从非临床到临床心律失常风险阶段评估体系研究进展

Advances in risk assessment systems from non-clinical to clinical arrhythmia stages

药物致心律失常风险产生严重不良反应而被撤市是监管当局近年来关注的焦点问题。2005年国际人用药品注册技术协调会(ICH)发布了心律失常风险评价的临床前S7B和临床E14指南作为通用评价标准,前者包括体外hERG(human ether-a-go-go-related gene)实验和基于动物体内的QT研究,后者为人体全面QT研究(thorough QT study,TQT研究)。由于TQT成本高昂且结果保守使得引入新的替代方法成为指南修订的方向。E14指南于2015年基于PK/PD的理念引入了浓度-QT分析(concentration-QTc,C-QTc),通过充分利用高质量非临床阶段的双阴性数据(在基于高临床暴露下的体外hERG试验阴性和体内QTc延长的风险阴性)使得TQT替代研究成为可能。本文梳理了E14的发展修订历程及最新进展,然后通过案例分析描述TQT替代研究的各种场景,介绍了非临床-临床心律失常风险评估流程,以期为中国的心律失常风险评价体系提供借鉴。

The withdrawal of drugs from the market due to serious adverse reactions arising from the risk of cardiac arrhythmia has been a major concern for regulatory authorities in recent years.In 2005,the International Council for the Harmonisation of Registration of Medicinal Products for Human Use(ICH)issued preclinical S7B and clinical E14 guidelines for the evaluation of arrhythmia risk.The former includes in vitro hERG experiments and in vivo animal-based QT studies,while the latter is the TQT study(thorough QT study,TQT study).The high cost and conservative results of TQT studies have led to the introduction of new alternative methods,and the E14 guidelines were revised in 2015 and introduced concentration-QT analysis(C-QTc),based on the PK/PD(pharmacokinetics/pharmacodynamics)concept,by making full use of high-quality double-negative data from the non-clinical phase(double-negative,low risk of hERG tests at high clinical exposure,and low risk of QTc prolongation in vivo QTc study)makes it possible to substitute TQT studies based on specific situations.This article reviews the history of the development of E14 and its latest developments,analyses the specific situations in which C-QT can replace TQT studies through case studies,introduces the preclinical-clinical arrhythmia risk stage assessment system and compares the drug assessment process and decision making under different versions of E14 guidelines,with a view to providing a reference for the arrhythmia risk assessment system in China.