Handling of Japanese Data for Confirmation of Comparability of Biosimilars to the Original Biopharmaceuticals — PMDA Early Consideration Summary

In Plain Language

The document addresses how Japanese clinical data should be considered when a biosimilar developer seeks to show that its product is comparable to the original biopharmaceutical. It describes a situation in which clinical trials conducted only in non-Japanese subjects are submitted instead of trials that include Japanese subjects. In that situation, the applicant needs to explain why ethnic factors do not affect the clinical trial results, drawing on information about the product, the original biopharmaceutical and relevant clinical data. The document points to possible differences in biology and in medical practice, as well as differences in the biosimilar’s quality attributes, as matters to assess. Its aim is to clarify the principles for considering whether non-Japanese clinical data can be extrapolated to Japanese subjects, while emphasising that each biosimilar should be evaluated in light of its own properties and trial design.

What This Guidance Covers

The document concerns the handling of Japanese data when confirming the comparability of a biosimilar to its original biopharmaceutical. It focuses on an application scenario where clinical trials conducted in non-Japanese subjects alone are submitted as evaluation data, rather than conducting clinical trials that include Japanese subjects. It describes the explanations an applicant needs to provide to support extrapolating those trial data to Japanese subjects.

The document refers to clinical trials for confirming pharmacokinetic (PK) equivalence and efficacy equivalence, and to evaluating PK, efficacy and safety. It also specifically includes immunogenicity when discussing whether quality-attribute differences could affect ethnic differences in clinical outcomes. It does not set out a general evaluation of all aspects of biosimilar development, nor does it give a single study design or numerical test for deciding whether Japanese data are needed. No further exclusions are specified in the document.

Why It Matters

The document describes a change in how Japanese data may be handled. It states that, in Japan, at least one of a clinical trial to confirm PK equivalence or a clinical trial to confirm efficacy equivalence had been required to include Japanese subjects to evaluate comparability with the original biopharmaceutical. It contrasts this with generic drugs, for which Japanese data are not mandatory to evaluate bioequivalence.

The document then explains that the relevant Q&A on the biosimilar guideline was revised. As a result, data from clinical trials conducted in non-Japanese subjects could be extrapolated to Japanese subjects if ethnic factors were considered to have no impact on the trial results. This document complements that administrative notice by presenting PMDA’s current regulatory perspective more clearly, based on its experience. The central challenge is therefore not simply whether a trial included Japanese subjects, but whether the applicant can explain why ethnic factors would not affect the results relevant to the biosimilar comparison.

The document also cautions that its principles are general. Evaluation should be performed carefully for each biosimilar based on its properties and clinical trial design. It recommends using PMDA consultations as early as possible.

Key Recommendations

1. Explain why non-Japanese trial data can be extrapolated. If an application relies on clinical trial data from non-Japanese subjects alone instead of conducting trials that include Japanese subjects, the applicant needs to explain why ethnic factors do not affect the clinical trial results.

2. Assess the product’s sensitivity to ethnic factors. At consultation and approval application, the sensitivity of the product under development to intrinsic and extrinsic ethnic factors should be explained. The document says this explanation should be based on published literature, etc., on the original biopharmaceutical, using its table as a reference. The applicant should then explain the justification for extrapolating the non-Japanese clinical trial data to Japanese subjects.

3. Use relevant experience across races, regions and body weights where available. The document says that, if a product under development has been used in multiple races or regions and in patients with a wide range of body weights in overseas clinical trials, it is useful to discuss ethnic factors based on data from those trials.

4. Explain findings from the original biopharmaceutical. Whether ethnic-factor differences may affect PK, efficacy and safety results between Japanese and non-Japanese subjects should be explained based on subgroup analyses of clinical trial data or post-marketing data for the relevant original biopharmaceutical.

5. Discuss quality-attribute differences and their possible relevance. In assessing quality comparability between the biosimilar and the original biopharmaceutical, differences in quality attributes should be explained. If there are such differences, the applicant should explain whether they may affect ethnic differences between Japanese and non-Japanese subjects in PK, efficacy and safety, including immunogenicity. The document points to published literature, etc., as a basis for this explanation.

6. Consider the product and trial individually. The document describes its principles as general, not a substitute for careful evaluation of the properties and clinical trial design of each biosimilar. It recommends using PMDA consultations as early as possible.

