Key Takeaways from the PMDA Symposium on Japanese Phase I Trials Before MRCT Participation
2025.09.30
Introduction
On August 4, 2025, the Pharmaceuticals and Medical Devices Agency (PMDA) hosted a public symposium on the recently issued notification “Basic principles for conducting Phase I studies in Japanese before initiating multi-regional clinical trials (MRCTs) including Japan for drugs in which early clinical development is proceeding outside Japan” (December 25, 2023). This notification is highly relevant to global and Japanese regulatory teams, as it reshapes Japan’s participation in MRCTs and addresses long-standing challenges, including drug lag and drug loss.
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From a Uniform Rule to Case-by-Case Judgment
Previously, Japanese Phase I trials were often required before participation in MRCTs, which caused delays and/or prevented drug development in Japan. The new notification clarifies that:
- Phase I studies in Japanese are not mandatory in principle.
- Instead, necessity is assessed case by case, based on available safety and pharmacokinetic data.
- Particularly for rare diseases, pediatrics, and serious conditions, Japan can join MRCTs without prior Japanese Phase I trials if the product’s safety profile is reasonably acceptable.
PMDA’s Evaluation Criteria
When deciding whether a Japanese Phase I trial is necessary, PMDA considers:
- Risk Profile of the Investigational Drug – signals from non-clinical data, dose-dependent adverse events, safety margins, and class effects.
- Sensitivity to Ethnic Factors – potential pharmacokinetic differences, genetic polymorphisms, body weight/BMI, or known ethnic variability.
- Disadvantages of Japan’s Non-Participation – unmet medical needs, rarity of the disease, or feasibility of conducting standalone Japanese trials.
If Phase I is skipped, companies are expected to implement additional safeguards such as small Japanese safety cohorts, staged enrollment, intensive monitoring, or independent data monitoring committees.
Industry Survey Insights
A 2024 survey of 64 companies (JPMA, PhRMA, EFPIA members) revealed:
- Multiple oncology, non-oncology, and vaccines projects gained PMDA agreement to join MRCTs without prior Japanese Phase I trials.
- Common justifications included:
- Non-clinical and foreign clinical data demonstrating manageable safety
- No anticipated ethnic differences
- Strong monitoring plans in MRCTs
- Impact on strategy:
- More companies are considering including Japan in MRCTs
- Increased consultations with PMDA on Phase I requirements
- However, many companies still reported uncertainty and a need for clearer examples
CRO and Global Perspectives
CROs highlighted challenges in communication:
- Overseas biotech firms often focus on the phrase “Japanese Phase I is not required” without fully considering ethnic sensitivity and safety rationale.
- Practical interpretation still requires case-by-case justification with concrete scientific reasoning.
- Industry strongly requests quantitative examples and case studies to harmonize regional understanding.
Implications for Pediatric and Rare Disease Development
For pediatric and rare disease programs, the notification is especially impactful:
- Enables earlier participation in MRCTs without duplicative Phase I studies in Japan.
- Reduces delays in access to innovative therapies.
- Careful planning and safety oversight are still required for pharmacokinetic evaluations.
Conclusion
The PMDA’s new principles represent a significant regulatory evolution, shifting from rigid requirements to risk-based flexibility. For regulatory affairs professionals, this means:
- Closer collaboration with PMDA during clinical trial consultations,
- Careful documentation of rationale for Phase I omission,
- And leveraging this framework to accelerate development in areas of high unmet need.
Ultimately, this approach could significantly reduce drug lag in Japan while maintaining patient safety.
References:
「「海外で臨床開発が先行した医薬品の国際共同治験開始前の日本人での第Ⅰ相試験の実施に関する基本的考え方について」に関する公開シンポジウム」の開催について | 独立行政法人 医薬品医療機器総合機構
