Initiatives to Promote Pediatric Drug Development in Japan

1. Background

There have been growing concerns about the expansion of 'drug loss' in Japan, where pharmaceuticals approved in the European Union (EU) and the United States (U.S.) are not being developed for Japanese patients. This issue is particularly challenging for pediatric drugs and orphan drugs. In the U.S. and EU, pediatric drug development is mandatory, requiring pharmaceutical companies and other developers to submit a pediatric drug development plan to regulatory authorities at an early stage of development for drugs with new active ingredients or new indications for adults (after completion of Phase II studies in the U.S. and after completion of Phase I studies in the EU). Furthermore, when submitting a marketing authorization application for an adult drug, the applicant must include the pediatric drug development plan agreed upon with the regulatory authorities in the dossier. In contrast, pediatric drug development is not currently a regulatory requirement in Japan, leading to few instances where a pediatric drug development plan with the same indications as an adult drug has been agreed upon with the Pharmaceuticals and Medical Devices Agency (PMDA) by the time of submission of a marketing authorization application for the adult drug. Moreover, it is not uncommon for clinical trials in pediatric populations to have already been completed or to be ongoing overseas by the time a development plan for the pediatric drug in Japan is presented to PMDA. To advance pediatric drug development in Japan without lagging behind other countries, PMDA considers it crucial to understand the comprehensive drug development plan, including pediatric drug development, from the early stages of adult drug development. When necessary, PMDA should encourage pharmaceutical companies and other developers to pursue pediatric drug development in Japan. https://www.pmda.go.jp/files/000274940.pdf

2. Policy Intent

As part of its initiatives to promote pediatric drug development, PMDA has decided to provide essential advice and guidance based on a comprehensive understanding of the overall drug development plan, including the pediatric drug development plan, during its clinical trial consultations and other services. This decision follows discussions led by the Project Team for Addressing Inquiries Related to Pediatric Development Status, a cross-sectoral project team focused on regulatory science. PMDA established the Consultation Center for Pediatric and Orphan Drugs Development in July 2024 and started receiving applications for Consultation on Confirmation of Pediatric Drug Development Programs. Furthermore, as part of its cross-sectoral efforts in regulatory science, PMDA has consistently identified issues related to pediatric drug development and explored measures to facilitate pediatric drug development from the early stages of drug development for adults. The Summary of Discussions on Revision of the Pharmaceutical and Medical Device Act and Related Regulations (issued by the Pharmaceutical and Medical Device Regulatory Subcommittee of the Health Sciences Council, Ministry of Health, Labour and Welfare, on January 10, 2025) outlined a policy to address the need for further promotion of pediatric drug development and resolution of drug loss. This policy stipulates that applicants for marketing authorization of drugs with new active ingredients or new indications for adult use should be obligated to make efforts for planning of pediatric drug development programs. In the future, if there are revisions to the regulatory framework and operational practices for promoting pediatric drug development, resulting in changes to the basic principles regarding pediatric drug development, the basic principles and important considerations outlined in the attached document may also be subject to revision. https://www.pmda.go.jp/files/000274940.pdf

3. Target Products

The initiatives apply to drugs under development for adult use, particularly those expected to be used in children for the diseases and conditions targeted in adult drug development, including drugs with new active ingredients or new indications. https://www.pmda.go.jp/files/000274940.pdf

4. Eligibility Types

Eligibility for consultations includes applicants seeking clinical trial consultations for Phase II (Proof of Concept studies) or later stages of adult drug development who wish to confirm pediatric drug development plans or have PMDA verify the status of pediatric drug development. https://www.pmda.go.jp/files/000274940.pdf

5. Consultation Pathways

During clinical trial consultations for adult drugs, if the drug under development is expected to be used in children, PMDA will actively verify the status of pediatric drug development both domestically and internationally to encourage initiation in Japan without lagging behind other countries. If requested by the applicant, PMDA will confirm the pediatric drug development plan based on the 2024 Notification (Planning of Pediatric Drug Development Programs during Development of Drugs for Adults, PSB/PED Notification No. 0112-3, issued by the Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety Bureau, Ministry of Health, Labour and Welfare, dated January 12, 2024, partially revised on March 29, 2024). Applicants should include 'Confirmation of Pediatric Drug Development Plan' as a consultation item and provide necessary information as specified in the Implementation Guidelines for the Consultation on Confirmation of Pediatric Drug Development Programs. If information on pediatric drug development plans is not included in the consultation briefing document, PMDA may inquire through additional questions. Separate consultations should be utilized for appropriateness of study designs for pediatric drug development or adequacy of clinical data packages for pediatric populations, such as consultations after completion of Phase II studies for drugs. https://www.pmda.go.jp/files/000274940.pdf

6. Approval Application

The document does not directly address approval applications for pediatric drugs but emphasizes inclusion of agreed pediatric drug development plans in marketing authorization applications for adult drugs, as per U.S. and EU practices, to avoid drug loss in Japan. https://www.pmda.go.jp/files/000274940.pdf

7. Review Expectations

PMDA will provide advice or guidance during clinical trial consultations to ensure pediatric drug development in Japan is initiated without lagging behind adult development. The scope of confirmation based on the 2024 Notification is limited to what is covered under the Consultation on Confirmation of Pediatric Drug Development Programs service. https://www.pmda.go.jp/files/000274940.pdf

8. Post-approval Procedures

The document does not specify post-approval procedures, but notes that future revisions to regulatory frameworks may affect the outlined principles. https://www.pmda.go.jp/files/000274940.pdf

9. Practical Considerations

• In the consultation briefing document, applicants should indicate whether pediatric drug development programs exist in Japan and overseas, including details from the Implementation Guidelines, and describe the overall pediatric drug development plan if pediatric subjects are evaluated alongside adults.
• For drugs including pediatric subjects evaluable with adults, describe development plans for necessary pediatric age groups beyond the specific population.
• PMDA's approach assumes Japan's participation in multi-regional clinical trials for pediatric trials when planned in the U.S. and EU, unless ethnic factors differ.
• Development of pediatric dosage forms should align with marketing authorization applications for additions.
• References include: 1) Planning of Pediatric Drug Development Programs during Development of Drugs for Adults (PSB/PED Notification No. 0112-3, January 12, 2024); 2) Partial revision (PSB/PED Notification No. 0329-1, March 29, 2024); 3) Q&A (Administrative Notice, March 29, 2024). https://www.pmda.go.jp/files/000274940.pdf

10. Effective Date

The initiatives are effective as of the notification date, March 21, 2025, with the provisional translation as of April 2025. References like the 2024 Notification are partially revised on March 29, 2024. https://www.pmda.go.jp/files/000274940.pdf