创新药早期临床试验中强化QT研究设计的实施要点及策略

Key points and strategies of intensive QT study design in early clinical trials of investigational new drugs

心脏安全性是创新药物研发中备受关注的问题,2005年人用药品注册技术要求国际协调会(ICH) E14指导原则要求对所有作用于人体的全身用新药进行全面QT研究。但标准的全面QT研究存在设计复杂和实施困难等问题,费时、费力、耗资巨大,另外,大量的健康受试者被暴露在阳性对照中无疑增加了安全性风险。鉴于这些局限性,2015年ICH E14更新版提出强化QT研究的概念。本文阐述了创新药物强化QT研究的设计要点包括样本量、剂量范围、心电采集和心电数据判定,提出在剂量设计、安全性指标设计、入排标准、设备和算法、分析用QT指标方面的注意事项和策略。

Cardiac safety is a major concern in the development of investigational new drugs(IND). In 2005, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH) E14 required a through QT(TQT) study in all IND for systematic administration. However, the standard TQT study with characteristics of complicated design and difficult implementation is time-consuming, laborious and expensive. In addition, a large number of healthy subjects exposed to positive control increase the safety risk undoubtedly. In view of the limitations of TQT, the updated version of ICH E14 proposed the concept of intensive QT(IQT) research in 2015. In this paper, the design points of IQT research including sample size, dose range, electrocardiogram acquisition and data determination were summarized, and the precautions and strategies in dose design, safety index design, entry and discharge standards, equipment and algorithm, and QT indicators for analysis were proposed.