PDF(Pubmed)
Abstract：
Introduction: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline \"Testing for Carcinogenicity of Pharmaceuticals\". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported. It was postulated that these factors could be evaluated in a Weight-of-Evidence (WoE) approach to predict the outcome of a 2-year rat study. Methods: The ICH S1B(R1) Expert Working Group (EWG) conducted a Prospective Evaluation Study (PES) to determine the regulatory feasibility of this WoE approach. Drug Regulatory Authorities (DRAs) evaluated 49 Carcinogenicity Assessment Documents (CADs), which describe the WoE for submitted pharmaceutical compounds. Each compound was categorized into a carcinogenic risk category including a statement of the value of the 2-year rat study. The outcome of the completed 2-year rat studies was evaluated in relation to the prospective CAD to determine the accuracy of predictions. Results: Based on the results of the PES, the EWG concluded that the evaluation process for assessing human carcinogenic risk of pharmaceuticals described in ICH S1B could be expanded to include a WoE approach. Approximately 27% of 2-year rat studies could be avoided in cases where DRAs and sponsors unanimously agreed that such a study would not add value. Discussion: Key factors supporting a WoE assessment were identified: data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the parent compound and major human metabolites; results from secondary pharmacology screens for this compound and major human metabolites that inform carcinogenic risk; histopathology data from repeated-dose toxicity studies; evidence for hormonal perturbation; genotoxicity data; and evidence of immune modulation. The outcome of the PES indicates that a WoE approach can be used in place of conducting a 2-year rat study for some pharmaceuticals. These data were used by the ICH S1B(R1) EWG to write the R1 Addendum to the S1B Guideline published in August 2022.
摘要：
简介：国际人用药品技术要求协调理事会（ICH）于2012年启动了一项程序，以修订S1B指南“药品致癌性测试”。先前的回顾性分析表明，组织病理学危险因素在慢性毒性研究中的重要性，内分泌干扰的证据，和积极的遗传毒理学结果作为致癌风险的潜在预测指标。此外,已经报道了长期啮齿动物研究中药效学活性与致癌性结果之间的关系.据推测，这些因素可以通过证据权重（WoE）方法进行评估，以预测2年大鼠研究的结果。方法：ICHS1B（R1）专家工作组（EWG）进行了一项前瞻性评估研究（PES），以确定该WoE方法的监管可行性。药品监管机构（DRA）评估了49份致癌性评估文件（CADs），其中描述了提交的药物化合物的WoE。每种化合物都被归类为致癌风险类别，包括2年大鼠研究价值的陈述。评估已完成的2年大鼠研究的结果与前瞻性CAD相关，以确定预测的准确性。结果：根据PES的结果，EWG的结论是,ICHS1B中描述的评估药物人类致癌风险的评估过程可以扩展到包括WoE方法.在DRA和赞助商一致同意这样的研究不会增加价值的情况下，可以避免大约27％的2年大鼠研究。讨论：确定了支持WoE评估的关键因素：基于药物靶标生物学以及母体化合物和主要人类代谢产物的主要药理机制的数据告知致癌潜力；该化合物和主要人类代谢产物的二级药理学筛选结果告知致癌风险；来自重复剂量毒性研究的组织病理学数据；激素扰动的证据；遗传毒性数据；以及免疫调节的证据。PES的结果表明，可以使用WoE方法代替对某些药物进行为期2年的大鼠研究。这些数据被ICHS1B(R1)EWG用于编写2022年8月发布的S1B指南的R1附录。
