In a new draft guidance, issued on October 29, 2025, the FDA proposed major updates to simplify biosimilarity studies and potentially reduce clinical testing for therapeutic protein products. The guidance, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies Guidance for Industry,” is a long-awaited announcement that could streamline the biosimilar approval process.
To establish biosimilarity, the sponsor of a proposed product must submit data and information in its aBLA demonstrating that there are no “clinically meaningful differences” between its proposed product and the reference product in terms of safety, purity and potency of the product. The FDA may waive the requirement of clinical studies in this demonstration. 42 USC § 262(k)(2)(A)(ii). However, in guidance issued in April 2015, FDA explained that the nature and scope of any comparative clinical studies required in an aBLA would depend on the extent of any “residual uncertainty” about biosimilarity after the structural and functional characterization data had been analyzed. Under this framework, the FDA explained that, at a minimum, the agency generally expected all aBLAs to contain data and information from comparative pharmacokinetic (“PK”) and (where available) pharmacodynamic (“PD”) clinical trials, as well as a clinical immunogenicity assessment.
The FDA’s new guidance provides an “updated framework” based on the FDA’s “significant experience” evaluating data from comparative analytical and clinical studies in the time since the issuance of the 2015 guidance. Based on the FDA’s “evolving” scientific approach, which recognizes the sensitivity of currently available comparative analytical assessments, the FDA recommends that sponsors “carefully consider” what clinical studies would be necessary to support a demonstration of biosimilarity. The FDA has explained that comparative clinical efficacy studies are generally not as sensitive as comparative analytical assessments. Accordingly, if a comparative analytical assessment supports a demonstration of biosimilarity, then “an appropriately designed 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 terms of safety, purity, and potency.” Although the FDA notes that there are some circumstances where a clinical efficacy study may still be important to inform a demonstration of biosimilarity (e.g., for locally acting products, where comparative pharmacokinetics would be difficult or not meaningful), sponsors should consider the “streamlined approach” FDA has outlined 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 comparative analytical assessment; and a human pharmacokinetic similarity study is feasible and clinically relevant.
According to the FDA’s announcement released in connection with the draft guidance, clinical efficacy studies add 1–3 years on to the biosimilar approval process, and cost $24 million on average, frequently adding little information to the assessment of biosimilarity. Meanwhile, only 76 biosimilars, referencing a “small fraction of approved biologics,” have been approved in the fifteen years since the Biologics Price Competition and Innovation Act (“BPCIA”) created the biosimilar approval process. According to Health and Human Services Secretary Robert F. Kennedy Jr., “for too long, a burdensome approval process has kept patients from accessing more affordable biosimilars” and “[t]his bold action by the FDA accelerates biosimilar development, drives market competition, expands patient options, and advances our mission to Make America Healthy Again.”
Although the FDA’s new guidance offers promise to streamline biosimilar approvals, it remains to be seen how the FDA will apply the guidance in practice. For example, the FDA’s recommendation that applicants “carefully consider what clinical stud[ies] would be necessary” does not definitively state when a comparative analysis will be sufficient to enable regulatory decision making. In any case, the long-awaited guidance is a positive step forward for biosimilar developers.