从而违反了比例风险假设，并且对数秩检验遭受了统计能力的实质性损失。为了提高试验设计的有效性，针对固定样本和分组序贯试验设计,提出了多种加权对数秩检验.然而,在这样的一组顺序设计中，通常不建议进行无效的中期监测，因为可能延迟治疗效果，这可能导致较高的假阴性率。为了解决这个问题,我们提出了使用分段加权对数秩检验的组顺序设计，该检验提供了一种基于延迟时间后事件数的事件驱动方法。也就是说,在延迟时间后观察到计划的事件数量之前，不会进行临时检查。因此，避免了由于延迟治疗效果而导致的假阴性率的可能性。此外，用事件驱动的方法，拟议的群体序贯设计对潜在的生存是稳健的，应计分配和审查分配。使用Fleming-Harrington-(ρ，还讨论了γ）加权对数秩检验和新的加权对数秩检验。
