Duchateau Luc, Janssen Paul
Department of Physiology, Biochemistry and Biometrics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
Stat Med. 2005 May 30;24(10):1525-36. doi: 10.1002/sim.2048.
Before an active compound can be registered as a drug, it needs to be demonstrated that it does not cause particular unwanted compound specific side effects. Demonstrating non-inferiority of an active drug with placebo with respect to an unwanted side effect is often based on pharmacodynamic 3 x 3 cross-over trials, with the third treatment arm consisting of a positive control. The main comparison then is the pairwise comparison between active drug and placebo. In this paper, two different non-parametric methods with adjustment for period effect are compared with the non-parametric non-adjusted test and the parametric period-adjusted test with respect to size and power. The non-parametric test with period adjustment based on rank alignment has generally the largest power, but its size exceeds the nominal significance level. The non-parametric test with period adjustment based on stratification has low power for trials with a small number of subjects. The non-parametric test without period adjustment is a valid alternative in such cases, but its power decreases substantially in the presence of period effects. In the case of unbalanced designs, however, only the non-parametric test with period adjustment based on stratification can be used.
在一种活性化合物能够作为药物注册之前，需要证明它不会引起特定的、不良的化合物特异性副作用。证明活性药物与安慰剂在不良副作用方面的非劣效性通常基于药效学的3×3交叉试验，第三个治疗组由阳性对照组成。然后主要的比较是活性药物与安慰剂之间的成对比较。在本文中，将两种针对周期效应进行调整的不同非参数方法与非参数未调整检验以及参数化周期调整检验在检验效能和检验大小方面进行了比较。基于秩对齐进行周期调整的非参数检验通常具有最大的检验效能，但其检验大小超过了名义显著性水平。基于分层进行周期调整的非参数检验对于受试者数量较少的试验检验效能较低。在这种情况下，未进行周期调整的非参数检验是一种有效的替代方法，但其检验效能在存在周期效应时会大幅下降。然而，在设计不平衡的情况下，只能使用基于分层进行周期调整的非参数检验。
