The U.S. Food and Drug Administration (FDA) has released a pivotal 2025 draft guidance, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendation for Assessing the Need for Comparative Efficacy Studies.” In a related FDA news release, “FDA Moves to Accelerate Biosimilar Development and Lower Drug Costs,” the agency explains how the updated guidance is intended to reduce unnecessary clinical studies while maintaining rigorous standards for biosimilarity. This update marks a significant shift in the regulatory landscape for biosimilars, aiming to accelerate approvals, reduce costs, and align with global best practices. The guidance is a direct response to the Executive Order “Lowering Drug Prices by Once Again Putting Americans First,” which mandates the FDA to expedite biosimilar approvals to enhance competition and lower drug prices.
Historically, FDA required a comparative clinical study with efficacy endpoints (a comparative efficacy study or CES), as well as data from pharmacokinetic studies, along with additional justification and/or study data required to meet the threshold for interchangeability.
Key Updates in the 2025 FDA Draft Guidance
Comparative Efficacy Studies (CES)
The FDA now considers CES, previously a major bottleneck in biosimilar development, unnecessary in most cases. Instead, the agency emphasizes the use of:
- Advanced analytical technologies to support robust structural and functional comparability, including enhanced process control, multi-attribute methods, and next-generation characterization tools.
- Human pharmacokinetic (PK) studies to demonstrate targeted biosimilarity from the reference product.
CES can be waived if:
- The biosimilar and reference product are highly purified, derived from clonal cell lines, and well-characterized analytically.
- The relationship between key quality attributes and clinical efficacy is well understood and measurable.
- A human PK similarity study is feasible and clinically meaningful.
CES may only be required in rare circumstances where analytical and PK data cannot fully address residual uncertainty about clinical differences. There might be situations where a clinically relevant endpoint not related to efficacy is considered useful. In both cases, early interactions with the FDA are encouraged to secure agreement.
Interchangeability Simplified
The FDA is also revising its approach to interchangeability. The updated draft guidance “Considerations in Demonstrating Interchangeability With a Reference Product: Update” generally does not recommend “switching studies” (which test the safety of alternating between a biosimilar and its reference product), recognizing that these studies slow development and are often unnecessary.
What is Still Required?
- Comparative analytical assessment (CAA): Demonstrates high similarity in structure and function.
- Human PK similarity study: Confirms similar drug exposure in humans.
- Immunogenicity assessment: Evaluates potential for immune response.
Consistent Approaches to Biosimilar Development at EMA and Health Canada
European Medicines Agency (EMA)
The new draft EMA reflection paper published on April 1, 2025, suggests that a CES may not be necessary if there is strong evidence that the biosimilar is similar to the Reference Medicinal Product (RMP) in terms of clinical efficacy and safety, based on analytical comparability, in vitro pharmacology studies, and PK data. In these circumstances, it is acceptable to infer comparable clinical efficacy and safety based on demonstration of similarity in structure and function.
Pre-requisites for similarity assessment
The EMA outlines several prerequisites for a successful similarity assessment, including the following:
- A comprehensive understanding of the mechanism of action of the active substance
- Detailed characterisation of the structure and functionally relevant Quality Attributes (QAs)
- Availability of functional assays (in vitro pharmacology tests)
- A validated manufacturing process and control strategy
- A similarity assessment protocol covering analytical and functional comparability
When a CES may not be necessary
- According to the EMA, a CES may not be necessary when the totality of evidence from the comparability exercise is sufficiently robust, including the following conditions: The mechanism of action and structure-function relationship are well understood
- Robust analytical similarity is demonstrated, with all key QAs being highly similar to the RMP, in terms of structure and functional properties. Minor differences are justified and shown to be not clinically relevant
- In vitro functional data supports similarity, demonstrating comparable pharmacological activity and mechanism of action
- Comparable PK profile is demonstrated through PK studies (i.e. absorption, distribution, metabolism, excretion) with the RMP
- No critical differences in QAs are identified that could impact clinical outcomes (e.g. those altering the mechanism of action)
When a CES would be necessary
A CES would generally remain necessary in the following cases:
- The biosimilar is not well characterizable
- The mechanism of action and structure-function relationship is unclear
- The clinical impact of observed QA differences is uncertain
- PK characterisation is not feasible (e.g. locally applied products with negligible systemic absorption)
- The biosimilar fails to meet similarity criteria for critical QAs (noting that a CES cannot be used to justify substantial differences)
Health Canada
Health Canada’s newly proposed draft guidance for biosimilar biologic drugs, released in June 2025, marks a major regulatory shift: most biosimilar submissions will no longer require comparative phase III clinical efficacy and safety trials. Instead, the focus will be on robust analytical, pharmacokinetic (PK), and immunogenicity data to demonstrate similarity to the reference biologic.
- Elimination of Routine Phase III Trials: The draft guidance removes the requirement for large, comparative clinical efficacy and safety trials (typically phase III studies) in most cases. Sponsors must still provide safety and immunogenicity data, but these can be collected within comparative clinical pharmacology studies or other targeted trial designs.
- Emphasis on Analytical and PK/PD Data: approval will rely primarily on:
- Extensive comparative analytical studies (physicochemical, functional, stability).
- Comparative pharmacokinetic (PK) studies.
- Comparative pharmacodynamic (PD) studies, if feasible.
- Safety and immunogenicity assessments.
- Streamlined Indication Authorization: Biosimilars may be authorized for all indications held by the Canadian Reference Biologic Drug (CRBD), provided a high degree of similarity is established. Justification for each indication is no longer required.
- Clarification for Polypeptide Drugs: Short polypeptides produced by recombinant DNA methods are considered biologics and eligible for biosimilar approval. Chemically synthesized polypeptides are regulated as generics.
- Reduced Need for Animal Studies: In vivo non-clinical studies (animal studies) are generally not required if extensive in vitro similarity is demonstrated.
Implications of Global Regulatory Alignment for Biosimilar Development
- Alignment with International Trends: These regulatory changes reflect a broader global shift toward reducing unnecessary clinical trials for biosimilars when robust analytical and PK/PD data are sufficient.
- Faster, More Affordable Access: Shifting focus from routine clinical trials to analytical and PK studies could significantly reduce development time and costs, potentially accelerating patient access to biosimilars.
- Regulatory Modernization: These updated requirements are part of broader efforts to modernize biologic drug regulation, making requirements more flexible and science-based.
At Allucent, our experts integrate these approaches into practical solutions for biologic development programs. To learn more about our expertise in helping small to mid-size biopharmas bring biosimilars to light, visit our website: Regulatory Strategy | Allucent.
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