Industry spars over FDA plan to cut comparative efficacy studies for biosimilars

Biosimilar industry groups have expressed support for a recent guidance from the US Food and Drug Administration (FDA) that recommends the elimination of comparative efficacy studies (CES) for most biosimilar products and instead would rely on comparative analytical assessments (CAAs) to demonstrate comparability.

However, these groups have requested greater clarity on the circumstances under which CES studies should still be conducted and stressed that FDA should clarify that CAAs should be the “new default” for biosimilars.

However, the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents the innovator industry, stated that the CES should be retained for novel complex products, such as multi-specific antibodies and antibody-drug conjugates.

Commenters were responding to FDA’s draft guidance released in October 2025 on demonstrating biosimilarity to a reference listed drug (RLD) and its updated recommendations for assessing the need for CES studies. (RELATED: FDA proposes to cut comparative efficacy study requirements for most biosimilars, Regulatory Focus 29 October 2025).

The FDA received 23 comments on the draft guidance.

Shift to CAAs broadly supported

The guidance largely had the backing of groups representing the biosimilar industry.

The Biosimilars Forum stated that “the CES Draft Guidance recognizes the important evolution of FDA’s regulatory expectations for licensure of a biosimilar … We agree with FDA’s central conclusions in the CES Draft Guidance, that a CES is often not necessary to demonstrate biosimilarity and a comparative analytical assessment, rather than a CES, is generally more sensitive at detecting differences between a proposed biosimilar and the reference product.”

The Association for Accessible Medicines’ (AAM) Biosimilars Council supported FDA’s guidance and noted that the Council has long supported use of CAA or modern analytical methods to demonstrate biosimilar comparability.

“The Council has long advocated that CAA and other modern analytical methods are generally the most sensitive tools for identifying differences between a proposed biosimilar and its reference product. In contrast, CES, reliant on clinical endpoints, are typically not sufficiently sensitive to detect subtle differences and rarely add meaningful or actional information beyond what is already established through analytical and pharmacokinetic (PK) data.”

Drugmaker Sandoz stated that “the scientific validity of biosimilar development based on comparative analytical and clinical pharmacokinetic (PK) data alone is supported by the fact that CES are the least sensitive tool to detect differences between a biosimilar and its reference product, should they exist. Accordingly, in most cases, the CES does not provide useful information for the evaluation of biosimilars. This argument is supported by multiple studies from regulators and industry showing that the analytical and PK data alone were sufficient to demonstrate biosimilarity.”

Samsung Bioepis also supported the shift to using CAAs as the primary means of demonstrating biosimilarity. The company said that today’s “sensitive and specific in vitro functional biological and biochemical assays” are increasingly capable of reliably predicting in vivo functional behavior. This development supports the idea that CAAs is “sufficiently sensitive to detect differences.” The company further noted that the CES has been recognized as a “blunt instrument” and is considered one of the “least sensitive tools in our collective repertoire.”

Yet groups representing the biosimilar industry said FDA should provide greater clarity on when a CES does not have to be used to establish comparability. Groups further asserted that the guidance should make clearer that a CAA should be the “new default” for biosimilars.

The Biosimilars Council stated that “reducing unnecessary CES will lessen patient and industry exposure to clinical studies that do not meaningfully inform regulatory decision-making, while accelerating competition and expanding access to high quality biosimilars. Greater clarity regarding when CES are not expected will also improve predictability for sponsors, reduce development costs, and encourage investment in biosimilar development, particularly for products that may otherwise lack competition.”

The Council proposed adding language in the discussion section of the guidance stating that “a CES should only be considered if there is an outstanding scientific question necessary to conclude on similarity that such a study could address.”

The Biosimilars Forum agreed with the Council’s recommendations for FDA to include clearer language stating that CAS should be the default for establishing biosimilar comparability.

“We interpret the CES Draft Guidance as conveying that, in most instances, biosimilarity can be demonstrated based on a comparative analytical assessment (“CAA”), a clinical pharmacokinetic study, and as an assessment of immunogenicity. We urge FDA to revise the guidance to explicitly clarify that a streamlined approach is regarded as the new default for biosimilar development, with a CES conducted only if it addresses a specific question necessary for regulatory decision making that cannot be obtained by the CAA, a clinical PK study, and an assessment of immunogenicity,” the group wrote.

Sandoz also said that “we urge FDA to revise the guidance to explicitly clarify that the streamlined development approach is regarded as the new default for biosimilars. A CES should be conducted only if it addresses specific questions necessary for regulatory decision making that cannot be answered by the CAA, the clinical PK study, and the immunogenicity assessment.”

PhRMA: CES needed for novel products

On the other hand, PhRMA suggested that the FDA continue to recommend manufacturers conduct a CES for specific products, particularly novel complex products like multi-specific antibodies and antibody-drug conjugates.

PhRMA noted that although FDA has acquired significant experience in evaluating the analytical differences between proposed biosimilar products and their reference products, the existing evidence is limited to a specific subset of therapeutic proteins, such as certain well-characterized monoclonal antibodies and fusion proteins.

The group noted that “these learnings may not apply to other products, such as novel complex products, including multi-specific antibodies and antibody-drug conjugates.”

The group further noted that “there remain scenarios where CES might be necessary to ensure similar clinical performance, including for biological products with unknown or poorly characterized mechanisms of action and products with intrinsic heterogeneity, among other potential scenarios.”

Comments

Industry spars over FDA plan to cut comparative efficacy studies for biosimilars

Related topics

Recommended content

Welcome to the new RAPS Digital Experience