The Tests They Are A-Changing: FDA Takes Action on Biosimilars

Biosimilars, costing about 50% of their reference products, have generated $56 billion in healthcare savings since 2015, with $20 billion saved in 2024 alone.  Compared to the small molecule market though, that’s pocket change.  It should come as no surprise therefore that FDA is actively working on plans to increase the uptake of biosimilars.

HHS detailed a biologics-specific “Patient Affordability Crisis” in a recent Fact Sheet, expressing concerns about “treatment abandonment, with patients rationing doses, skipping treatments, or going without medication entirely, resulting in disease progression, hospitalizations, and worse health outcomes” arising from high costs of biologics and provider hesitancy to adopt biosimilars.  Recognizing the need to address this issue, HHS, on October 29, 2025 announced its plan to:

• Eliminate unnecessary clinical trials in favor of improved analytical testing methods;
• Facilitate pharmacy-level substitution by removing barriers to interchangeability designation; and
• Reduce barriers to market entry by providing clearer guidance and more efficient processes to speed up approvals and reduce development uncertainty.

Along with this Fact Sheet, FDA published a guidance on October 29, 2025 essentially calling for the end of comparative clinical studies for a large swath of biosimilars.  Previous guidance advised that 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 comparative analytical studies, an assessment of toxicity, comparative human PK and PD studies (if there is a relevant PD measure(s)), and a clinical immunogenicity assessment.”  This new guidance, however, explains that due to evolving scientific approaches and additional experience in evaluating biosimilarity, comparative clinical studies may no longer be necessary to support a demonstration of bioequivalence.  This is because a comparative analytical assessment is “generally more sensitive” than a comparative clinical study now that “currently available analytical technologies can structurally characterize highly purified therapeutic proteins and model in vivo functional effects with a high degree of specificity and sensitivity using in vitro biological and biochemical assays.”  Generally, FDA now believes that the comparative analytical analysis may be sufficient if an appropriately designed human pharmacokinetic similarity study and an assessment of immunogenicity is performed.

Essentially, FDA is opening the door to more approvals without comparative clinical efficacy studies.  But the Guidance does not offer much in the way of knowing whether a comparative analytical analysis will be sufficient.  It only directs sponsors to “carefully consider what clinical study(ies) would be necessary” and “consider a streamlined approach where” a comparative efficacy study may not be necessary.  The recommendations state that a streamlined approach should be considered 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 analysis; and
• A human pharmacokinetic similarity study is feasible and clinically relevant.

The Guidance does not offer much more in assessing whether comparative efficacy studies remain necessary, as it is a case-by-case analysis, but it’s definitely a good start.

The Agency believes this move will facilitate the development of new biosimilar products by eliminating costly and time-consuming studies.  Indeed, an FDA analysis found that comparative efficacy studies usually take 1-3 years and cost $24 million on average but add “little scientific value compared with advanced analytical testing.”

This guidance builds on FDA’s apparent move to increase flexibility in the biosimilar space.  In the last few years, the Agency has signaled its intent to eliminate the interchangeability distinction for biosimilars, and this intent was reiterated in the HHS Press Release announcing this Guidance.  There, HHS states “The agency through a separate initiative also plans to make it easier for biosimilars to be developed as interchangeable with brand-name biologics, helping patients and pharmacists choose lower-cost options more easily.”  This has been long-spoken of, but no action has been taken yet.  For now, we wait with bated breath to see if this Guidance and any accompanying policy changes will facilitate the kind of entry we’ve seen on the small molecule generic side on the biosimilar side.