Independent educational summary. This page summarises the PMDA document “Considerations for Non-clinical Studies of Combination Prescription Drugs with Similar Formulations (Early Consideration)” in plain language and was created by Clinical Biostats by editing and summarising it. It is not an official PMDA publication and is not legal or regulatory advice. Consult the official document; PMDA provides the English version for reference purposes, and the Japanese original prevails if the versions differ.
In Plain Language
This document addresses whether a developer of a combination prescription drug with a formulation similar to existing products needs to conduct new non-clinical studies of pharmacological effects or toxicity before applying for marketing authorization. It says those studies may be omitted when differences from relevant approved combination drugs are not considered likely to affect efficacy or safety, taking account of the composition and other stated considerations. The document gives examples involving the amounts or concentrations of active ingredients and impurity profiles, and also points to safety findings from clinical studies of the product under development. If the applicant considers new studies unnecessary, the application dossier is required to explain why, using the composition differences and the latest guidelines and published literature as a basis. PMDA consultation may be sought, as appropriate, if needed.
What This Guidance Covers
The document concerns combination prescription drugs with similar formulations. It defines these as prescription drugs whose active ingredients and the respective proportions of those ingredients are considered similar to those of combination drugs that have already been approved or to those listed in the Japanese Pharmacopoeia. The document refers to these approved or Pharmacopoeia-listed products together as “approved combination drugs.”
It identifies dialysis solutions, infusion solutions, and enteral nutrition formulas as products being developed in this category. The scope is the approach to non-clinical studies to be conducted by the time of a marketing authorization application (MAA). More specifically, it addresses when new studies on pharmacological effects or toxicity may be omitted because formulation differences are not considered to affect efficacy or safety.
The document does not describe a general exemption from all non-clinical work, nor does it state that every product with a broadly similar composition can omit these studies. Its consideration is conditional: the applicant’s assessment of the differences, the relationship to relevant approved combination drugs, and the safety information described in the document all matter.
Why It Matters
The document describes a development situation in which the formulation being developed is intended to have a composition similar to an approved combination drug, and the differences in composition are considered unlikely to affect efficacy or safety. In that situation, new studies of pharmacological effects or toxicity may not necessarily be required for the formulation applied for marketing authorization. The document clarifies the approach to deciding whether such studies should be conducted by the time of the MAA.
The practical issue is how to support that decision rather than treating similarity alone as sufficient. A difference in active ingredient content or concentration, or in the impurity profile, needs to be considered for its possible effect on efficacy or safety. The document also points to clinical safety findings for the formulation under development, judged in light of the safety profiles of relevant approved combination drugs. This framing connects the composition-based rationale with observed safety information.
Key Recommendations
The document’s central point is that new pharmacological-effect or toxicity studies may be omitted for an MAA when differences in composition from approved combination drugs are not considered to affect efficacy or safety, based on the considerations it sets out. The points below preserve that conditional wording: they are not a statement that studies can always be omitted for similar formulations.
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Assess the difference in active ingredient content or concentration. The document gives as one example a combination drug under development in which the content or concentration of each active ingredient falls within the range found in relevant approved combination drugs. “Relevant approved combination drugs” means approved combination drugs with similar indications, dosage and administration, and related characteristics described in the document.
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Consider how to explain an amount or concentration outside the relevant range. The document also describes cases where the content or concentration of an active ingredient in the product under development falls outside the range of the relevant approved combination drugs. In such cases, the impact on efficacy or safety may be explained using existing information or knowledge. The document gives Dietary Reference Intakes for Japanese as an example of such information; it does not set out a numerical decision threshold for this example.
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Consider impurity-profile differences. Differences in impurity profiles from approved combination drugs are among the composition differences to assess when considering whether efficacy or safety could be affected. The document does not provide a specific impurity limit or a separate testing rule in this Early Consideration.
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Consider clinical safety findings for the product under development. The document identifies the absence of unexpected adverse events in clinical studies of the formulation under development, based on the safety profiles of the relevant approved combination drugs, as another consideration in support of omitting new pharmacological-effect or toxicity studies.
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Explain the rationale in the application dossier. If the applicant considers new studies unnecessary for the MAA, the document says it is required to explain the rationale for omitting them in the application dossier. The explanation is to be based on the impact of formulation differences compared with the relevant approved combination drugs, as well as the latest guidelines and published literature.
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Consider PMDA consultation if needed. The applicant may seek PMDA consultation on the validity of omitting new studies, as appropriate. The document presents consultation as something the applicant may use if needed, not as a universal step stated for every application.
