Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
Institute of Health Science Innovation for Medical Care (HELIOS), Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8648, Japan.
Orphanet J Rare Dis. 2024 Jan 2;19(1):5. doi: 10.1186/s13023-023-03000-0.
The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan.
A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials.
It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval.
由于未知的病理生理学和缺乏动物模型，孤儿药的非临床和临床开发都很困难。美国食品和药物管理局（FDA）指导原则和欧洲药品管理局（EMA）指南都描述了孤儿药的开发，但缺乏具体信息，如动物物种和研究设计。在此背景下，本研究旨在根据日本批准的孤儿药审查报告阐明评估非临床疗效的有效方法。
共调查了日本 2010 年 1 月至 2019 年 12 月批准的 184 种孤儿药，包括 84 种抗癌药和 100 种非抗癌药。一些抗癌药物在非临床研究中没有明显疗效数据的情况下就进入了临床开发阶段。由于缺乏已建立的细胞系，一些药物使用了患者来源的细胞。用于非临床研究的细胞是为那些对先前治疗有抗药性的癌症、靶分子中特定氨基酸突变的肿瘤以及具有特定生物标志物的实体瘤设计的。对于一些非抗癌药物，由于不存在动物模型，因此使用类似疾病的动物模型和正常动物进行评估。生物标志物已被专门用于正常动物的评估，并在一些临床试验中作为终点。
可以根据潜在孤儿药的疾病特征灵活设计非临床研究来评估药物疗效。这些方法在 EMA 指南或 FDA 指南中没有详细描述，因此可能会获得批准。
