Kordzakhia George, Brechenmacher Thomas, Ishida Eiji, Dmitrienko Alex, Zheng Winston Wenxiang, Li David Fuyuan
a U.S. Food and Drug Administration , Silver Spring , MD , USA.
b Quintiles IMS , Tokyo , Japan.
J Biopharm Stat. 2018;28(1):113-128. doi: 10.1080/10543406.2017.1399900. Epub 2017 Dec 14.
It is increasingly common to encounter complex multiplicity problems with several multiplicity components in confirmatory Phase III clinical trials. These components are often based on several endpoints (primary and secondary endpoints) and several dose-control comparisons. When constructing a multiplicity adjustment in these settings, it is important to control the Type I error rate over all multiplicity components. An important class of multiple testing procedures, known as gatekeeping procedures, was derived using the mixture method that enables clinical trial sponsors to set up efficient multiplicity adjustments that account for clinically relevant logical relationships among the hypotheses of interest. An enhanced version of this mixture method is introduced in this paper to construct more powerful gatekeeping procedures for a specific type of logical relationships that rely on transitive serial restrictions. Restrictions of this kind are very common in Phase III clinical trials and the proposed method is applicable to a broad class of multiplicity problems. Several examples are provided to illustrate the new method and results of simulation trials are presented to compare the performance of gatekeeping procedures derived using this method and other available methods.
在确证性III期临床试验中，遇到包含多个多重性成分的复杂多重性问题越来越常见。这些成分通常基于多个终点（主要终点和次要终点）以及多个剂量-对照比较。在这些情况下构建多重性调整时，控制所有多重性成分的I型错误率很重要。一类重要的多重检验程序，即把关程序，是使用混合方法推导出来的，该方法使临床试验申办者能够建立有效的多重性调整，以考虑感兴趣的假设之间临床上相关的逻辑关系。本文引入了这种混合方法的增强版本，以针对依赖传递串行限制的特定类型逻辑关系构建更强大的把关程序。这种限制在III期临床试验中非常常见，并且所提出的方法适用于广泛的多重性问题。提供了几个例子来说明新方法，并给出了模拟试验结果，以比较使用该方法和其他可用方法推导的把关程序的性能。
