On October 29, 2025, FDA published new draft guidance titled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative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.”FDA, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies: Guidance for Industry (Oct. 2025), https://www.fda.gov/media/189366/download (2025 Draft Guidance). The draft guidance contains FDA’s recommendations for when sponsors should consider a streamlined approach to biosimilar development and forego conducting a clinical efficacy study to support a biosimilar application.
FDA has long encouraged sponsors to take such a streamlined approach to their biosimilar development programs; in 2023, for example, FDA held a workshop to specifically discuss “reevaluating the need” for comparative clinical efficacy studies in biosimilar development.FDA, Increasing the Efficiency of Biosimilar Development Programs – Reevaluating the Need for Comparative Clinical Efficacy Studies (Sep. 2023), https://www.fda.gov/drugs/news-events-human-drugs/increasing-efficiency-biosimilar-development-programs-reevaluating-need-comparative-clinical. The new draft guidance synthesizes FDA recommendations from this effort and is accompanied by a new fact sheet directed at “insufficient biosimilar market competition.”FDA, FACT SHEET: Bringing Lower-Cost Biosimilar Drugs to American Patients, https://www.fda.gov/media/189382/download?attachment (2025 Fact Sheet). The fact sheet and new draft guidance provide the clearest signal yet that FDA intends to reduce its reliance on comparative clinical data in its biosimilar reviews. FDA has also indicated there may be more changes for both biosimilar and interchangeable products in the near future, with Commissioner Makary saying FDA thinks “all biosimilars should be interchangeable” and plans to issue final guidance on interchangeability to eliminate the “bureaucratic switching studies that have been required.”US Department of Health and Human Services, Biosimilars Reform, https://www.youtube.com/watch?v=uqqMfugt-U8, at 13:52, 29:55.
Section 351(k) of the Public Health Service Act (PHSA) requires an application for licensure of a biosimilar product to include, among other things, a demonstration that the product is “biosimilar to a reference product.”42 U.S.C. § 262(k)(2)(A)(i). The statute requires that this demonstration be based on data derived from “analytical studies,” “an assessment of toxicity,” and “a clinical study or studies ... that are sufficient to demonstrate safety, purity, and potency” in the conditions of use for which the reference product is licensed.Id. However, the statute provides FDA with the discretion to waive any data requirement for a biosimilar application if FDA deems it “unnecessary.”Id. § 262(k)(2)(A)(ii).
Regardless of the data FDA ultimately requires for the demonstration of biosimilarity, an application under Section 351(k) must support an overall finding that the proposed biosimilar product is “highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”Id. § 262(i)(2).
FDA has long said that the primary purpose of a clinical efficacy study in biosimilar development is to resolve “residual uncertainty” about whether clinically meaningful differences exist between the proposed product and the reference product following comparative analytical testing, pharmacokinetic (PK) and pharmacodynamic (PD) testing, and a clinical immunogenicity assessment.See, e.g., FDA, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (Apr. 2015), at 7, 18, https://www.fda.gov/media/82647/download (2015 Guidance). Since 2015, FDA has advised sponsors to take a “stepwise approach” to biosimilar development under which sponsors evaluate the need for comparative clinical testing only after conducting a series of initial steps, including comparative analytical and PK/PD analyses.Id. at 7. FDA’s longstanding view is that comparative analytical testing in particular — the comprehensive, head-to-head evaluation of how a proposed biosimilar product’s key structural and functional properties differ from the reference product — is the foundation for a demonstration of biosimilarity.See FDA, Biosimilars Info Sheet: Level 2: Regulatory and Scientific Concepts, https://www.fda.gov/media/182186/download. According to FDA, comparative analytical data are “generally much more sensitive than clinical studies in detecting differences between products.”Id. Thus, while FDA has generally expected sponsors to conduct comparative analytical and PK/PD testing, it has made clear that “the type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis.”2015 Guidance at 9.
