Division of Cardiac and Vascular Sciences, St George's, University of London, London, UK.
Drug Saf. 2010 Jan 1;33(1):1-14. doi: 10.2165/11319160-000000000-00000.
The International Conference on Harmonisation E14 Guidance was successful in largely standardizing the conduct of the so-called thorough QT/QTc studies (TQTS). Nevertheless, there is still a spectrum of frequently encountered problems with details of design, conduct and interpretation of TQTS. Several of these challenges are reviewed here, starting with explaining that the TQTS goal is only to identify drugs for which the proarrhythmic risk might be considered excluded for the purposes of regulatory benefit-risk assessment. Suggestions are made on how to categorize and quantify or exclude proarrhythmic risk if the TQTS is positive. There is a conceptual need for TQTS, and this is discussed, together with reasons why restricted clinical registries cannot prove the absence of proarrhythmic liability of any drug. Appropriate drug doses investigated in TQTS should be derived from the maximum clinically tolerable dose rather than from the known or expected therapeutic dose. With the help of concentration-QTc modelling, the standard therapeutic dose can be omitted from TQTS, especially if the study is expected to be negative. Conditions for single-dose TQTS acceptability are reviewed. The role of the so-called positive control is assessed, contrasting the role of a same-class comparator for the investigated drug. A single 400 mg dose of moxifloxacin is advocated as the present 'gold standard' assay sensitivity test. The necessity of careful placebo control is explained and the frequency of ECG assessments is considered. The central tendency and outlier analyses are discussed, together with the correct approaches to baseline adjustment. The review concludes that the design and interpretation of TQTS must not be approached with mechanistic stereotypes, and highlights the importance of relating the QTc changes to drug plasma levels.
《国际协调会议 E14 指导原则》成功地在很大程度上规范了所谓的全面 QT/QTc 研究（TQTS）的实施。然而，在 TQTS 的设计、实施和解释的细节方面，仍然存在一系列常见问题。本文从解释 TQTS 的目标仅是确定那些其致心律失常风险可能被认为排除在监管获益-风险评估之外的药物开始，回顾了其中的一些挑战。对于 TQTS 阳性的药物，提出了如何对致心律失常风险进行分类、量化或排除的建议。TQTS 具有概念上的必要性，本文对此进行了讨论，并讨论了为什么受限的临床登记册不能证明任何药物没有致心律失常的责任。TQTS 中研究的适当药物剂量应来自最大临床耐受剂量，而不是已知或预期的治疗剂量。借助浓度-QTc 建模，可以从 TQTS 中省略标准治疗剂量，特别是如果研究预计为阴性。本文回顾了单剂量 TQTS 可接受性的条件。评估了所谓阳性对照的作用，将其与所研究药物的同类比较药物的作用进行了对比。提倡使用单次 400 毫克莫西沙星剂量作为目前的“黄金标准”检测灵敏度测试。解释了仔细进行安慰剂对照的必要性，并考虑了 ECG 评估的频率。讨论了中心趋势和离群值分析，以及正确的基线调整方法。综述结论认为，TQTS 的设计和解释不能采用机械的刻板印象，强调必须将 QTc 变化与药物血浆水平联系起来。
