Dmitrienko Alexei, Offen Walter W, Westfall Peter H
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Stat Med. 2003 Aug 15;22(15):2387-400. doi: 10.1002/sim.1526.
In this paper we describe methods for addressing multiplicity issues arising in the analysis of clinical trials with multiple endpoints and/or multiple dose levels. Efficient 'gatekeeping strategies' for multiplicity problems of this kind are developed. One family of hypotheses (comprising the primary objectives) is treated as a 'gatekeeper', and the other family or families (comprising secondary and tertiary objectives) are tested only if one or more gatekeeper hypotheses have been rejected. We discuss methods for constructing gatekeeping testing procedures using weighted Bonferroni tests, weighted Simes tests, and weighted resampling-based tests, all within the closed testing framework. The new strategies are illustrated using an example from a clinical trial with co-primary endpoints, and using an example from a dose-finding study with multiple endpoints. Power comparisons with competing methods show the gatekeeping methods are more powerful when the primary objective of the trial must be met.
在本文中，我们描述了用于处理在具有多个终点和/或多个剂量水平的临床试验分析中出现的多重性问题的方法。针对此类多重性问题，开发了有效的“把关策略”。将一组假设（包括主要目标）视为“把关者”，只有在一个或多个把关者假设被拒绝时，才对另一组或多组假设（包括次要和三级目标）进行检验。我们讨论了在封闭检验框架内使用加权Bonferroni检验、加权Simes检验和基于加权重采样的检验来构建把关检验程序的方法。通过一个具有共同主要终点的临床试验实例以及一个具有多个终点的剂量探索研究实例，对新策略进行了说明。与其他竞争方法的功效比较表明，当试验的主要目标必须达成时，把关方法更具功效。
