G.S. Friedrichs , M.M. Abernathy , D. Ackley , M. Clark , J.K. DaSilva , C.M. Foley , A. Greiter-Wilke , K.A Henderson , J.J. Kremer , B.H. Morimoto , S. Paglialunga , M.K. Pugsley , C.P. Regan , E.I. Rossman , J.A. Segretti , M. Traebert , H.M. Vargas , T.A. Wisialowski
{"title":"重新评估 ICH S7A 核心电池中的安全药理学呼吸研究:临床前实用性和临床转化的多公司评估。","authors":"G.S. Friedrichs , M.M. Abernathy , D. Ackley , M. Clark , J.K. DaSilva , C.M. Foley , A. Greiter-Wilke , K.A Henderson , J.J. Kremer , B.H. Morimoto , S. Paglialunga , M.K. Pugsley , C.P. Regan , E.I. Rossman , J.A. Segretti , M. Traebert , H.M. Vargas , T.A. Wisialowski","doi":"10.1016/j.yrtph.2024.105706","DOIUrl":null,"url":null,"abstract":"<div><div>Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were ‘positive’ preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. 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引用次数: 0
摘要
优化 ICH 安全性指南研究以纳入监管申请对于节约资源、减少动物使用和高效药物开发至关重要。2001 年通过的 ICH S7A 安全药理学(SP)研究指南确定了在首次人体试验(FIH)之前评估潜在药物分子急性安全性的核心研究系列。为了评估呼吸系统研究在预测临床 AE 方面的效用,七家制药公司汇集了临床前和临床呼吸系统研究结果。新型分子的大型数据库包括标准 S7A 呼吸系统研究(n = 459)和 FIH 研究(n = 309)的所有相关数据。分析数据涉及这些分子的进展、这些分子的临床不良事件报告以及达到的暴露量。这些 S7A 呼吸检测结果对化合物的进展没有影响,309 种候选药物中只有 12 种在临床前呈 "阳性",并在临床试验中报告了呼吸相关的 AE(如咳嗽、呼吸困难等),总发生率为 3.9%。或然率表/统计数据表明这些临床前检测结果缺乏一致性。总之,我们的大量分析清楚地表明,临床前呼吸测定无法为检测临床相关的呼吸不良事件提供任何预后价值。
Reevaluating safety pharmacology respiratory studies within the ICH S7A core battery: A multi-company evaluation of preclinical utility and clinical translation
Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were ‘positive’ preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. Overall, our extensive analysis clearly indicated that the preclinical respiratory assay fails to provide any prognostic value for detecting clinically relevant respiratory adverse events.
期刊介绍:
Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health.
Types of peer-reviewed articles published:
-Original research articles of relevance for regulatory aspects covering aspects including, but not limited to:
1.Factors influencing human sensitivity
2.Exposure science related to risk assessment
3.Alternative toxicological test methods
4.Frameworks for evaluation and integration of data in regulatory evaluations
5.Harmonization across regulatory agencies
6.Read-across methods and evaluations
-Contemporary Reviews on policy related Research issues
-Letters to the Editor
-Guest Editorials (by Invitation)