Considerations for Non-clinical Studies of Combination Prescription Drugs with Similar Formulations in Japan

1. Purpose and Background

The Considerations for Non-clinical Studies of Combination Prescription Drugs with Similar Formulations (Early Consideration) issued by the Pharmaceuticals and Medical Devices Agency (PMDA) on November 18, 2025 clarifies the approach to non-clinical studies that should be conducted prior to marketing authorization application (MAA) for combination prescription drugs with formulations similar to already approved combination drugs.

“Combination prescription drugs with similar formulations” refers to prescription drugs whose active ingredients and their proportions are considered similar to those of combination drugs that have already been approved or are listed in the Japanese Pharmacopoeia and are being developed with comparable compositions. Development examples include dialysis solutions, infusion solutions, and enteral nutrition formulas. Because the composition is similar to that of approved products, differences are generally not expected to affect efficacy or safety.

2. Approach to Non-clinical Studies

2.1 Omission of New Non-clinical Studies

For combination prescription drugs with similar formulations, new non-clinical pharmacology or toxicology studies may not necessarily be required if compositional differences from the relevant approved combination drugs are unlikely to affect efficacy or safety. The following conditions support omission:

• When the content or concentration of each active ingredient in the proposed drug falls within the range of approved combination drugs with similar indications, dosages, and administration routes.
• When differences in impurity profiles or other formulation factors can be scientifically justified as unlikely to affect the safety or pharmacological effects.
  Under these circumstances, developers may justify the omission of new non-clinical studies based on existing scientific evidence.

2.2 Scientific Justification Requirements

Even when non-clinical studies are omitted, applicants must submit sufficient scientific rationale demonstrating that the formulation differences are unlikely to impact clinical performance. Supporting evidence may include comparative analytical data, literature references, and existing safety/pharmacology data from approved products or pharmacopoeial standards. This ensures that product development proceeds efficiently while maintaining regulatory assurance of safety.

3. Development Examples and Implications

Typical products falling under this guidance include dialysis solutions, infusion fluids, and enteral nutrition formulas that are formulated similarly to existing approved therapies. In such cases, the PMDA expects that developers will leverage existing non-clinical evidence and scientific understanding rather than conduct redundant studies, as long as differences are justified and supported by data.

4. Applicant Responsibilities

Developers should prepare a non-clinical study justification package within the marketing authorization application (MAA), detailing why new pharmacology or toxicology studies are not necessary. This includes comparative analytical profiles, rationale for similarity, and references to prior data or literature supporting the conclusion. Early consultation with PMDA can help align expectations and clarify data requirements.

Conclusion

The guidance on non-clinical studies for combination prescription drugs with similar formulations in Japan aims to streamline development by allowing omission of new pharmacology/toxicology studies when scientific evidence demonstrates that formulation differences will not affect safety or efficacy. Applicants must provide scientific justification and engage with PMDA to ensure robust regulatory submissions aligned with Japanese requirements.