Background: Immunogenicity generally refers to the property inducing antibody production or cell-mediated immunity. When therapeutic biopharmaceuticals, acting as antigens, produce antibody against the biopharmaceuticals such anti-drug antibody (ADA) may affect clinical pharmacokinetics (PK), efficacy, and/or safety. Therefore, immunogenicity of biopharmaceuticals needs to be carefully evaluated in clinical trials. ICH M4 guideline requires the assessment of immunogenicity during the new drug application (NDA) review process for biopharmaceutics. However, it is unknown how the Japanese regulatory agency reviews immunogenicity. We evaluated whether or not ADA production, its impact on PK, efficacy, and/or safety were discussed in their review report. Methods: We collected all the publicly available review reports from June 2001 (first approval of rituximab in Japan) to July 2022, and descriptions of immunogenicity were analyzed. Results: As of July 2022, there were 78 antibodies approved in Japan and 242 review reports in total. Consequently, approximately 70% (170/242) of all review reports described some information on ADA. As for the 170 reports, approximately 95%, 12%, 71%, 48%, 56%, and 9% reported ADA incidence, max titer, effects on PK, efficacy, safety, and ethnic difference, respectively. Conclusion: This is the first research reporting the contents of immunogenicity assessment during the review process of NDA in Japan. Since the assessment of ADA incidence, impact on PK, efficacy, and safety are important, their robust summaries may be required. Max titer and ethnic difference, although not always discussed during the NDA review process, should be carefully summarized in relation to ADA in the submission documents.
