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Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies: Draft Guidance for Industry

DraftCenter for Drug Evaluation and Research,Office of New Drugs,Office of Therapeutic Biologics and Biosimilars10/29/2025
Totality of the EvidenceBiosimilarity

Description

This draft guidance describes considerations regarding a comparative clinical study or studies with efficacy endpoints (a comparative efficacy study or CES) intended to support a demonstration that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting a marketing application under the Public Health Service Act (PHS Act).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

4
Reference Product

The biological product to which a biosimilar is compared

Therapeutic Protein Product

Focus of the guidance for determining when a CES may inform biosimilarity

Interchangeable Product

Biosimilar product determined to be interchangeable with the reference product

Biosimilar

Biological product shown to be highly similar to an FDA-licensed reference product; Biological product demonstrated to be highly similar to a reference product

Stakeholders

1
Sponsor

Entity responsible for submitting applications under section 524B

Regulatory Context

Regulatory Activities

3
Biologics License Application

BLA for biological products

351(k) Application

Application seeking licensure of a biological product as biosimilar or interchangeable

351(k) BLA

Biologics license application submitted under section 351(k) of the PHS Act

Attributes

1
Safety, Purity, and Potency

Terms in which there must be no clinically meaningful differences; Standards required to be demonstrated for biological product licensure

Technical Details

Substances

1
Therapeutic Proteins

Highly purified proteins that can be structurally characterized

Testing Methods

4
Comparative Efficacy Study

Clinical study to detect differences in efficacy between biosimilar and reference products

Human PK and PD Studies

Comparative studies used to support biosimilarity

Clinical Immunogenicity Assessment

Used to determine if there are clinically meaningful differences

Analytical Studies

Data derived from these studies are required for a 351(k) BLA

Processes

2
Comparative Analytical Assessment

Assessment used to detect differences between two products at a structural and functional level

Comparative Efficacy Study

Clinical study with efficacy endpoints to support a demonstration of biosimilarity

Clinical Concepts

3
Pharmacodynamics

Study of the biochemical and physiological effects of drugs

Pharmacokinetics

Study of how the body interacts with administered substances

Immunogenicity

Assessment of the immune response to the biological product

Identified Hazards

Hazards

1
Toxicity

Assessment of toxicity required in a 351(k) BLA

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies: Draft Guidance for Industry | Guideline Explorer | BioRegHub