On October 29, 2025, the FDA published new draft guidance titled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies.” The draft guidance includes the recommendations of the FDA in cases where sponsors should consider a simplified approach to biosimilar development and therefore waive conducting a clinical efficacy study to support of a biosimilar application.
This draft guidance highlights recommendations for demonstrating biosimilarity to a reference product, pointing out that following comparative analytical testing, pharmacokinetic (PK) and pharmacodynamic (PD) testing, and in the presence of a clinical immunogenicity assessment demonstrating a high degree of similarity and the absence of clinically significant differences between the proposed product and the reference product, Comparative Efficacy Studies (CES) are not necessary.
The FDA advises considering a simplified approach when:
- the reference product and proposed biosimilar product are manufactured from clonal cell lines, are highly purified, and can be well-characterized analytically;
- the relationship between quality attributes and clinical efficacy is generally understood for the reference product, and these attributes can be evaluated by assays included in the CAA;
- a human pharmacokinetic similarity study is feasible and clinically relevant.
Comparative efficacy studies are therefore only needed to resolve cases of “residual uncertainty” or for products for which clinical endpoints or PK data are not feasible or clinically relevant.
The new draft guidance indicates that the agency now considers comparative clinical efficacy studies to be the exception rather than the rule for biosimilar development programs, at least for therapeutic protein products.
SOURCES:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product-updated-recommendations