中心效应及中心间样本不均衡对临床疗效评价的影响

目的: 本文分析和探讨在多中心临床试验中,中心效应、中心与处理的交互作用以及各中心样本量不均衡对治疗效果评价的影响。方法: 以二分类资料两组比较为例,采用计算机模拟试验,分别探讨各中心10种不同样本分配比例、3种中心效应时,对临床疗效的检验效能及Ⅰ类错误的影响。结果: 在不存在中心效应,或有中心效应但中心与处理间无交互作用情况下,不同样本量的分配比例对检验效能的影响不大,Ⅰ类错误可控。当中心与处理间存在交互作用时,即使中心间样本量均衡,检验效能也有所下降,Ⅰ类错误亦增加,随着各中心样本均衡性变差,检验效能随之略有降低,I类错误亦随之少许增加。结论: 在多中心临床试验中,若中心与处理间存在交互作用,会对疗效评价有影响,而中心间样本均衡性对结果影响较小。在临床试验设计时应给予高度重视。

Influence of center effects and imbalanced sample sizes between centers on therapeutic evaluation in clinical trials

AIM: To evaluate the effects on the test power and type I error of center effect, treatment-by-center interaction and imbalanced sample sizes among centers in a multi-center clinical trials. METHODS: We focused on binary outcome and limited our study on the comparison of two groups. 60 scenarios (10 allocated proportions, 3 types of center effects with and without main effect of treatment) were considered. Using Monte-Carlo simulation studies, we estimated the test power or type I error in each scenario. RESULTS: When there was no central effect or no treatment-by-center interaction, the simulated powers were approximately equal to 0.80 and the type I errors were well controlled at 0.05 in various scenarios. The imbalance of sample sizes among centers had no affected on the power and type I error in these scenarios. However, when there was an interaction between treatments and centers, the power decreased, and the type I error inflated. The imbalance of sample sizes among centers slightly affected the power and type I error. CONCLUSION: In a multicenter clinical trial, the treatment-by-center interaction has a large effect on the test power and type I error, while the imbalance of sample sizes among center has no or only a limited effect. Therefore, we should pay more attention to the interaction between center and treatment in designing a multi-center clinical trial.