ICH S5(R3)药物生殖毒性研究指导原则草案的新技术要求及其挑战

Introduction to the new technical requirements and challenges of the draft ICH S5(R3) guideline on reproductive toxicity for human pharmaceuticals

生殖毒性研究是药物非临床安全性评价的重要内容。国际人用药品注册技术协调会(ICH)S5药物生殖毒性指导原则已有20多年,基于科学、技术和监管的知识和认识的变化,以及对生殖毒性试验方法不断的经验积累,ICH于2017年7月公布了其修订版本S5(R3)的草案(征求意见稿)。本文首先介绍了S5(R3)草案新增或更新的主要内容,包括明确了适用范围、整体试验策略的新思路、替代试验方法及其他试验系统、兼顾与其他指导原则的一致性、剂量选择的新要求、疫苗的特殊考虑、体内试验的方法设计上的更新、联合试验设计新思路、人体风险评估的理念等等。然后结合国内研究现状,探讨了该指导原则新技术要求对申请人/研究者以及药品审评人员/机构所带来的新挑战,主要包括试验策略、技术方法以及风险评估的挑战。

The study of reproductive toxicity is one of important components of non-clinical safety studies for pharmaceuticals. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use（ ICH） S5 Guideline on Reproductive Toxicity was issued over 20 years ago. Based on the changes in scientific,technological and regulatory knowledges and the continuous accumulation of experience in reproductive toxicity testing methods,ICH released a draft of its revised version of S5（ R3） in July 2017 for public consultation.In this article,the main updated contents of S5（ R3） draft were firstly introduced,including clarified scope of application,new ideas for overall testing strategies,alternative test methods and other test systems,consistency with other guidelines,new requirements for dose selection,special considerations for vaccines,design updates for routine tests in vivo,new design ideas of combination of experiments,and concept of human risk assessment,etc.Furthermore,combined with the domestic research status,the new challenges for sponsors/researchers and drug reviewers/institution from new technology requirements of S5（ R3） were discussed,which mainly included the challenges from test strategies,technical methods,and risk assessment.