Pediatric usage is approved more often in the US than in Japan. To our knowledge, no study has evaluated the pediatric-specific development gap by comparing the presence of pediatric usage for the same indications approved in Japan and the US, reflecting pediatric-specific drug loss in Japan. We investigated 404 indications for 278 drugs, and the results suggested that there is a pediatric development gap between Japan and the US, focusing on indications approved in both countries. Since this study targeted the indications approved for either adult or pediatric populations (mostly adult population) in both countries, this gap would directly represent the pediatric-specific development gap between Japan and the US. Recent drug loss issues in Japan were attributed to US/EU-based start-up companies, which had become key players in drug development and needed out-licensing to Japanese companies or large pharmaceuticals for expansion into Japan [17]. Given the target indications in our study, this pediatric-specific development gap cannot be explained by the challenges of expanding into the Japanese market.
Regarding the ATC category, a relatively large gap was observed in the systemic use of anti-infectives. In general, the poor marketability of anti-infective drugs has led to recent inactive drug development in this field [18]. Marketability may be more uncertain in pediatric populations. Despite these challenges, 65% of the indications have been approved for pediatric usage in the US. The results suggest that PREA could contribute to promoting pediatric development of anti-infective drugs because 88% (30/34) of the indications were requested for pediatric assessment. PREA promotes pediatric assessment even for diseases that are not financially attractive but have high unmet medical needs in the pediatric population in the US, leading to a relatively large pediatric development gap with Japan.
When focusing on indications approved for pediatric usage in the US, the factors distinguishing the approval status of pediatric usage in Japan can be identified. Multivariate regression analysis of the indications for pediatric usage in the US revealed that the simultaneous approval of adult and Japan-first development positively affected the inclusion of pediatric usage in Japan. US-first development is the major strategy for global drug development [19, 20]. Although Japan-first development is not a common strategy for drugs that had been developed globally, including in Japan and the US, this study suggests that it positively affects pediatric development in Japan. When pediatric assessments in clinical trials were performed separately from the adult population, pediatric usage was less likely to be included in Japan, consistent with a previous study [10].
US regulations could have positively impacted drug development in Japan [21]. The number of indications, including pediatric usage, was higher in the US than in Japan among those in which pediatric assessment was requested; however, pediatric assessment request was not a significant factor in the multivariate regression analysis of indications with pediatric usage in the US, indicating that the impact of PREA was limited. Previous studies have shown that most drugs approved for adults continue to enter the market without pediatric information and lack pediatric prescribing data for extensive periods, even after PREA is implemented, owing to poor compliance with the submitted pediatric assessment plan [22]. Moreover, the scope difference in mandatory pediatric assessment requirements did not influence prescription information for pediatric use between the US and Europe, although the EU pediatric regulations provided a broader mandate for pediatric drug development [23]. Our findings align with those of previous studies, suggesting a different regulation of whether mandating pediatric development did not significantly affect prescription information for pediatric use between Japan and the US, where there is no legislation mandating pediatric assessments. The RACE for Children Act came into effect in 2020, and oncology products targeting orphan diseases in the adult population that were potentially effective for pediatric cancer became the scope of mandatory pediatric assessment. Early evidence suggests that the RACE for Children Act was effective in closing the loopholes in previous legislation and creating new opportunities for innovation in developing therapies for childhood cancers, which may potentially change the current situation [24].
When we looked at 39 indications that had been approved only in the US, 82.1% (32/39) had been approved for pediatric usage based on the MRCT results in the US. Only two indications were evaluated for the pediatric population in MRCTs, including in Japan, out of 12 indications evaluated for the adult population, suggesting that different developmental approaches could be chosen even if MRCTs, including those in Japan and the US, have been conducted in the adult population. For example, ravulizumab for paroxysmal nocturnal hemoglobinuria was approved for adult patients in both countries based on the same pivotal MRCT that both Japan and the US participated in. However, in the US, it was additionally approved for pediatric patients aged 1 month or older based on a separate MRCT that Japan did not participate in. The trial design for the pediatric population is affected by several factors, but the option would be limited compared to the adult population because of the small population size and special considerations of the trial design. To efficiently assess safety and efficacy in the pediatric population, MRCTs involving other countries such as the US should be considered as long as medical needs in the pediatric population exist in Japan.
This study had several limitations. First, the follow-up period was not balanced and may not have been long enough to capture all supplemental pediatric usage approvals. Since the timing of supplemental pediatric usage approval is affected by several factors such as disease characteristics, patent status, and study enrollment, it would take longer than the follow-up period of this study to obtain supplemental pediatric usage approval. Although median follow-up time (Japan: 4.02 years, US: 5.95 years) could cover median time-lags of 4–5 years between the initial approval and the first supplemental pediatric indication approval in Japan and the US, longer follow-up period in the US might positively affect pediatric usage approval [10] Second, this study did not consider failed pediatric development because the label information was our focus. Forty-two percent of completed pediatric trials failed to establish either safety or efficacy, leading to an inability to label the product for use in children [25]. Thus, some indications without pediatric usage could be tested in the pediatric population but could not establish satisfactory evidence as in the adult population.