Abstract：
Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.
摘要：
在过去的十年中，随着技术的进步，药物开发的心脏安全监管指南经历了几次重大转变。分析模型和研究最佳实践改变了这一格局。有一次,一项专门的全面QT(TQT)研究几乎完全评估了一种新化学实体(NCE)的临床心律失常风险评估.然而,自从引入国际协调理事会（ICH）E14/S7BQ＆A5.1和6.1TQT替换以来，在健康志愿者的递增剂量研究中或在有动力的患者研究中，为药物开发者提供了评估心律失常风险的替代途径，分别。此外,研究结果以及进行非临床研究的方式(即，利用最佳实践）可以指示在临床研究中需要阳性对照和/或影响标记结果。药物赞助商现在面临着进行专门的TQT研究或要求TQT替代的选择。影响途径选择的潜在因素包括NCE作用机制，药代动力学特性，和安全概况，以及商业考虑。本教程将重点介绍综合心律失常风险预测模型的监管框架，以概述药物安全性，描述TQT替代请求可能被拒绝的潜在原因，并讨论何时推荐独立TQT。
