FDA Proposes To Eliminate Comparative Clinical Efficiency Studies For Biosimilars

In a new draft guidance issued on October 29, 2025, the U.S. Food and Drug Administration (FDA) announced that it will drastically pare back the requirement of data from comparative clinical efficiency studies (CES) to the demonstration of biosimilarity in 351(k) biologics license applications (BLAs).¹ Now 15 years after the passage of the Biologics Price Competition and Innovation Act, which created the biosimilars pathway, FDA views such studies as, by and large, "resource-intensive" and "unnecessary" for biosimilar development and approval.

The draft guidance was rolled out as part of a press event on FDA's intention to streamline biosimilar development and improve access to biosimilars. The other key aspect of FDA's rollout is its intention to designate all biosimilars as interchangeable — a move that is intended to facilitate pharmacy substitution under state laws. As FDA Commissioner Makary stated, the agency is focused on the promise of biosimilars to lower drug prices, a major administration priority. "By streamlining the biosimilar development process and helping advance interchangeability," he explained, "we can achieve massive cost reductions for advanced treatments for cancer, autoimmune diseases, and rare disorders affecting millions of Americans."²

Background

The biosimilars pathway defines a biosimilar as a biological product that is "highly similar" to and has "no clinically meaningful differences from" an approved innovator product, referred to as a reference product. Interchangeable biosimilars are biosimilars that have met additional standards and, as such, are able to be substituted for the reference product without the intervention of the prescribing health care provider.³ In both cases, the biosimilar or interchangeable applicant is required by statute to submit data from analytical studies and an assessment of toxicity to support the demonstration of biosimilarity — as well as "a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics)" sufficient to demonstrate safety, purity, and potency in at least one indication for which the reference product is approved.⁴ Traditionally, FDA has required a CES, as well as data from pharmacokinetic studies, to meet this clinical study requirement,⁵ with additional justification and/or study data required to meet the threshold for interchangeability.⁶

New Guidance Eliminates CES in Most Circumstances

As stated in the new Updated Draft Scientific Considerations Guidance, however, FDA's thinking has evolved based on experience, an evolution in the agency's scientific approach to determining the need for CES, and improvements in analytical technologies. FDA fnow believes that in many circumstances analytical data will be more sensitive than CES in detecting differences between a proposed biosimilar and its reference product.⁷ In at least those circumstances, a CES will not be needed to demonstrate biosimilarity. This includes 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] CAA; and
• A human pharmacokinetic similarity study is feasible and clinically relevant."⁸

FDA retains the flexibility to require a CES in some circumstances, but the agency is clearly taking a very flexible approach with respect to the statutory clinical study requirement for demonstrating biosimilarity. This is particularly the case as most biosimilars will have a feasible and clinically relevant pharmacokinetic similarity study on which to rely.

For a proposed biosimilar that is "highly similar" to a reference product as demonstrated in a comparative analytical assessment, FDA will require only "an appropriately designed human pharmacokinetic similarity study and an assessment of immunogenicity" to meet the standard for biosimilarity.⁹ Given the agency's additional flexible posture with respect to requiring additional clinical "switching studies" for interchangeability, and the announcement that FDA will designate all approved biosimilars as interchangeable, this means that at least some biosimilars will be pharmacy substitutable based largely on data from a comparative analytical assessment, pharmacokinetic similarity data, and immunogenicity assessment.

This policy shift is being billed by the administration as a move to increase quick and affordable access to biosimilars, noting among other things, that the high cost of biosimilar development contributes to a lack of biosimilar competition compared to generic products for small-molecule drugs.¹⁰ While there are many factors associated with the slow rate of adoption of biosimilars in the United States, FDA's actions are taking a calculated risk that bypassing the conduct of CES will contribute to accelerating future biosimilar market entry and uptake.

Footnotes

1 FDA, Draft Guidance, "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies" (Oct. 2025) (Updated Draft Scientific Considerations Guidance).

2 FDA News Release, "FDA Moves to Accelerate Biosimilar Development and Lower Drug Costs" (Oct. 29, 2025).

3 41 U.S.C. §§ 262(i)(2)-(4).

4 42 U.S.C. § 262(k)(2)(A)(i).

5 See FDA, Guidance, "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product" (Apr. 2015).

6 FDA, Draft Guidance, "Considerations in Demonstrating Interchangeability With a Reference Product: Update" (June 2024).

7 Updated Draft Scientific Considerations Guidance at 3.

8 Id. at 4.

9 Id.

10 FDA, "FACT SHEET: Bringing Lower-Cost Biosimilar Drugs to American Patients."

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