Practical Implications

Interpretation: For a sponsor considering an application based on trials conducted only in non-Japanese subjects, the document points toward assembling a connected explanation rather than treating the absence of Japanese subjects as a stand-alone issue. That explanation can draw on the original biopharmaceutical’s published information, relevant subgroup or post-marketing data, and the biosimilar’s own quality-comparability assessment. The aim is to address whether ethnic factors could affect the results that support the comparability assessment.

• For clinical and regulatory teams: identify early whether the proposed evidence includes Japanese subjects or relies on non-Japanese trials alone. If relying on the latter, plan how to explain the relevance of ethnic factors and the basis for extrapolation, including at consultation and approval application.
• For statisticians and clinical scientists: consider what available clinical trial subgroup analyses or post-marketing data for the original biopharmaceutical can say about differences between Japanese and non-Japanese subjects in PK, efficacy and safety. The document does not prescribe a particular analysis method or a numerical threshold.
• For pharmaceutical and quality teams: describe relevant differences in quality attributes between the biosimilar and the original biopharmaceutical, then consider whether those differences could matter to ethnic differences in PK, efficacy or safety, including immunogenicity.
• For investigators and clinical operations teams: information from overseas trials involving multiple races or regions and a wide range of body weights may be useful in discussing ethnic factors, where such trial data exist.
• For cross-functional teams: treat the assessment as product-specific. The document recommends early PMDA consultation, especially as the principles are general and the evaluation depends on product properties and trial design.

Technical Details

The document does not provide a statistical formula or a quantitative decision rule. Instead, it offers a set of topics for a reasoned assessment, including a table of product characteristics that may be less or more sensitive to ethnic factors. The table is described as a reference, and its footnote says that relevant items should be explained according to the properties of each product under development.

The table contrasts characteristics described as “Not sensitive to ethnic factors” with those described as “Sensitive to ethnic factors.” It includes the following points:

The table separates intrinsic factors from extrinsic factors. The first eleven rows concern intrinsic factors, including product properties and biological or genetic considerations. The last three concern extrinsic factors: potential inappropriate use, use with many concomitant medications, and differences in medical practice environment. The contrasts help organise the explanation, but the document does not describe them as a scoring system or state that any single item determines whether extrapolation is justified.

The document also describes two other evidence reviews. First, subgroup analyses of clinical trial data or post-marketing data for the original biopharmaceutical should be used to explain whether ethnic-factor differences may affect PK, efficacy and safety between Japanese and non-Japanese subjects. Second, any quality-attribute differences between the biosimilar and the original should be described; if differences exist, their possible relevance to ethnic differences in PK, efficacy and safety, including immunogenicity, should be explained based on published literature, etc.

In discussing ethnic factors, the document identifies ICH E5(R1), ICH E17 and a Japanese administrative Q&A on phase 1 studies in Japanese subjects before multi-regional clinical trials as possible references. These are cited in the document as references on ethnic factors and clinical trial planning; this summary does not add requirements from those materials.

Who Should Read It

This document is relevant to biosimilar developers and sponsors preparing an approval application, particularly when considering clinical data from non-Japanese subjects without trials that include Japanese subjects. It may also be useful to regulatory affairs staff, clinical scientists, statisticians, pharmaceutical and quality teams, and researchers assessing how the original biopharmaceutical’s clinical information and the biosimilar’s quality attributes inform the comparability rationale. Clinical operations teams may find it relevant when considering the contribution of overseas trials that included multiple races or regions and a wide range of body weights.

Official PMDA Source

• Official title: Handling of Japanese Data for Confirmation of Comparability of Biosimilars to the Original Biopharmaceuticals (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Office of Cellular and Tissue-based Products
• Date on the cover: September 19, 2025
• PMDA PDF: Official PMDA document
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA list page. 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 the two differ. PMDA describes Early Consideration documents as reference information reflecting its views at the time of publication; those views may change as scientific knowledge develops.

Related Clinical Biostats Resources

• Bioequivalence: Average Bioequivalence (2x2 Crossover) — A related resource on average bioequivalence methods and a 2x2 crossover design.
• Sample Size for Bioequivalence Studies — A related resource on planning sample size for bioequivalence studies.