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The U.S. Food and Drug Administration (FDA) has released a landmark draft guidance on biosimilar submission requirements (the "draft guidance", link here). The draft guidance removes a previous requirement for biosimilar Phase III clinical efficacy studies (CES). This move aligns the FDA with recent regulatory developments in Europe and a recent Canadian regulatory proposal, marking a potential global convergence on biosimilar approval standards.
If these changes are adopted, biosimilar development is poised to become faster and more cost-effective, with potentially far-reaching consequences:
- An increase in biosimilar submissions —lower development costs and shorter timelines will encourage more entrants to the market.
- Earlier biosimilar certifications—accelerated regulatory pathways will compress the window for patent enforcement and litigation preparation.
- Heightened importance of patent strategy—innovator companies must proactively assess and strengthen their patent portfolios to anticipate earlier biosimilar filings and increased litigation risk, in much shorter timeframes.
The FDA's draft guidance is open for public consultation for 60 days following its publication in the Federal Register.
Below, we summarize the key elements of the FDA's proposal and compare them to Health Canada's parallel draft guidelines.
Shift away from Phase III Biosimilar Clinical studies
Previously, the FDA required CES to establish biosimilarity. According to the draft guidelines, the FDA is now accepting comparative analytical assessment (CAA) in place of CES. The draft guidelines go as far as recommending the streamlined CAA approach in specific circumstances. Overall, the guidelines signal a clear shift away from CES as a primary means of establishing similarity between a biosimilar and reference product, particularly where:
(1) the reference product and proposed biosimilar can be well-characterized analytically (e.g., products derived from monoclonal cell lines and/or highly purified products);
(2) the relationship between quality attributes and clinical efficacy is generally understood for the reference product; and
(3) a human pharmacokinetic study is feasible and clinically relevant.
However, the FDA notes that there remains exceptions where CES may inform or demonstrate biosimilarity. For example, locally acting products (e.g., intravitreally administered products) for which comparative PK studies is not feasible may still benefit from CES.
International Alignment
The FDA's position reflects a broader international trend.
Health Canada: On June 13, 2025 Health Canada released a draft guidance (link here) which removed the requirement for comparative safety and efficacy clinical trials, focusing instead on analytical and PK data. Clinical studies are generally limited to comparative PK trials. Consultation on Health Canada's draft guidance has since closed.
European Medicines Agency: On April 1, 2025, the European Medicines Agency published a draft reflection paper (link here) questioning the need for comparative clinical studies for biosimilars. The EMA stated that "[w]aiving certain clinical data requirements would simplify the development and evaluation process" of biosimilars "while maintaining the highest standards of safety and efficacy". Consultation on the reflection paper has since closed.
The following table provides a comparison of Health Canada's Draft Guidance and the FDA Draft Guidance:
| FDA (Oct 2025 Draft) | Health Canada (June 2025 Draft) | |
| Removal of CES requirement. | "A comparative analytical assessment (CAA) is generally more sensitive than a CES to detect differences between two products, should any exist, that may preclude a demonstration of biosimilarity. [...] FDA recommends that sponsors consider a streamlined approach where a CES may not be necessary to support a demonstration of biosimilarity. The adequacy of the data from a CAA, pharmacokinetic similarity data, and immunogenicity assessment to support a demonstration of biosimilarity, would be evaluated based on the totality of the evidence submitted in the biologics license application." |
"In most cases, a comparative clinical efficacy and safety trial(s) is not required. Safety and comparative immunogenicity data are still required and should be collected within the comparative clinical pharmacology studies but could be supplemented with data collected using other trial designs (e.g., studies designed to specifically focus on safety and/or immunogenicity)." |
| Pharmacokinetic (PK) Studies and Immunogenicity studies |
"Generally, if the CAA supports a demonstration that the proposed biosimilar is highly similar to 97 its reference product, notwithstanding minor differences in clinically inactive components, an 98 appropriately designed human pharmacokinetic similarity study and an assessment of 99 immunogenicity may be sufficient to evaluate whether there are clinically meaningful 100 differences between the proposed biosimilar and the reference product in terms of safety, purity, and potency" |
"Comparative pharmacokinetic (PK) studies should be conducted to rule out PK differences between the biosimilar candidate and the CRBD." "Comparison of immunogenicity should be incorporated into the comparative clinical pharmacology studies. Most important are those antibodies that have the potential to impact safety and/or efficacy. Comparative studies should characterize the incidence and magnitude of anti-drug antibody (ADA) response, the time-course of ADA development, ADA persistence, PK, and the potential impact on efficacy and/or safety." |
| Indication Authorization | - | "The decision to authorize the requested indications is dependent on the demonstration of a high degree of similarity between the biosimilar candidate and CRBD based on data derived from comparative quality, non-clinical and clinical studies. Where a high degree of similarity to the CRBD has been established, indications may be granted for the biosimilar candidate based on evidence of the safety and efficacy of the CRBD gathered in both the pre- and post-market settings." |
| Exceptions where CES likely relevant. |
"We note there remain circumstances when a CES may inform a demonstration of biosimilarity, e.g., for locally acting products such as intravitreally administered products where comparative pharmacokinetics is not feasible or clinically relevant. Also, there may be circumstances where a comparative clinical study with a clinically relevant endpoint other than an efficacy endpoint may be useful to support a demonstration of biosimilarity." |
"Clinical efficacy and safety studies are typically not required for a biosimilar candidate to a CRBD with well characterized safety, efficacy, and immunogenicity profiles..." (Biosimilar candidates lacking well characterized safety, efficacy, and immunogenicity profiles may still require clinical studies to establish biosimilarity). "If a comparative clinical efficacy and safety trial(s) is deemed necessary, sponsors should provide a rationale to explain the purpose of the trial(s) in the context of a biosimilar submission." |
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