Considerations for Determining the Necessity of Comparative Efficacy Studies in Demonstrating Biosimilarity between Biosimilars and Reference Products — PMDA Early Consideration Summary

In Plain Language

A comparative efficacy study (CES) directly compares how well a biosimilar and its reference product work in patients. The document addresses whether such a study is always needed to establish biosimilarity, given that modern analytical methods can compare product characteristics in detail and that comparative quality and pharmacokinetic evidence may help assess similarity. It says a CES may be considered unnecessary when comparative quality studies, comparative pharmacokinetic (PK) studies or comparative PK/pharmacodynamic (PD) studies, and an adequate understanding of the product characteristics together support the conclusion that quality differences do not affect efficacy, safety, or immunogenicity. This is a conditional possibility, not a general exemption: applicants should explain their scientific rationale in a face-to-face consultation meeting with PMDA. The document outlines the quality, clinical, and other information to present so that the case can be considered on its evidence.

What This Guidance Covers

The document applies to medicinal products within the scope of the “Guidelines for Ensuring the Quality, Safety, and Efficacy of Biosimilars” identified in the document. It focuses specifically on considerations for determining whether a comparative efficacy study is necessary when demonstrating biosimilarity between a biosimilar and its reference product. It describes information applicants should discuss with PMDA when proposing that biosimilarity can be established without conducting a CES.

The document does not state that comparative efficacy studies are unnecessary for all biosimilars, nor does it provide a simple rule that automatically determines when one can be omitted. Instead, its basic principle is conditional: a CES may be considered unnecessary when the quality and clinical evidence, together with an adequate understanding of product characteristics, establish that differences in quality attributes do not affect efficacy, safety, and immunogenicity, and that biosimilarity can be established. The document asks applicants to consult PMDA case by case about whether a CES is necessary.

It also does not replace the wider biosimilar development considerations described in the guidelines named in its scope. Its stated purpose is to supplement the administrative notice identified in its introduction on determining the necessity of a CES and to present PMDA’s current regulatory perspective more clearly.

Why It Matters

The document describes a change in the scientific and regulatory context for biosimilar development. Comparative efficacy studies have traditionally been conducted alongside comparative quality and PK studies. However, biotechnology analytical methods have improved in both comprehensiveness and performance. The document notes that comparative efficacy studies have been suggested to be less sensitive than comparative quality studies for detecting differences between a biosimilar and its reference product.

The document also points to accumulated experience in biosimilar development and approval review. In some cases, biosimilarity has been considered adequately established without a CES. At the same time, there has been international discussion about the circumstances in which a CES may be unnecessary. The document responds to this context by setting out the types of evidence and explanations applicants should bring to a PMDA consultation, rather than treating the presence or absence of a CES as a decision detached from the other evidence.

The central issue is not simply whether two products have similar measured characteristics. Applicants also need to explain whether any differences found could matter to how the products work, their safety, or the immune response they may prompt. The document’s approach connects the comparison of product attributes to their potential clinical consequences.

Key Recommendations

1. Establish similarity through an evidence-based assessment of quality and clinical data. The document says it is necessary to clarify the extent of similarity in quality attributes through comparative quality studies with the reference product. Selection of the attributes to compare should be scientifically justified and include physicochemical, structural, and functional attributes. Applicants also need to demonstrate that any differences identified do not affect efficacy, safety, and immunogenicity.

2. Consider the full evidence package before proposing that a CES is unnecessary. A CES may be considered unnecessary when comparative quality studies, comparative PK studies or comparative PK/PD studies, and an adequate understanding of product characteristics demonstrate both that quality differences do not affect efficacy, safety, and immunogenicity and that biosimilarity to the reference product can be established. These conditions are central to the document’s basic principle; a proposal should not rely on one kind of evidence in isolation.

3. Consult PMDA case by case and explain the rationale. Applicants are encouraged to consult PMDA on a case-by-case basis, including through face-to-face consultation meetings, on whether a CES is necessary. When discussing whether a CES is necessary, applicants should clearly explain why they consider biosimilarity can be established without the study. The document outlines information for the consultation materials; it does not describe a universal decision rule that replaces case-specific discussion.

4. Present the quality-related evidence and its interpretation. Consultation materials should address the mechanism of action (MoA) for the biosimilar under consultation; available information on relationships between its quality attributes and PK, efficacy, safety, and immunogenicity; an overview of analytical methods; similarities or differences in the cell substrates used; and the plan or results of comparative quality studies. For the reference product’s approved indications, at least those intended for the biosimilar’s initial marketing authorization application, an explanation should be provided on whether the MoA has similarities or differences among the indications. Applicants should explain why the selected test items, number of lots, and evaluation methods are appropriate, including the results of risk assessments for each quality attribute. Available results, including preliminary comparative quality study results, should be presented. Any potential impact of identified quality differences on efficacy, safety, and immunogenicity should be explained with appropriate scientific justification.

5. Describe the clinical evidence and the proposed use of indications. For the comparative PK study, provide the protocol or results and describe the study population, dosage and administration, evaluation endpoints, methods for equivalence assessment, and number of subjects. Explain the conduct and appropriateness of the safety evaluation, the immunogenicity assessment and, if applicable, the PD evaluation in the comparative PK study. Consultation materials should also include the clinical data package and the rationale for extrapolating indications. For the reference product’s approved indications, at least those intended for the biosimilar’s initial marketing authorization application, explain the rationale for considering that such indications can be obtained.

