Investigator-Initiated Trials as a Clinical Development Approach for Orphan Drugs Compared with Industry-Sponsored Trials in Japan.

Orphan drug development faces substantial economic and operational challenges, particularly in small patient populations where conventional industry-sponsored trials (ISTs) may be difficult to conduct. In Japan, investigator-initiated trials (IITs) have been used to support the development of treatments for rare diseases and other areas of high unmet medical need; however, the characteristics of orphan drug approvals supported by IITs compared with those supported by ISTs have not been fully evaluated. This study analyzed pivotal trials supporting orphan drug approvals in Japan between 2015 and 2024 and compared the trial and regulatory characteristics of IIT- and IST-supported approvals. Among 1,269 drugs approved, 260 orphan drugs were included in the final analysis. IITs were used as pivotal trials in 11.2% of approvals. All IITs were Japan-only trials, whereas 52.4% of ISTs involved global trials. The Japanese patient population coverage ratio was higher for IIT-supported than IST-supported approvals in the overall comparison (median 2.2% vs. 0.5%, p = 0.003). However, the difference was attenuated when the comparison was restricted to Japan-only ISTs. Multivariable logistic regression analysis identified additional indications, Phase II trials, and smaller estimated target populations in Japan (100-999 patients) as characteristics associated with IIT-supported approvals. When the number of study sites was modeled continuously in a sensitivity analysis, fewer study sites were associated with IIT-supported approvals. Among orphan drugs approved in Japan, IIT-supported approvals showed distinct trial characteristics compared with IST-supported approvals. These findings describe characteristics of approved IIT-supported medicines and may inform future academia-led orphan drug development.