Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu City, 879-5593, Japan.
Clinical Pharmacology Center, Oita University Hospital, Yufu, Japan.
AAPS J. 2024 Oct 8;26(6):109. doi: 10.1208/s12248-024-00980-0.
Anti-drug antibodies (ADAs) generated in response to biopharmaceuticals can significantly impact pharmacokinetics (PK) and overall drug efficacy. Thus, the ICH M4 guidelines mandate summarizing immunogenicity data from clinical trials in drug approval applications. However, following the approval of the first antibody drug in Japan in 2001, no cross-sectional investigation has focused on immunogenicity during the regulatory review process. Therefore, this study aims to examine the review reports and prescribing information of antibody drugs approved in Japan to identify key points related to immunogenicity evaluation. We conducted a cross-sectional analysis of review reports for antibody drugs approved between June 2001 and July 2022 by the Japanese regulatory authority. Specifically, we evaluated the ADA positivity rate, presence of neutralizing antibodies, antibody titers, and effects of ADA on PK, efficacy, and safety. We also compared this information with that provided in the prescribing information. Our analysis revealed that the ADA positivity rate and its effects on PK, efficacy, and safety were critical aspects of the review process. The emphasis on these factors varied depending on the number of applications and disease area. The information presented in the prescribing information was largely consistent with that discussed in the review reports. Overall, this study provides the first cross-sectional evaluation of immunogenicity considerations in the regulatory review of antibody drugs in Japan. Our findings can contribute to the efficiency of clinical trial planning and preparation of approval applications, to potentially improve the overall drug development process and address the drug loss problem in Japan.
抗药物抗体（ADA）是针对生物制药产生的，会显著影响药代动力学（PK）和整体药物疗效。因此，ICH M4 指南要求在药物批准申请中总结临床试验的免疫原性数据。然而，自 2001 年日本批准第一种抗体药物以来，在监管审查过程中，没有针对免疫原性的横断面调查。因此，本研究旨在检查日本批准的抗体药物的审查报告和说明书，以确定与免疫原性评估相关的要点。我们对日本监管机构批准的 2001 年 6 月至 2022 年 7 月期间批准的抗体药物的审查报告进行了横断面分析。具体而言，我们评估了 ADA 阳性率、中和抗体的存在、抗体滴度以及 ADA 对 PK、疗效和安全性的影响。我们还将这些信息与说明书中的信息进行了比较。我们的分析表明，ADA 阳性率及其对 PK、疗效和安全性的影响是审查过程的关键方面。这些因素的重视程度取决于申请数量和疾病领域。说明书中提供的信息在很大程度上与审查报告中讨论的信息一致。总的来说，本研究首次对日本抗体药物监管审查中的免疫原性考虑进行了横断面评估。我们的研究结果可以提高临床试验规划和批准申请准备的效率，从而可能改善整体药物开发过程，并解决日本的药物损失问题。
