Wang Sue-Jane, James Hung H M, O'Neill Robert T
OTS/CDER, US FDA, Silver Spring, MD 20993-0002, USA.
Biom J. 2010 Dec;52(6):798-810. doi: 10.1002/bimj.200900207.
A two-stage adaptive design trial is a single trial that combines the learning data from stage 1 (or phase II) and the confirming data in stage 2 (or phase III) for formal statistical testing. We call it a "Learn and Confirm" trial. The studywise type I error rate remains to be at issue in a "Learn and Confirm" trial. For studying multiple doses or multiple enpdoints, a "Learn and Confirm" adaptive design can be more attractive than a fixed design approach. This is because intuitively the learning data in stage 1 should not be subjected to type I error scrutiny if there is no formal interim analysis performed and only an adaptive selection of design parameters is made at stage 1. In this work, we conclude from extensive simulation studies that the intuition is most often misleading. That is, regardless of whether or not there is a formal interim analysis for making an adaptive selection, the type I error rates are always at risk of inflation. Inappropriate use of any "Learn and Confirm" strategy should not be overlooked.
两阶段适应性设计试验是一种单一试验，它将来自第1阶段（或II期）的学习数据与第2阶段（或III期）的确认数据结合起来进行正式的统计检验。我们将其称为“学习与确认”试验。在“学习与确认”试验中，全研究的I型错误率仍然是一个问题。对于研究多种剂量或多个终点，“学习与确认”适应性设计可能比固定设计方法更具吸引力。这是因为直观地讲，如果在第1阶段没有进行正式的中期分析，而只是对设计参数进行适应性选择，那么第1阶段的学习数据不应受到I型错误审查。在这项工作中，我们从广泛的模拟研究中得出结论，这种直觉往往具有误导性。也就是说，无论是否进行正式的中期分析以进行适应性选择，I型错误率始终存在膨胀的风险。任何“学习与确认”策略的不当使用都不应被忽视。
