BLOG

Japan’s Early Consideration on Nonclinical Requirements for Similar-Formula Prescription Combination Products

2025.12.09

• Early Consideration Papers
• PMDA

Introduction to the PMDA’s New Guidance

According to the information released by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) in its document “類似処方医療用配合剤の非臨床試験に関する留意事項（Early Consideration）000278004.pdf”, the agency provides clarification on how nonclinical pharmacology and toxicology studies should be considered for similar-formula prescription combination products such as dialysis solutions, infusion fluids, and enteral nutrition products.
The aim is to ensure appropriate safety evaluation while avoiding unnecessary nonclinical studies, thereby improving development efficiency for combination formulations.

Criteria for Waiving Nonclinical Studies

PMDA outlines situations where new nonclinical pharmacology or toxicology studies may not be required, provided scientific justification is sufficient.

Key conditions include:

• When compositional differences between the new combination product and existing approved formulations (or Japanese Pharmacopoeia-listed products) are not expected to impact safety or efficacy.
• When increases or decreases in component concentrations can be scientifically justified using existing knowledge such as dietary reference intakes and published literature.
• When clinical data indicate that adverse events are consistent with known safety profiles of comparable approved formulations, and do not induce clinically meaningful new safety concerns.

This approach enables rational elimination of redundant nonclinical studies while maintaining regulatory assurance of safety.

Required Documentation and Scientific Justification

Even when nonclinical studies are omitted, PMDA requires applicants to submit sufficient scientific evidence to support the decision.

Applicants should provide:

• Comparative data of the new formula against existing approved formulations, including component concentrations and impurity profiles.
• Past nonclinical and clinical knowledge, relevant guidelines, and public literature demonstrating that safety expectations are sufficiently covered.
• A clear rationale explaining why compositional differences do not warrant additional nonclinical investigations.

PMDA also encourages applicants to consider pre-consultation meetings if clarification is needed.

Scope of Products Covered

This guidance applies primarily to:

• Dialysis solutions
• Parenteral infusion products
• Enteral nutrition products
• Other similar prescription combination formulations where individual components are well understood and already used clinically

The guidance focuses on formulations where the overall composition is similar to existing products, and where safety risks can be reasonably predicted from prior knowledge.

Regulatory Significance and Implications

This initiative reflects Japan’s broader move to streamline regulatory requirements for low-risk formulation changes and reduce unnecessary development burden.

The guidance is expected to:

• Shorten development timelines for combination products
• Reduce the need for animal studies when not scientifically justified
• Increase predictability and transparency for applicants
• Improve alignment with scientific risk-based approaches used globally

For industry—especially companies developing infusion, dialysis, and nutrition formulations—this provides a clearer pathway for regulatory planning and early-phase development strategy.

Conclusion

PMDA’s “Early Consideration” guidance on similar-formula prescription combination products marks a meaningful step toward more efficient, science-based regulatory assessment.
By clarifying conditions under which nonclinical study requirements may be waived, Japan aims to support timely development while maintaining patient safety.
Applicants planning new combination formulations are encouraged to leverage existing data, prepare robust scientific justifications, and engage with PMDA early in the process.