ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis.
ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis.
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DOI：
10.1517/14740338.4.3.509
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发表时间：
2005-05-01
影响因子：
3.1
通讯作者：
Crumb, William
中科院分区：
文献类型：
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作者：
Cavero, Icilio;Crumb, William
人用药品注册技术要求国际协调会议（ICH）是由三个主要的世界合作伙伴（日本、美国和欧洲共同体）发起的，他们共同制定了一套相互接受的法规，涉及新药获得市场批准必须满足的安全性、质量和有效性要求。该组织已经编写的非临床安全药理学文件包括两个指导原则：2000年采用的S7A和2001年以来以草案形式采用的S7B指导原则。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诱导的不良反应。S7B建议采用一般非临床试验策略，以确定非心血管药物延迟心室复极的倾向，这种影响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，该战略提出了实验性分析和对其他相关信息的严格审查，以将“风险证据”标签应用于化合物。令人遗憾的是，该指南未能令人满意地处理一些关键问题，例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依赖于目前正在编写的新ICH指导原则E14。E14是S7B指南的临床对应物，该指南指出非临床数据是人体药物诱导复极延迟的不良预测因素。本文总结和评估了S7A指南的主要方面，因为其基本原则也适用于S7B指南。后一份文件的各种现有草案提出的战略的差异进行了严格审查，一些悬而未决的，关键的问题。有必要扩展S7B文件的目的，以验证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准则最后版本方面的困难，专家工作组可以考虑按照最初的意图在S7A文件中引入S7B准则建议，或者推迟通过统一的文本，直到获得新的科学数据，从而能够解决该准则和E14准则目前有争议的方面。
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.