Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium
Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium
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DOI：
10.1016/j.ahj.2013.11.004
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发表时间：
2014-03-01
影响因子：
4.8
通讯作者：
Stockbridge, Norman
中科院分区：
文献类型：
--
作者：
Sager, Philip T.;Gintant, Gary;Stockbridge, Norman
这篇白色论文总结了心脏安全研究联盟/健康与环境科学研究所/美国食品药品监督管理局赞助的智囊团于2013年7月23日在美国食品药品监督管理局银泉白色橡树设施举行的科学提案。目的是在定义心脏安全性领域的新范式方面达成共识，在该领域中，主要使用非临床体外试验评估预防风险。基于尖端扭转型室性心动过速致心律失常的可靠机制考虑的人体模型。这种新的范式将重点从目前的方法转移，该方法强烈依赖于QTc延长（致心律失常的替代标志物），并可能在后期药物开发期间重新进行临床全面QT研究。这些讨论代表了当前的想法和建议，以促进我们对公共卫生案例的了解和理解，采用一种新的、综合的非临床体外/计算机模拟范例，即综合体外致心律失常试验，评估候选药物的致心律失常责任，并制定一个公私合作计划，以表征数据内容、质量、以及在缺乏全面QT研究的情况下评估预防性风险所需的方法。本文旨在鼓励多方利益相关者就该倡议提出意见，但不代表监管指南。
This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration-sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.