USFDA Updates Consideration for CES for Biosimilars in Draft Guidance

The USFDA has published a draft guidance updating scientific considerations for the use of comparative efficacy studies (CES) in demonstrating biosimilarity. The focus of the guidance is on therapeutic protein products.

Building on experience gained since the April 2015 guidance on the subject, FDA’s scientific approach consider that comparative analytical assessment (CAA) is more sensitive than CES in detecting differences between a proposed biosimilar and its reference product. Advances in analytical technologies allow for detailed structural characterization of highly purified therapeutic proteins, while in vitro biological and biochemical assays can effectively model in vivo functional effects with high specificity and sensitivity.

FDA highlights that the limited sensitivity of CES may stem from factors such as therapeutic dose range selection, characteristics of the clinical study population, and the choice of primary endpoints.

The updated guidance suggests that if CAA demonstrates high similarity—despite minor differences in clinically inactive components—then a well-designed pharmacokinetic (PK) similarity study and immunogenicity assessment may suffice to support biosimilarity. This marks a shift from the 2015 framework, which typically required analytical studies, toxicity assessments, clinical studies to demonstrate that there are no clinically meaningful differences between the biosimilar and reference product.

• USFDA: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies (Draft, October 2025)
• USFDA: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015)