Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies
On October 29, 2025, the Food and Drug Administration (FDA) released their draft guidance, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies” which is open to the public for comment. This draft guidance describes considerations regarding a comparative clinical study or studies with efficacy endpoints (a comparative efficacy study or CES) intended to support a demonstration that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting a marketing application under the Public Health Service Act (PHS Act) [1] . How does this impact the tissue industry? Let’s take a closer look!
Traditionally, biosimilar applicants have been required to conduct comparative clinical studies to directly assess efficacy and safety relative to the reference product. For tissue banking, this update signals a regulatory shift that may influence product development, approval pathways, and operational processes. With the evolving landscape of biosimilar product development, this draft guidance provides updated scientific recommendations to sponsors developing biosimilar products through a risk-based framework for determining when comparative clinical efficacy studies (those directly comparing a biosimilar candidate to its reference product in humans), may be waived or deemed unnecessary. The FDA emphasizes the use of advanced analytical methods, comprehensive structural and functional characterization, as well as robust pharmacokinetic/pharmacodynamic (PK/PD) assessments as primary tools for evaluating biosimilarity.
Some key items include:
Encouraging reliance on state of the art analytical and functional studies to demonstrate high similarity.
Clarifying the circumstances under which comparative efficacy studies may be required, such as when residual uncertainty remains after analytical and PK/PD assessments.
Promoting a totality of evidence approach with increased flexibility in study design based on scientific justification.
Providing guidance on how sponsors should document and communicate their risk assessments and decision-making processes in regulatory submissions.
So how does this impact the tissue banking industry? Tissue banks involved in the development and distribution of biologically derived products that may fall under biosimilarity regulations will need to consider new expectations including but not limited to:
Streamlining product development: with these new changes, this would potentially reduce requirements for comparative efficacy studies and potentially shorten development timelines and lower costs for biosimilar tissue-based products.
Enhanced analytical standards: companies must invest in advanced analytical technologies and expertise to meet heightened expectations for structural and functional characterization.
The guidance requires closer collaboration between scientific, regulatory, and quality teams to ensure risk assessments are robust, well-documented, and aligned with the FDA’s expectations.
The updated pathway may facilitate faster market entry for qualifying biosimilar tissue products, increasing competition and expanding patient access.
Some implementation strategies for consideration are:
Perform a gap assessment by conducting a thorough review of current biosimilar development protocols, focusing on analytical capabilities, PK/PD study design, and data documentation practices.
Upgrade analytical instruments and invest in staff training to ensure the ability to perform advanced structural and functional analyses.
Build and ensure cross-disciplinary collaboration by fostering regular communication between research, quality, and regulatory teams to build comprehensive and defensible biosimilarity justifications.
Engage proactively with the FDA through formal meetings and pre-submission consultations to clarify expectations and reduce regulatory uncertainty.
Implement structured frameworks for documenting risk assessments, decision-making rationales, and data interpretation in line with the FDA guidance.
While the guidance offers opportunities for efficiency, it also introduces several risks and challenges that tissue banks must address:
Insufficient or inadequate analytical data may lead to requests for additional studies, causing delays and increased costs.
Ambiguity or regulatory uncertainty in the application of the risk-based framework could result in inconsistent regulatory outcomes or misinterpretation of requirements.
Smaller tissue banks may face resource constraints, such as challenges in acquiring necessary technologies or expertise to meet enhanced analytical demands.
Incomplete or poorly documented risk assessments may undermine regulatory submissions for data integrity and lead to rejection or extended review cycles.
Transitioning organizational processes to align with new guidance may encounter internal resistance or require significant operational shifts.
This draft guidance marks a pivotal update in the regulatory framework for biosimilar development, especially for the tissue banking industry. By emphasizing advanced analytical methods and a risk-based approach to comparative efficacy studies, the guidance offers opportunities for greater efficiency but also demands heightened scientific rigor and robust documentation. Tissue banks entering this realm of regenerative medicine should proactively assess their current practices, invest in necessary resources, and foster interdisciplinary collaboration to navigate the evolving biosimilarity landscape. Ongoing engagement with regulators and continued adaptation will be critical to harnessing the benefits of these regulatory changes while mitigating associated risks.
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