Transition from drug lag to drug loss in pediatric oncology: a comprehensive evaluation of the Japan-U.S. approval gap.

Introduction: Pediatric drug development in Japan faces significant challenges caused by the case rarity and limited commercial incentives. Although the United States (U.S.) RACE Act in 2017 has accelerated pediatric oncology approvals in the U.S., it has coincided with a widening approval gap between the U.S. and Japan. This retrospective observational study aimed to clarify the current status of pediatric oncology drug lag and apparent drug loss through 2025 and to explore structural factors associated with pediatric approval status in Japan. Methods: We assessed the Japanese approval status of pediatric oncology drugs with U.S. Food and Drug Administration indications from 2000 to 2025. Drug lag was evaluated using Kaplan-Meier analysis, primarily focusing on drugs that successfully obtained Japanese approval, and clinical development factors associated with apparent drug loss were analyzed using Fisher's exact test and multivariable logistic regression. Decision tree analysis (CART) was performed to identify the structural hierarchy of clinical characteristics associated with Japanese approval status. Results: The approval rate of pediatric drug-indication pairs in Japan significantly declined from 81.8% before 2017 to 31.8% after 2017. Kaplan-Meier analysis suggested that, among drug-indication pairs that ultimately achieved pediatric approval in Japan, the median time to approval was shortened from 48.9 months to 21.1 months. Multivariate and CART analysis identified that the trial phase supporting approval in the U.S. and sponsor type were the key factors most strongly associated with approval in Japan. When the U.S. study supporting approval was limited to early-phase trials or was absent, 92.9% of drugs failed to achieve approval in Japan. Discussion: While delays in drug approval may have shortened, the disparity in therapeutic access between Japan and the U.S. is increasingly driven by persistent not yet approved in Japan. To address this gap, Japan should transition toward an integrated strategy that balances robust domestic bridging-leveraging foreign pediatric and Japanese adult data extrapolation-with proactive participation in the global clinical development engine from its earliest phases.