On October 29, 2025, the Food & Drug Administration (FDA) issued draft guidance clarifying the role of comparative efficacy studies (CES) in biosimilar product development. The release of this guidance during a government shutdown underscores the FDA’s commitment to streamlining biosimilar development.
In 2010, Congress enacted the Biologics Price Competition and Innovation Act, establishing an abbreviated licensure pathway for biosimilars under Section 351(k) of the Public Health Service (PHS) Act. Section 351(i) of the PHS Act defines “biosimilarity” to mean “that the biological 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.”
In 2015, the FDA published its original Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, outlining its regulatory expectations on this subject. It emphasized that CES studies would generally be necessary unless sponsors could justify otherwise, specifically stating:
A comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product based on structural and functional characterization, animal testing, human PK [pharmacokinetics] and PD [pharmacodynamics] data, and clinical immunogenicity assessment. A sponsor should provide a scientific justification if it believes that a comparative clinical study is not necessary.
CESs are expensive, typically requiring enrollment of 400–600 subjects at an average cost of $25 million per trial. These studies often delay product approval because they can take up to three years to complete.
Under the 2025 draft guidance, sponsors may now take a more streamlined approach in demonstrating biosimilarity by relying on a combination of comparative analytical assessments and comparative pharmacokinetic data. This approach is expected to expedite biosimilar development.
This policy shift reflects advancements in analytical technologies, which now allow for structural characterization of purified proteins and modeling of in vivo functions with exceptional specificity and sensitivity. It also builds on the FDA’s accumulated experience. To date, the FDA has approved 76 biosimilars and has ample evidence to justify the consideration of more sophisticated – and less costly – approaches to biosimilar development.
Before this guidance, the FDA had already provided product-specific advice allowing sponsors to forgo clinical efficacy studies for monoclonal antibody biosimilars. The publication of this draft guidance now formalizes and clarifies that position for all potential sponsors.
The guidance aligns with the Executive Order Lowering Drug Prices by Once Again Putting Americans First, which directs the FDA to accelerate biosimilar approvals. It is also consistent with the thinking of other regulatory authorities, such as the European Medicines Agency (EMA), which recently released a draft reflection paper aimed at reducing the clinical data requirements for biosimilar development and approval in the EU. The efforts of both regulatory authorities to reduce economic barriers to entry should further harmonize and accelerate regulatory pathways for these critically important products.
Interested parties can submit comments to Docket No. FDA-2011-D-0605.
If you have any questions, or would like additional information, please contact one of the attorneys on our FDA: Drug & Device team.
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