FDA Issues Updated Framework for Biosimilar Reviews

On Wednesday, Oct. 29, the Food and Drug Administration (FDA) issued draft guidance proposing to update its biosimilar review framework. Under the new approach, most biosimilar applications will no longer require comparative efficacy studies (CES) if pharmacokinetic and immunogenicity data show the product is biosimilar to its reference biologic. For many biosimilars, this will pave the way for approval without a costly clinical efficacy trial.

Until now, the FDA has generally expected biosimilar application sponsors to conduct CES, which are clinical trials designed to show that a proposed biosimilar and its reference product have no clinically meaningful differences in therapeutic effect when administered to a patient. This expectation came from the Public Health Service Act, which says biosimilar applications must contain data from “a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate the safety, purity, and potency” of the biosimilar in comparison to the reference biologic. The Public Health Service Act also provides that the FDA may determine that this element of an application is unnecessary. Earlier guidance released by the FDA in 2015 said biosimilar sponsors could provide a scientific justification if it believed that a comparative clinical study was not necessary, and while the agency has not required CES for some products in the past, these waivers have been limited.

In the updated draft guidance, the FDA noted that since 2015, the agency had “gained significant experience” in evaluating biosimilar products and has found that comparative analytical assessments (CAA)—analytical assays that can measure molecular and functional differences—are better than CES at detecting differences between biosimilar and reference products. For this reason, the draft guidance now advises that an appropriately designed pharmacokinetic similarity study and an assessment of immunogenicity may be sufficient to determine whether there are differences between the biosimilar and reference product, and under a streamlined approach, CES will often not be necessary. The draft guidance cautions that there are some circumstances when comparative clinical studies may still be needed, namely for products injected into the eye and in circumstances when non-efficacy clinical endpoints (i.e., safety) may still be needed to determine biosimilarity. The FDA encourages sponsors to discuss their proposed approaches with the agency early in product development, before initiating clinical studies.

The announcement of the updated review framework continues a trend at the FDA to streamline biosimilar approvals. Since taking the helm of the FDA earlier this year, Commissioner Marty Makary has repeatedly argued that the framework had been too burdensome for biosimilar developers, saying that he wanted to make it more like the small molecule generic drug review process, which does not require clinical efficacy studies. FDA career officials, including Sarah Yim, the director of the Office of Therapeutic Biologics and Biosimilars, have been working on streamlining CES requirements since at least 2023, saying then that the FDA should “be moving away from the stepwise approach” to biosimilar applications. Additionally, in recent years, the FDA has generally not required additional studies for new biosimilars to be deemed interchangeable with their reference biologic, allowing biosimilar products to be substituted at the pharmacy counter. Additional forthcoming guidance is expected to clarify that switching studies are no longer required.

At a press conference held on Oct. 29, 2025, the Department of Health and Human Services (HHS) Secretary Robert F. Kennedy Jr., Commissioner Makary and the Centers for Medicare and Medicaid (CMS) Administrator Mehmet Oz announced the updated review framework for biosimilars. They framed the draft guidance as part of the administration’s broader effort to lower drug costs by boosting biosimilar saturation by cutting development cost. Despite these changes, however, biosimilar manufacturers have argued that additional reforms, including reforms to pharmacy benefit manager (PBM) practices, are necessary to make biosimilars more competitive with reference products.

Next Steps

Official notice of the draft guidance is expected to be published in the Federal Register soon, at which time it will be open for public comment for 60 days. Makary said that he expects the guidance will be finalized in three to six months.

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