Cavero Icilio, Crumb William
Expert Opin Drug Saf. 2006 Mar;5(2):335-40. doi: 10.1517/14740338.5.2.335.
The Health and Environmental Sciences Institute (HESI) convened a two-day workshop to explore the biological mechanisms responsible for inherited, acquired and induced long QT interval syndromes. Investigational areas included QT dynamics, cell biology, nonclinical models of Torsade de Pointes (TdP) arrhythmia as well as how to ascertain the predictability of such models for human outcome were discussed. Magisterial lectures from academia covered state-of-science knowledge on these domains, whereas industry and regulatory authority representatives dealt with the advantages, disadvantages and desirable requisites of nonclinical assays to assess drug-associated cardiac safety. Proposals for future research projects were not sufficiently factual to allow discrimination between pragmatic and ideal solutions. A key objective of the workshop was to foster initiatives addressing development of nonclinical proarrhythmic models for identifying without failure drug candidates with the potential to cause threshold QT interval increases of regulatory concern (5-10 ms) in healthy volunteers and a TdP event in 1/10(5)-10(7) patients. In the authors' opinion, fulfilling this goal (an FDA prerequisite for abrogating E14 'thorough QT study' requirement) pertains more to a Faustian quest than to a realistic, nonclinical safety pharmacology assignment. Indeed, biological assays are, by nature, characterised by an implicit degree of uncertainty, contradicting the precautionary principle of zero error expectancy. For the moment, relatively successful strategies should rely on expertly designed and executed S7B core assays, complemented as needed, by reliable proarrhythmia tests. These studies should be preceded, when available, by application of powerful in silico fingerprint technology mining databases containing pertinent public and proprietary (liberally released) cardiac safety information on reference, marketed, withdrawn and failed drugs.
健康与环境科学研究所（HESI）召开了一次为期两天的研讨会，以探讨导致遗传性、获得性和诱发性长QT间期综合征的生物学机制。研究领域包括QT动态、细胞生物学、尖端扭转型室速（TdP）心律失常的非临床模型，以及如何确定此类模型对人类结果的可预测性。学术界的权威讲座涵盖了这些领域的科学现状知识，而行业和监管机构代表则讨论了评估药物相关心脏安全性的非临床试验的优缺点和理想要求。未来研究项目的提案缺乏足够的事实依据，无法区分务实和理想的解决方案。该研讨会的一个关键目标是推动各项举措，以开发非临床促心律失常模型，从而准确识别出有可能在健康志愿者中导致QT间期增加达到监管关注阈值（5-10毫秒）且在1/10⁵-10⁷患者中引发TdP事件的药物候选物。在作者看来，实现这一目标（这是美国食品药品监督管理局取消E14“全面QT研究”要求的前提条件）更像是一种浮士德式的追求，而非现实的非临床安全药理学任务。事实上，生物学试验本质上具有一定程度的不确定性，这与零误差预期的预防原则相矛盾。目前，相对成功的策略应依赖精心设计和执行的S7B核心试验，并在需要时辅以可靠的促心律失常试验。在进行这些研究之前，如果有可用的强大计算机模拟指纹技术，应先应用该技术挖掘包含有关参考药物、上市药物、撤市药物和失败药物的相关公共和专有（自由发布）心脏安全信息的数据库。
