Addressing the drug development challenge for rare pediatric diseases in Japan: a case study of isotretinoin

Drug lag in rare pediatric diseases remains a significant challenge in Japan despite its sophisticated healthcare system. We examined this issue through a case study of isotretinoin, an established standard drug for high-risk neuroblastoma (affecting 45–60 new patients annually in Japan) since the 2000s that has not been granted regulatory approval in Japan as of 2025. Analysis of regulatory documents and clinical practices revealed that while isotretinoin has demonstrated improved event-free survival rates in international trials when used as maintenance therapy for high-risk neuroblastoma, multiple barriers have hindered its domestic approval. These include the challenges of conducting clinical trials in limited pediatric populations, substantial development costs, diminishing market attractiveness due to Japan's demographic shift, and restrictions on “mixed billing system” which means combining covered insurance treatments with uncovered treatments under the universal health insurance system in Japan. Currently, patients must rely on costly private imports or clinical trial participation to access the drug, leading to financial burdens and treatment discontinuation risks. Recent regulatory reforms, including the establishment of the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs in 2009 and amendments enabling investigator-led trials, have facilitated progress. An investigator-led Phase II clinical trial evaluating isotretinoin’s safety and efficacy is ongoing since 2023, with expected completion in 2026. However, the lengthy timeline of approximately 25 years from global adoption to potential approval highlights persistent challenges in pediatric drug development and Japan’s isolation from global drug development networks. This case demonstrates the need for innovative policy approaches to ensure sustainable drug development for rare pediatric diseases in an aging society.