Early Consideration on Handling of Japanese Data for Confirmation of Comparability of Biosimilars to the Original Biopharmaceuticals in Japan

Background and purpose

Japan has historically expected biosimilar development programs to include Japanese subjects in at least one comparative clinical trial (either for pharmacokinetic (PK) equivalence or efficacy equivalence) to support comparability to the original biopharmaceutical. PMDA explains that the purpose of biosimilar clinical trials is to confirm comparability with the reference product, and notes that Japanese data are not mandatory for bioequivalence evaluation of generic drugs. Following the revision of the Q&A on Guideline for Ensuring the Quality, Safety, and Efficacy of Biosimilars (Administrative Notice dated January 25, 2024), PMDA states it became possible to extrapolate clinical trial data generated in non-Japanese subjects to Japanese subjects if ethnic factors are considered to have no impact on clinical trial results. This Early Consideration document clarifies PMDA’s current regulatory perspective and encourages early consultation because evaluation remains product- and design-specific. Source: PMDA Early Consideration (September 19, 2025)

When an application may rely on non-Japanese clinical data alone

If a sponsor submits clinical trial data conducted only in non-Japanese subjects (instead of conducting a trial that includes Japanese subjects), PMDA expects a scientific explanation that ethnic factors do not affect the results of the relevant clinical trial. Source: PMDA Early Consideration (September 19, 2025)

PMDA’s three viewpoints for justifying extrapolation to Japanese subjects

1) Sensitivity to intrinsic and extrinsic ethnic factors

At consultation and at approval application, the sponsor should explain the product’s sensitivity to:

• Intrinsic ethnic factors (e.g., genetic factors; physiological and pathological factors; and drug properties that could drive population differences), and
• Extrinsic ethnic factors (e.g., medical practice environment for the target disease, including diagnostic approach and standard treatment; patterns of concomitant therapy; and other social/healthcare factors).

PMDA provides an illustrative table to support a structured discussion. Examples include:

Factor (examples)	Less sensitive to ethnic factors	More sensitive to ethnic factors
PK behavior	Linear	Non-linear
PD curve	Flat	Steep
Therapeutic dose range	Wide	Narrow
Metabolism	Minimal or multiple pathways	Highly metabolized, especially a single pathway
Genetic factors affecting PK/efficacy/safety	Small ethnic differences	Large ethnic differences
Bioavailability	High	Low
Protein binding potential	Low	High
Interaction potential (drug–drug/food/disease)	Low	High
BMI/body weight impact	Small	Large
Local action with minimal systemic exposure	Applicable	Not applicable
Inappropriate use potential	Low	High
Concomitant medication burden	Low	High
Medical practice environment (Japan vs overseas)	No meaningful differences	Meaningful differences

PMDA also points to using established frameworks on ethnic factors and multi-regional clinical trials as references when organizing the rationale. Source: PMDA Early Consideration (September 19, 2025)

2) Evidence from Japanese subgroup analyses or post-marketing data of the reference product

Sponsors should explain whether ethnic factors could affect PK, efficacy, and safety outcomes between Japanese and non-Japanese subjects using:

• Japanese subgroup analyses from clinical trials of the original biopharmaceutical, and/or
• Post-marketing data for the original biopharmaceutical.

The intent is to anchor the extrapolation argument in what is already known about the reference product across populations. Source: PMDA Early Consideration (September 19, 2025)

3) Quality attribute differences between the biosimilar and the reference

In quality comparability assessment, sponsors should describe any differences in quality attributes between the biosimilar and the original biopharmaceutical. If differences exist, PMDA expects an explanation—supported by published literature where relevant—of whether those differences could influence potential ethnic differences in PK, efficacy, or safety, including immunogenicity. Source: PMDA Early Consideration (September 19, 2025)

Practical implications for biosimilar developers

• Plan the “ethnic factor” rationale early: build a concise evidence package from the reference product’s global dataset (including any Japanese subgroup results) and a structured assessment of intrinsic/extrinsic factors.
• Use quality findings to focus the argument: if your biosimilar shows attribute differences vs the reference, explicitly assess whether they could change population sensitivity (especially immunogenicity).
• Engage PMDA early: PMDA emphasizes that these are general principles and that decisions should be made case-by-case based on product properties and trial design—so early consultation can reduce rework and align expectations.

Source: PMDA Early Consideration (September 19, 2025)