Carbon Biosciences, Lexington, Massachusetts, USA.
Boehringer Ingelheim, Ridgefield, Connecticut, USA.
Hum Gene Ther. 2022 Nov;33(21-22):1126-1141. doi: 10.1089/hum.2022.090. Epub 2022 Sep 14.
The nonclinical safety assessments for gene therapies are evolving, leveraging over 20 years of experimental and clinical experience. Despite the growing experience with these therapeutics, there are no approved harmonized global regulatory documents for developing gene therapies with only the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) S12 guidance on nonclinical biodistribution currently under discussion. Several health authorities have issued guidance over the last 15 years on the nonclinical safety aspects for gene therapy products, but many of the recommendations are limited to high-level concepts on nonclinical safety aspects or altogether silent on key topics. Historically, this approach was appropriately vague given our relatively small dataset of nonclinical experience, where a comprehensive and detailed regulatory guidance approach was unlikely to be appropriate to address all scenarios. However, harmonization of key considerations and assumptions can provide a consistent basis for developing the appropriate nonclinical safety development plans for individual programs, reducing uncertainty across regulatory regions and unnecessary animal use. Several key areas of nonclinical safety testing are nearing maturation for a harmonized approach, including species selection, certain aspects of study design, study duration, and unintended genomic integration risks. Furthermore, several emerging topics are unaddressed in current regulatory guidance for gene therapy products, which will become key areas of differentiation for the next generation of therapeutics. These topics include redosing, juvenile/pediatric safety, and reproductive/developmental safety testing, where relevant experience from other modalities can be applied. The rationale and potential study design considerations for these topics will be proposed, acknowledging that certain aspects of gene therapy development are not considered appropriate for harmonization. This article provides an overview of the current nonclinical safety regulatory landscape, summarizes typical nonclinical safety study designs, highlights areas of uncertainty, and discusses emerging topics that warrant consideration. Specific recommendations and perspectives are provided to inform future regulatory discussions and harmonization efforts.
基因治疗的非临床安全性评估正在发展，借鉴了 20 多年的实验和临床经验。尽管这些治疗方法的经验越来越丰富，但目前只有 ICH（人用药物技术要求国际协调理事会）S12 指南正在讨论中，尚无针对基因治疗开发的批准的全球统一监管文件。过去 15 年来，有几个卫生当局就基因治疗产品的非临床安全性方面发布了指南，但许多建议仅限于非临床安全性方面的高级概念，或者对关键主题完全保持沉默。从历史上看，鉴于我们相对较少的非临床经验数据集，这种方法是适当模糊的，在这种情况下，全面和详细的监管指导方法不太可能适合解决所有情况。然而，关键考虑因素和假设的协调可以为制定个别项目的适当非临床安全性开发计划提供一致的基础，减少监管区域之间的不确定性和不必要的动物使用。几个非临床安全性测试的关键领域正在接近协调一致的方法，包括物种选择、研究设计的某些方面、研究持续时间和意外基因组整合风险。此外，当前基因治疗产品的监管指南中没有涉及几个新出现的主题，这些主题将成为下一代治疗方法的关键区别点。这些主题包括再给药、青少年/儿科安全性和生殖/发育安全性测试，其他模式的相关经验可以应用于这些领域。本文将对当前非临床安全性监管格局进行概述，总结典型的非临床安全性研究设计，突出不确定性领域，并讨论需要考虑的新出现的主题。具体建议和观点将为未来的监管讨论和协调努力提供信息。
