Executive Summary
The Food and Drug Administration (FDA) has issued new draft guidance signaling a policy shift toward reducing the need for comparative efficacy (CES) studies in biosimilar applications. The FDA’s approach aims to accelerate biosimilar development timelines, lower costs, and increase competition for biologics.1
Background
Biological products, or biologics, are large, complex molecules produced in living systems such as therapeutic proteins, antibodies, and gene- or cell-based therapies. Under the Public Health Service Act (42 U.S.C. § 262(i)), a biosimilar is a biological product that is highly similar to an FDA-licensed reference product with no clinically meaningful differences in terms of safety, purity, and potency.
Traditionally, to obtain approval, biosimilar applicants were required to demonstrate biosimilarity through data obtained from a clinical study or studies.
The Draft Guidance
The FDA’s October 2025 draft guidance, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies,” (Draft Guidance) marks a major step toward simplifying biosimilar development.2 The Draft Guidance focuses on therapeutic proteins and builds on the FDA’s September 2025 guidance, which highlights the central role of advanced analytical comparability studies in establishing biosimilarity.3
According to the Draft Guidance, if a comparative analytical assessment (CAA) supports a demonstration that a proposed biosimilar is highly similar to its reference product, a human pharmacokinetic similarity study and an assessment of immunogenicity may be sufficient to evaluate whether there are clinically meaningful differences between the proposed biosimilar and the reference product. In such cases, a CES “may not be necessary” to support a demonstration of biosimilarity.
The Draft Guidance however made clear that in this streamlined approach, “the CAA, pharmacokinetic similarity data, and immunogenicity assessment to support a demonstration of biosimilarity, would be evaluated based on the totality of the evidence submitted in the biologics license application.” The Draft Guidance further delineates that the streamlined approach should be considered when:
- the reference product and the proposed biosimilar are manufactured from clonal cell lines, are highly purified, and can be well-characterized analytically;
- the relationship between quality attributes (e.g., structure, post-translational modifications, etc.) and clinical efficacy is generally understood for the reference product, and these attributes can be evaluated by assays included in the CAA; and
- human pharmacokinetic study is feasible and clinically relevant.
These developments show the FDA’s increasing confidence that analytical methods can establish biosimilarity without full-scale clinical studies. However, the FDA acknowledges that there remain circumstances “when a CES may inform a demonstration of biosimilarity.” In view of the regulatory changes and implications, the FDA encourages biosimilar applicants to communicate with the FDA early in product development prior to the initiation of relevant studies.
Implications for Biosimilar Product Development
- Reduced Clinical Burden: Previously required clinical studies may be waived for many biosimilar candidates, potentially halving development time and reducing costs.
- Emphasis on Analytical Rigor: Analytical and functional characterization are becoming more important in establishing biosimilarity.
Strategic Considerations for Biologic Developers
- R&D and Portfolio Planning: Stay abreast of legislative and FDA regulatory changes regarding biosimilarity requirements and plan accordingly. For example, where applicable, make use of the streamlined process outlined by prioritizing robust analytical and pharmacokinetic data packages.
- Product Lifecycle Management: Update commercialization timelines and related patent and regulatory lifecycle management strategies in view of the changing legislative and FDA regulatory environment.
- Trade Secret Protection for Analytical Assays: Review patent and trade secret strategies to gain a competitive advantage.
Conclusion
The Draft Guidance marks a significant policy shift toward the use of analytical methods to establish biosimilarity. With the FDA and legislative bodies targeting accelerated development timelines, lower costs, and increase competition, additional changes are expected. As such, biologic developers should stay abreast of legislative and regulatory changes and effectively implement strategies to maintain a competitive advantage.
[1] U.S. Food and Drug Administration, Scientific considerations in demonstrating biosimilarity to a reference product: Updated recommendations for assessing the need for comparative efficacy studies (Draft Guidance for Industry) (Oct. 2025), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product-updated-recommendations.
[2] Id.
[3] U.S. Food and Drug Administration, Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations (Draft Guidance for Industry) (Sept. 2025), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-therapeutic-protein-biosimilars-comparative-analytical-assessment-and-other-quality.
