Mielke Matthias, Munk A, Schacht A
Institut für Mathematische Stochastik, Georg-August-Universität Göttingen, Maschmühlenweg 8-10, D-37073 Göttingen, Germany.
Stat Med. 2008 Nov 10;27(25):5093-110. doi: 10.1002/sim.3348.
The objective of this paper is to develop statistical methodology for non-inferiority hypotheses to censored, exponentially distributed time to event endpoints. Motivated by a recent clinical trial in depression, we consider a gold standard design where a test group is compared with an active reference and with a placebo group. The test problem is formulated in terms of a retention of effect hypothesis. Thus, the proposed Wald-type test procedure assures that the effect of the test group is better than a pre-specified proportion Delta of the treatment effect of the reference group compared with the placebo group. A sample size allocation rule to achieve optimal power is presented, which only depends on the pre-specified Delta and the probabilities for the occurrence of censoring. In addition, a pretest is presented for either the reference or the test group to ensure assay sensitivity in the complete test procedure. The actual type I error and the sample size formula of the proposed tests are explored asymptotically by means of a simulation study showing good small sample characteristics. To illustrate the procedure a randomized, double blind clinical trial in depression is evaluated. An R-package for implementation of the proposed tests and for sample size determination accompanies this paper on the author's web page.
本文的目的是开发针对删失的指数分布事件发生时间终点的非劣效性假设的统计方法。受最近一项抑郁症临床试验的启发，我们考虑一种金标准设计，即将一个试验组与一个活性对照组以及一个安慰剂组进行比较。检验问题是根据效应保留假设来制定的。因此，所提出的 Wald 型检验程序确保试验组的效应优于对照组与安慰剂组相比治疗效应的预先指定比例 Delta。提出了一种实现最优检验效能的样本量分配规则，该规则仅取决于预先指定的 Delta 和删失发生的概率。此外，还针对对照组或试验组提出了一个预检验，以确保整个检验过程中的分析灵敏度。通过模拟研究渐近地探索了所提出检验的实际一类错误和样本量公式，结果显示出良好的小样本特性。为说明该程序，对一项抑郁症的随机双盲临床试验进行了评估。作者网页上随附了一个用于实施所提出检验和确定样本量的 R 包。
