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临床试验中的多重性考虑
Multiplicity Considerations in Clinical Trials


Alex Dmitrienko ... 其他 • 2018.05.31

临床试验中的多重性或采用多种比较,增加了偶然关联被视为因果关系的可能性。这个问题通常出现在有多个临床目标的临床试验中,这些临床目标基于对多个终点的评价或多剂量对照比较、对数个患者人群的评价和其他因素。在存在竞争性临床目标时,多重性考虑在疗效证据评估中起重要作用。进行的比较越多,看似显著的比较实际并非如此的可能性越高。

选择合适的统计学策略来处理多重性,对于在临床试验中进行可靠推断和最大限度地提高成功率至关重要。关于临床试验中出现的多重性问题,早期文章发表于20世纪60—90年代1-4。在临床试验文献中,这个主题引起了很大关注,自20世纪90年代以来,出现了许多新的统计学方法来进行多重性校正5,6

世界各地的监管机构已经认识到在确证性3期临床试验中处理多重性的重要性。对于支持新适应证的严格对照的临床试验,提出的要求包括预先设定适当的统计学方法用于控制Ⅰ类错误率(假阳性率,或错误地拒绝真实原假设的比例)。美国食品药品监督管理局(FDA)最近发布了关于处理临床试验中多个终点的全面指南7,欧洲药品管理局(EMA)也发布了临床试验中多重性问题的指南8,9

在这篇综述中,我们描述了临床试验中常见的多重性问题,以及旨在控制错误率的统计学方法(称为多重性校正)。我们还利用病例研究来说明推荐的方法。我们重点说明用于确定特定疗效声明的确证性3期试验。然而,多重性问题的适当处理在旨在产生假设的探索性试验(例如剂量探索2期试验)中也起重要作用。





作者信息

Alex Dmitrienko, Ph.D., and Ralph B. D’Agostino, Sr., Ph.D.
From Mediana, Overland Park, KS (A.D.); and Boston University, Boston (R.B.D.). Address reprint requests to Dr. Dmitrienko at alex.dmitrienko@gmail.com.

 

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