论文标题
无缝II/III期试验的封闭组顺序设计,并选择了亚群选择
A gated group sequential design for seamless Phase II/III trial with subpopulation selection
论文作者
论文摘要
由于第三阶段试验的高成本和高失败率,无缝II/III期设计越来越受到试验效率。 II/III期设计的潜在吸引力是在承诺进行III期试验的全部成本之前允许随机概念验证阶段。试验期间的人口选择允许试验适应和集中投资,在最有可能提供患者利益的情况下。受到临床试验的激励,发现人口具有双重主要终点的潜在益处,而自由生存(PFS)和整体生存率(OS),我们提出了一个封闭式的群组顺序设计,以进行无缝的II/III期试验设计,并选择了人口选择。研究的设计控制了家庭错误率,并允许多次临时分析能够提早停止功效或徒劳。模拟和一个说明性的例子表明,所提出的封闭组的顺序设计比常用的经典序列设计可以具有更多的功率,如果互补子组的治疗效果较小,则可以减少患者对患者的效率较低的治疗。拟议的设计有可能节省药物开发成本,并更快地满足未满足的医疗需求。
Due to the high cost and high failure rate of Phase III trials, seamless Phase II/III designs are more and more popular to trial efficiency. A potential attraction of Phase II/III design is to allow a randomized proof-of-concept stage prior to committing to the full cost of the Phase III trial. Population selection during the trial allows a trial to adapt and focus investment where it is most likely to provide patient benefit. Motivated by a clinical trial to find the population that potential benefits with dual-primary endpoints progression free survival (PFS) and overall survival (OS), we propose a gated group sequential design for a seamless Phase II/III trial design with population selection. The investigated design controls the familywise error rate and allows multiple interim analyses to enable early stopping for efficacy or futility. Simulations and an illustrative example suggest that the proposed gated group sequential design can have more power than the commonly used classical group sequential design, and reduces the patient's exposure to less effective treatment if the complementary sub-group has less significant treatment effect. The proposed design has the potential to save drug development cost and more quickly fulfill unmet medical needs.