Practical Implications
Interpretation: For a sponsor, the main practical task is to make the omission rationale product-specific and traceable. A general statement that the new product resembles an existing combination drug would not, by itself, address the considerations named in the document. The dossier should explain the relevant composition differences and why they are not considered to affect efficacy or safety, drawing on the latest guidelines and published literature as the document says.
A development team can organize its assessment around the comparison with relevant approved combination drugs: identify the comparison products, describe the active ingredient contents or concentrations and impurity profiles, and make clear whether any content or concentration is outside the range of those products. If it is outside the range, the document’s example points to explaining the expected impact using existing information or knowledge. This is an explanation of how the stated considerations could be arranged in practice, not an additional PMDA requirement.
Clinical and non-clinical teams may need to bring their information together. The document specifically links the safety profiles of relevant approved combination drugs with whether unexpected adverse events have been observed in clinical studies of the formulation under development. It does not supply a required format, dataset, or threshold for making that assessment, so the summary should not be read as establishing one.
For regulatory teams and writers, the dossier rationale should distinguish the evidence that supports the assessment from the conclusion being drawn. The document expressly calls for the rationale and identifies composition differences, the latest guidelines, and published literature as its basis. If the validity of omission remains uncertain, PMDA consultation may be considered as appropriate.
Technical Details
The document uses a comparison-based approach rather than a stated formula or numerical decision rule. Its key terms and decision considerations can be understood in the following sequence.
“Approved combination drugs” means combination drugs already approved or listed in the Japanese Pharmacopoeia. The document’s “relevant approved combination drugs” are those with similar indications, dosage and administration, etc.
Consider differences in active ingredient content or concentration and impurity profiles relative to approved combination drugs. The document gives being within the range of relevant approved combination drugs as one example supporting the consideration.
If an active ingredient’s content or concentration is outside the range of relevant approved combination drugs, the document says the impact on efficacy or safety may be explained using existing information or knowledge. Dietary Reference Intakes for Japanese is the example provided.
Assess whether unexpected adverse events have been observed in clinical studies of the formulation under development, based on the safety profiles of the relevant approved combination drugs.
If the applicant considers new pharmacological-effect or toxicity studies unnecessary for the MAA, explain the rationale in the application dossier, based on the impact of formulation differences and the latest guidelines and published literature.
The footnote identifies Dietary Reference Intakes for Japanese as the “Dietary Nutrient Intake Standards” (MHLW Notification No. 199, 2015). It describes these standards as established by the Minister of Health, Labour and Welfare pursuant to Article 16-2 of the Health Promotion Act, with the aim of maintaining and promoting public health and preventing lifestyle-related diseases by specifying amounts of energy and various nutrients to be consumed through diet.
No specific numerical thresholds, study designs, sample sizes, or statistical methods are set out in this document. Its focus is the rationale for deciding whether new studies on pharmacological effects or toxicity may be omitted in the circumstances described.
Who Should Read It
This document is most relevant to sponsors and development teams working on prescription combination products whose active ingredients and proportions are considered similar to those of approved or Japanese Pharmacopoeia-listed combination drugs. The examples named include dialysis solutions, infusion solutions, and enteral nutrition formulas.
It may also be useful to non-clinical scientists assessing whether new pharmacological-effect or toxicity studies are needed, clinical teams reviewing safety findings, statisticians supporting the organization or interpretation of study information, and regulatory affairs or medical writing teams preparing an MAA dossier. Its central practical use is to understand the considerations PMDA identifies when an applicant proposes to omit those new studies.
Official PMDA Source
- Official title: Considerations for Non-clinical Studies of Combination Prescription Drugs with Similar Formulations (Early Consideration)
- Issuing body: Pharmaceuticals and Medical Devices Agency, Office of New Drug II
- Date on the cover: November 18, 2025
- PMDA PDF: Official PMDA document
- PMDA list page: PMDA Early Consideration documents
Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.
Consult the official document; this summary does not replace it. PMDA provides the English version for reference purposes, and the Japanese original prevails if there is any inconsistency between the Japanese original and the English translation.
PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication; those views may change as scientific knowledge develops.
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Key Takeaways
- The document concerns non-clinical studies for combination prescription drugs with similar formulations, including the examples of dialysis solutions, infusion solutions, and enteral nutrition formulas.
- New studies on pharmacological effects or toxicity may be omitted when composition differences from approved combination drugs are not considered to affect efficacy or safety, based on the document’s considerations.
- Consider active ingredient amounts or concentrations, impurity-profile differences, and whether unexpected adverse events have been observed in clinical studies of the formulation under development.
- If the applicant considers new studies unnecessary, the application dossier is required to explain the rationale using the formulation differences, the latest guidelines, and published literature.
- PMDA consultation on the validity of omission may be sought, as appropriate, if needed.