Consistent with this view, FDA has taken steps in the last decade to streamline biosimilar development and minimize requirements for comparative clinical efficacy trials. For example, in September 2021, as part of the reauthorization of the Biosimilar User Fee Act (BsUFA), FDA committed to establishing a regulatory science pilot program to both improve the efficiency of biosimilar product development and advance the development of interchangeable products.See FDA, BsUFA III Regulatory Research Pilot Program: Research Roadmap, https://www.fda.gov/media/164751/download (“Research Roadmap”). In the following two years, FDA held workshops to provide an open platform for discussions on the pilot program,FDA, FDA Workshop: Increasing the Efficiency of Biosimilar Development Programs, Sep. 19, 2022 https://www.fda.gov/drugs/news-events-human-drugs/fda-workshop-increasing-efficiency-biosimilar-development-programs-09192022; FDA, Increasing the Efficiency of Biosimilar Development Programs – Reevaluating the Need for Comparative Clinical Efficacy Studies, Sep. 12-13, 2023, https://www.fda.gov/drugs/news-events-human-drugs/increasing-efficiency-biosimilar-development-programs-reevaluating-need-comparative-clinical. and in 2023, FDA released its research plan, stating that while “[r]ecent efforts have resulted in alternatives to comparative clinical studies for certain biosimilars ... many biosimilar development programs continue to conduct comparative efficacy studies.”Research Roadmap at 5. Earlier this year, FDA released its interim report and held another public meeting to discuss progress on its dual goals of increasing reliance on analytical data in demonstrations of biosimilarity and developing alternatives to studies involving human participants, setting the stage for FDA’s latest action.FDA, BsUFA III Regulatory Research Pilot Program: Interim Report, July 2025, https://www.fda.gov/media/187445/download?attachment; FDA, FDA Public Meeting; BsUFA III Regulatory Science Program Interim Public Meeting, Sep. 25, 2025 https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/fda-public-meeting-bsufa-iii-regulatory-science-program-interim-public-meeting-09182025.
FDA states that it has “gained significant experience in evaluating analytical differences between proposed biosimilar products and their reference products and understanding the impact of those analytical differences.”2025 Draft Guidance at 3. FDA also notes that analytical technologies have evolved to structurally characterize and model the in vivo functional effects of therapeutic proteins with a high degree of specificity and sensitivity.Id. As a result of these developments, FDA states that for therapeutic protein biosimilars, if the data from a comparative analytical assessment supports a demonstration that the proposed product is highly similar to its reference product, an appropriately designed human PK similarity study and an assessment of immunogenicity may suffice for FDA to evaluate whether there are clinically meaningful differences between the proposed biosimilar and the reference product in terms of safety, purity, and potency.Id. at 4.
FDA recommends that sponsors now “carefully consider” what clinical studies would be necessary to support a demonstration of biosimilarity when designing their development programs.Id. FDA specifically recommends sponsors consider a streamlined approach when:
FDA notes there will be circumstances when a comparative efficacy study may still be needed to fully inform a demonstration of biosimilarity, such as for locally acting products where a comparative PK study is neither feasible nor clinically relevant, though there may be further opportunity to explore a comparative clinical study with a clinically relevant endpoint other than an efficacy.Id. In either case, FDA encourages sponsors to discuss their proposed approach with FDA “early in product development and prior to initiating clinical studies.”Id.
FDA’s new draft guidance signals that the agency now views comparative clinical efficacy studies as an exception rather than the rule for biosimilar development programs, at least for therapeutic protein products. This shift from 2015 FDA guidance will likely encourage more sponsors to launch biosimilar development programs, including for biologics that currently have no biosimilars. But the draft guidance offers little insight into FDA’s thinking on when analytical data, in combination with PK and immunogenicity assessments, will suffice for licensure, even under those circumstances in which FDA recommends sponsors consider a streamlined approach. Since FDA continues to view the comparative analytical assessments as the foundation of a biosimilar development program, FDA’s thinking on this will likely offer critical insight into the agency’s approach to future biosimilar approvals.
We expect FDA to offer additional insight on its biosimilar initiatives at the BsUFA III Reauthorization Kickoff Public Meeting on December 3, 2025.FDA, “BsUFA IV: Fiscal Years 2028-2032,” https://www.fda.gov/industry/biosimilar-user-fee-amendments/bsufa-iv-fiscal-years-2028-2032.