6. Explain practical difficulty conducting a CES for a rare disease. If the target disease is rare and conducting a CES is difficult, the grounds for that difficulty should be clearly explained. The document specifically includes information on the number of patients with the target disease among the points to explain.

Practical Implications

Interpretation: For sponsors, the document makes the case for not conducting a CES one that should be assembled across product-quality and clinical evidence. A request to consider a CES unnecessary needs a reasoned account of why the observed or possible quality differences do not affect efficacy, safety, or immunogenicity, and how the overall evidence supports biosimilarity. The document does not give a fixed checklist of numerical acceptance thresholds for this decision.

Interpretation: For statisticians and clinical study teams, the listed consultation information draws attention to the design and interpretability of comparative PK evidence. The protocol or results should make the population, dosing, endpoints, equivalence-assessment methods, and subject numbers clear. Safety and immunogenicity evaluation should also be explained, along with PD evaluation where relevant. These points make the design and the evidence it produces visible to reviewers considering the broader case.

Interpretation: For analytical and pharmaceutical scientists, the document places emphasis on the justification for attribute selection, analytical methods, lot numbers, and evaluation methods. It also calls for the results of risk assessments for each quality attribute and a scientific explanation of the possible consequences of differences. This means the comparison is not just a list of measurements: the applicant’s materials should connect the attributes examined with their potential relevance to the product’s performance and risks.

Interpretation: For regulatory teams, the consultation is an opportunity to present the rationale and evidence together, including the intended initial indications and the basis for extrapolating indications. Where disease rarity makes a CES difficult, the document calls for a clear explanation of the grounds, including patient-number information. The document’s wording supports advance, case-specific discussion with PMDA; it does not promise that a particular package will lead to a CES being considered unnecessary.

Technical Details

Several terms help clarify how the evidence fits together. A quality attribute is a characteristic of a medicinal product assessed in quality studies. The document specifically names physicochemical, structural, and functional attributes. A comparative quality study examines the biosimilar and reference product to clarify how similar these attributes are. The document stresses that the attributes selected for comparison should be relevant and chosen on a scientifically justified basis.

The document refers to comparative PK studies and, where relevant, comparative PK/PD studies as part of the evidence considered alongside comparative quality studies. It asks applicants to describe the study population, dosage and administration, evaluation endpoints, methods for equivalence assessment, and number of subjects. It does not specify a particular equivalence margin, sample-size formula, or statistical procedure in this document. The method used for equivalence assessment is one of the items applicants should explain.

The decision logic can be read as a sequence of linked questions. First, were the quality attributes chosen and compared appropriately? Second, what differences were found, and what is the scientific basis for assessing their potential impact on efficacy, safety, and immunogenicity? Third, do comparative PK or PK/PD evidence and the understanding of product characteristics support biosimilarity in light of those quality findings? Finally, can the applicant explain the clinical data package and the intended indications, including the rationale for extrapolation? The document does not turn these questions into a mechanical score or a single statistical test.

For the quality comparison, the consultation materials should cover preliminary results if available as well as completed comparative quality study results. Applicants should explain the number of lots and methods used, and include the results of risk assessments for each quality attribute. The key technical point is to link the attribute-level comparison to the possible effects of any difference, not simply to report that an assay was performed.

For the clinical component, the document asks applicants to explain not only the comparative PK study but also its associated safety and immunogenicity assessment, and PD evaluation if applicable. It separately asks for the clinical data package and an indication-extrapolation rationale. Thus, when the proposed initial application includes reference-product indications, the materials should explain the rationale for considering that those indications can be obtained. The text does not give a specific formula or universal evidentiary threshold for this explanation.

Who Should Read It

This document is most relevant to teams developing biosimilars within the scope stated in the document’s application section, particularly when considering whether a comparative efficacy study is needed. It will be useful to regulatory affairs staff preparing a PMDA consultation, clinical and pharmacology teams planning comparative PK or PK/PD studies, statisticians involved in equivalence assessments, and analytical and pharmaceutical scientists planning comparative quality studies. It is also relevant to safety and immunogenicity specialists, and to teams considering indication extrapolation or facing practical difficulty conducting a CES for a rare disease.

Official PMDA Source

• Official title: Considerations for Determining the Necessity of Comparative Efficacy Studies in Demonstrating Biosimilarity between Biosimilars and Reference Products (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Office of Cellular and Tissue-based Products
• Date on cover: May 18, 2026
• PMDA PDF: Official PMDA document (PDF)
• 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 for its full context; this summary does not replace it. PMDA provides the English version for reference, and the Japanese original prevails if the two differ. Early Consideration documents are reference information reflecting PMDA’s views at the time of publication; those views may change as scientific knowledge develops.

Related Clinical Biostats Resources

• Bioequivalence: Average Bioequivalence (2x2 Crossover) provides background on average bioequivalence assessment in a crossover design, a related concept for understanding comparative PK study methods.
• Equivalence Test for Means (TOST) explains a statistical approach to equivalence testing that may help readers understand the equivalence-assessment methods applicants describe.
• Sample Size for Bioequivalence Studies discusses sample-size planning for bioequivalence studies, a related consideration when explaining comparative PK study design.