Xue Hongqi, Ferber Georg, Freebern Ellen, Darpo Borje
Sr. Principal Biostatistician, Clario, 1818 Market St, Suite 2600, Philadelphia, 19103, PA, USA.
Statistik Georg Ferber GmbH, Riehen, Switzerland.
J Pharmacokinet Pharmacodyn. 2025 Aug 28;52(5):48. doi: 10.1007/s10928-025-09998-z.
Concentration-QTc (C-QTc) analysis was accepted to serve as an alternative to the by-time point analysis with intersection-union test (IUT) as the primary basis for decisions to classify the arrhythmogenic risk of a drug by ICH E14 Q&As (R3) in December 2015. Since then, this analysis method has been widely applied by industry as it significantly reduces the sample size to achieve the same power as with IUT. There are many model-based power calculation approaches available for C-QTc through simulation in the literature, however, there is still no standard method with a clear formula to determine the sample size for C-QTc analysis to exclude a small effect on the QTc interval. The current model-based simulation approaches are too complicated to prevent them from being widely used, which is not commensurate with the popular status. We have developed a systematic method based on t-tests to determine the sample size for different study designs using the C-QTc analysis method and applied it to many studies. The results of the sample sizes utilizing this method are consistent with simulation studies and validated by real analyses.
浓度-校正QT间期（C-QTc）分析被认可作为时间点分析的替代方法，2015年12月的《国际人用药品注册技术协调会（ICH）E14问答（R3）》将交叉并集检验（IUT）作为通过药物致心律失常风险分类决策的主要依据。从那时起，这种分析方法已被制药行业广泛应用，因为它能显著减少样本量，同时达到与IUT相同的检验效能。目前在文献中有许多基于模型的通过模拟进行C-QTc效能计算的方法，然而，对于C-QTc分析，仍没有一个带有明确公式的标准方法来确定样本量，以排除对QT间期的微小影响。当前基于模型的模拟方法过于复杂，难以广泛应用，这与它的普遍应用地位不相称。我们已经开发出一种基于t检验的系统方法，用于使用C-QTc分析方法为不同研究设计确定样本量，并将其应用于许多研究中。利用该方法得出的样本量结果与模拟研究一致，并通过实际分析得到了验证。
