Hierarchical testing of multiple endpoints in group-sequential trials
Hierarchical testing of multiple endpoints in group-sequential trials
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DOI：
10.1002/sim.3748
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发表时间：
2010-01-30
影响因子：
2
通讯作者：
Bretz, Frank
中科院分区：
文献类型：
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作者：
Glimm, Ekkehard;Maurer, Willi;Bretz, Frank
我们考虑在主要由主要终点驱动的组序贯临床试验中分层检验（关键）次要终点的情况。“主要驱动”是指计划在主要终点累积一定数量的患者或事件的时间点进行中期分析，试验将运行至其中一次中期分析达到主要终点的统计学显著性或最终分析。我们既考虑了主要终点显著时立即停止试验的情况，也考虑了主要终点显著后继续试验以进一步研究次要终点的情况。此外，我们研究了如何实现强大的控制familywise错误率（FWER）在预先指定的显着性水平α的主要和次要假设。我们系统地探讨了各种多样性调整方法。起始点是一种初始策略，即当主要终点显著时，在α水平检验次要终点。Hung等人（J. Biopharm. Stat. 2007; 17：1201-1210）已经表明，这种幼稚策略不能将FWER维持在α水平。我们推导出朴素策略中次要终点的拒绝概率的精确上限。这表明了许多多重测试策略，并提供了一个基准，用于决定一种方法是保守的还是可以在保持FWER α的同时进行改进。我们使用一个基于真实的案例研究的数值例子来说明不同层次测试策略的结果。版权所有（C）2009约翰威利父子有限公司
We consider the situation of testing hierarchically a (key) secondary endpoint in a group-sequential clinical trial that is mainly driven by a primary endpoint. By 'mainly driven', we mean that the interim analyses are planned at points in time where a certain number of patients or events have accrued on the primary endpoint, and the trial will run either until statistical significance of the primary endpoint is achieved at one of the interim analyses or to the final analysis. We consider both the situation where the trial is stopped as soon as the primary endpoint is significant as well as the situation where it is continued after primary endpoint significance to further investigate the secondary endpoint. In addition, we investigate how to achieve strong control of the familywise error rate (FWER) at a pre-specified significance level alpha for both the primary and the secondary hypotheses. We systematically explore various multiplicity adjustment methods. Starting point is a naive strategy of testing the secondary endpoint at level alpha whenever the primary endpoint is significant. Hung et al. (J. Biopharm. Stat. 2007; 17:1201-1210) have already shown that this naive strategy does not maintain the FWER at level alpha. We derive a sharp upper bound for the rejection probability of the secondary endpoint in the naive strategy. This suggests a number of multiple test strategies and also provides a benchmark for deciding whether a method is conservative or might be improved while maintaining the FWER at alpha. We use a numerical example based on a real case study to illustrate the results of different hierarchical test strategies. Copyright (C) 2009 John Wiley & Sons, Ltd.