Incubation Center for Advanced Medical Science, Kyushu University, Fukuoka, Japan.
Incubation Center for Advanced Medical Science, Kyushu University, Fukuoka, Japan.
Clin Ther. 2018 Nov;40(11):1813-1822. doi: 10.1016/j.clinthera.2018.09.007. Epub 2018 Oct 24.
Advances in methods designed to evaluate preclinical toxicity have not kept up with progress in regenerative medicine. Preclinical toxicity studies of regenerative therapies must be designed logically and should be flexible to accurately reflect toxicity of products under development. The purpose of this review is to discuss requirements of preclinical toxicity studies of this type developed in Japan.
We conducted MEDLINE and PubMed literature searches to identify recent reports relevant to regenerative medicine. Information regarding approved drugs and public announcements, including existing guidelines and guidance in Japan, was collected from the website of Japan's Ministry of Health, Labor and Welfare (https://www.mhlw.go.jp/index.html) and the Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp/).
Four cell therapy products have been developed and approved in Japan so far. The principal preclinical toxicity data submitted to regulatory authorities in the Pharmaceuticals and Medical Devices Agency in Japan are summarized here. The potential for tumor formation, a major concern in such clinical applications, is assessed in 3 ways: tumor-forming capacity of the original cell, quantitation of residual pluripotent stem cells in the product, and the possibility that a tumor will form at the product's engraftment site. Although gene therapy and oncolytic virus products are under development, these types of products are not yet approved in Japan. Guidelines relevant to the development of these products are now being created based on existing guidelines and considerations established by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.
Because of cell tropism and heterologous immunity, animal species or strains useful for preclinical studies of regenerative therapies are often restricted. Nonetheless, preclinical toxicity studies must be designed to predict results relevant to humans.
旨在评估临床前毒性的方法的进步并未跟上再生医学的进展。再生疗法的临床前毒性研究必须经过逻辑设计，并且应当具有灵活性，以准确反映正在开发的产品的毒性。本文的目的是讨论在日本进行的此类临床前毒性研究的要求。
我们进行了 MEDLINE 和 PubMed 文献检索，以确定与再生医学相关的最新报告。有关已批准药物和公开公告的信息，包括日本厚生劳动省（https://www.mhlw.go.jp/index.html）和药品和医疗器械管理局（https://www.pmda.go.jp/）网站上的现有指南和指导原则，均已收集。
迄今为止，日本已经开发并批准了 4 种细胞治疗产品。本文总结了向日本药品和医疗器械管理局提交的主要临床前毒性数据。主要通过以下 3 种方式评估此类临床应用中主要关注的肿瘤形成潜力：原始细胞的肿瘤形成能力、产品中残留多能干细胞的定量以及产品植入部位是否可能形成肿瘤。尽管正在开发基因治疗和溶瘤病毒产品，但这些类型的产品尚未在日本获得批准。目前正在根据现有指南和人用药品技术要求国际协调理事会的考虑因素制定与这些产品开发相关的指南。
由于细胞趋向性和异源免疫，用于再生疗法临床前研究的动物物种或品系通常受到限制。尽管如此，临床前毒性研究仍必须旨在预测与人类相关的结果。
