USFDA’s Draft Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

The U.S. Food and Drug Administration (FDA) has released a new draft guidance titled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies” (October 2025).

This document represents a major shift in the FDA’s scientific and regulatory approach to biosimilar product development, particularly regarding when comparative efficacy studies (CES) may or may not be required to support a 351(k) Biologics License Application (BLA).

Biosimilar Product:

A biological product that is highly similar to an FDA-licensed reference product, notwithstanding minor differences in clinically inactive components, and that has no clinically meaningful differences in terms of safety, purity, and potency.

The Biologics License Application (BLA) submitted under section 351(k) of the Public Health Service (PHS) Act enables abbreviated licensure for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. Sponsors must demonstrate that the proposed product is highly similar to the reference, with no clinically meaningful differences in safety, purity, or potency, except for minor differences in inactive components. Recent years have brought significant improvements in analytical assessment technologies. The FDA recognizes that these methods are often more sensitive than comparative efficacy studies (CES) at distinguishing minor differences between highly purified therapeutic proteins. Therefore, a well-designed comparative analytical assessment (CAA), supported by human pharmacokinetic (PK) data and immunogenicity assessment, may be sufficient in many cases, and a CES is not always required. a. When a CES May Not Be Needed

According to the updated guidance, a comparative efficacy study may not be necessary when:

• The comparative analytical assessment (CAA) demonstrates that the proposed biosimilar is highly similar to the reference product.

• Human pharmacokinetic (PK) studies show similar exposure and clearance profiles.

• Immunogenicity assessments confirm that no meaningful immune response differences exist.

• The product is a well-characterized therapeutic protein, such as monoclonal antibodies, recombinant hormones, or enzymes, manufactured using highly purified clonal cell lines.

In such cases, FDA recommends that sponsors consider a streamlined development approach relying on the totality of the evidence — emphasizing analytical and functional comparability instead of extensive clinical efficacy trials.

b. When a CES May Still Be Required

Comparative efficacy studies may still be warranted for:

• Locally acting products (e.g., ophthalmic or intravitreal formulations) where systemic PK assessment is not feasible.

• Novel or complex mechanisms of action where structure–function relationships are not fully understood.

• Cases where analytical characterization or PK data reveal residual uncertainty that could impact clinical outcomes.

Sponsors are encouraged to engage FDA early via pre-submission meetings to discuss study design expectations.

FDA continues to apply the “totality of evidence” approach — a holistic evaluation of data from:

1. Analytical studies (structure, post-translational modifications, activity).

2. Animal studies (toxicity, if needed).

3. Human PK/PD studies.

4. Clinical immunogenicity assessments.

If these data streams consistently demonstrate similarity, the Agency may waive the requirement for a comparative efficacy trial. This approach aligns with international regulatory trends, including those of the European Medicines Agency (EMA) and the World Health Organization (WHO).

This draft guidance significantly reduces clinical trial burden for biosimilar sponsors, allowing:

• Faster and more cost-efficient development.

• Increased patient access to high-quality, affordable biologics.

• Regulatory predictability through consistent application of risk-based principles.

For more details, please refer to the guidance provided: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies