Cavero Icilio, Crumb William
Expert Opin Drug Saf. 2005 May;4(3):509-30. doi: 10.1517/14740338.4.3.509.
The International Conference on Harmonization (ICH) stems from the initiative of three major world partners (Japan, USA, European Community) who composed a mutually accepted body of regulations concerning the safety, quality and efficacy requirements that new medicines have to meet in order to receive market approval. Documents on non-clinical safety pharmacology already composed by this organisation include two guidelines: the S7A adopted in 2000 and, its companion, the S7B guideline, in a draft form since 2001. The S7A guideline deals with general principles and recommendations on safety pharmacology studies designed to protect healthy volunteers and patients from potential drug-induced adverse reactions. The S7B recommends a general non-clinical testing strategy for determining the propensity of non-cardiovascular pharmaceuticals to delay ventricular repolarisation, an effect that at times progresses into life-threatening ventricular arrhythmia. In the most recent version of this document (June 2004), the strategy proposes experimental assays and a critical examination of other pertinent information for applying an 'evidence of risk' label to a compound. Regrettably, the guideline fails to deal satisfactorily with a number of crucial issues such as scoring the evidence of risk and the clinical consequences of such scoring. However, in the latter case, the S7B relies on the new ICH guideline E14 which is currently in preparation. E14 is the clinical counterpart of the S7B guideline which states that non-clinical data are a poor predictor of drug-induced repolarisation delay in humans. The present contribution summarises and assesses salient aspects of the S7A guideline as its founding principles are also applicable to the S7B guideline. The differences in strategies proposed by the various existing drafts of the latter document are critically examined together with some unresolved, crucial problems. The need for extending the objective of the S7B document to characterise the full electrophysiological profile of new pharmaceuticals is argued as this approach would more extensively assess the non-clinical cardiac safety of a drug. Finally, in order to overcome present difficulties in arriving at the definitive version of the S7B guideline, the Expert Working Group could reflect on the introduction of the S7B guideline recommendations in the S7A document, as originally intended, or on postponing the adoption of an harmonized text until the availability of novel scientific data allows solving presently contentious aspects of this and the E14 guidelines.
国际协调会议（ICH）源自世界三大主要合作伙伴（日本、美国、欧洲共同体）的倡议，他们制定了一套相互认可的法规，涉及新药为获得市场批准必须满足的安全性、质量和有效性要求。该组织已经制定的关于非临床安全药理学的文件包括两项指南：2000年采用的S7A指南，以及自2001年以来以草案形式存在的其配套指南S7B。S7A指南涉及安全药理学研究的一般原则和建议，旨在保护健康志愿者和患者免受潜在药物引起的不良反应。S7B建议采用一种一般的非临床测试策略，以确定非心血管药物延迟心室复极的倾向，这种效应有时会发展为危及生命的室性心律失常。在该文件的最新版本（2004年6月）中，该策略提出了实验分析方法，并对其他相关信息进行批判性审查，以便为化合物贴上“风险证据”标签。遗憾的是，该指南未能令人满意地处理一些关键问题，如对风险证据进行评分以及这种评分的临床后果。然而，在后一种情况下，S7B依赖于目前正在制定的新的ICH指南E14。E14是S7B指南的临床对应指南，该指南指出非临床数据对人类药物诱导复极延迟的预测性较差。本论文总结并评估了S7A指南的显著方面，因为其基本原则也适用于S7B指南。对后一文件现有各草案提出的策略差异进行了批判性审查，并探讨了一些未解决的关键问题。有人认为需要扩展S7B文件的目标，以描述新药的完整电生理特征，因为这种方法将更广泛地评估药物的非临床心脏安全性。最后，为了克服目前在达成S7B指南最终版本方面的困难，专家工作组可以考虑按最初设想将S7B指南的建议纳入S7A文件，或者推迟采用统一文本，直到有新的科学数据能够解决该指南和E14指南目前有争议的方面。
