On September 11, 2025, the U.S. Food and Drug Administration (FDA) issued new guidance for the development of therapeutic protein biosimilars, focusing on comparative analytical assessment and quality-related considerations. This guidance is crucial for sponsors and manufacturers navigating the regulatory landscape for biosimilar approval under section 351(k) of the Public Health Service Act (PHS Act)1.
I. Abbreviated Licensure Pathway.
Section 351(k) of the PHS Act provides an abbreviated pathway for biosimilars, requiring sponsors to demonstrate that their product is “highly similar” to an FDA-licensed reference product, with no clinically meaningful differences in safety, purity, or potency. The PHA defines a “reference product” as the single biological product licensed under section 351(a) against which a biological product is evaluated in a 351(k) application2. The FDA retains discretion to waive certain studies if justified by robust analytical data. While the FDA's recent guidance applies to biological products, this publication focuses on therapeutic protein products “and provides an overview of recommendations for the comparative analytical assessment and other important scientific considerations to support a demonstration of biosimilarity between a proposed therapeutic protein product and the reference product3.”
II. Comparative Analytical Assessment.
Sponsors are required to use state-of-the-art analytical technologies to characterize both the proposed biosimilar and the reference product. The guidance details factors such as expression systems, manufacturing processes, physicochemical properties, functional activities, impurities, reference materials, and stability. From a legal perspective, the comparative analytical assessment is the cornerstone of biosimilar approval. Any observed differences must be scientifically justified, and sponsors should document their rationale thoroughly. Failure to adequately address differences may result in delays or rejection of the application. Legal counsel should ensure that sponsors' submissions are comprehensive and defensible, particularly regarding product characterization and risk assessment.
In particular, the FDA's guidance emphasizes that “Sponsors should use appropriate analytical methodologies including available state-of-the art technologies, that have adequate sensitivity and specificity to detect and characterize differences between the proposed product and the reference product4.” The publication brings a couple of questions to consider – What does “state of the art” encompass? And how will start-ups with limited resources be able to meet this standard?
III. Data Analysis and Risk Assessment
The FDA recommends a stepwise approach to risk assessment, ranking quality attributes by their potential impact on clinical performance. Quantitative and qualitative analyses are required, with acceptance criteria based on reference product data. And counsel should be prepared to advise clients in the development of robust risk assessment tools which maintain clear documentation of their analytical methodologies. Disputes may arise over the interpretation of data or the sufficiency of evidence, so sponsors should be prepared to defend their approach in regulatory or legal proceedings.
VI. Intellectual Property and Exclusivity.
While not the primary focus of the guidance, biosimilar sponsors must be aware of potential intellectual property (IP) barriers, including patents and exclusivity periods associated with reference products. Here, conducting freedom-to-operate analyses and monitor ongoing litigation in the biosimilars space. The timing of biosimilar applications may be affected by patent disputes or regulatory exclusivity, and strategic planning is essential to avoid costly delays.
V. Practical Implications for Biotech Companies
- Early FDA Engagement: Sponsors are encouraged to consult with the FDA early in the development process to address specific scientific and regulatory questions.
- Comprehensive Documentation: All aspects of product development, from manufacturing to analytical testing, must be meticulously documented.
- Appropriate Capitalization: The FDA's guidance illustrates that state of the art equipment, having appropriate product lot sizes and rigorous testing fundamental requires any biotech start up to be adequately capitalized to undertake this process. This means evaluating capital strategies whether through private placements or through participating in debt markets.
- Legal Strategy: Companies should work closely with legal counsel to navigate regulatory requirements, IP challenges, and potential litigation risks.
The FDA's updated guidance sets a high bar for biosimilar development, emphasizing the importance of comparative analytical data and risk assessment. Legal counsel plays a critical role in ensuring that sponsors' submissions meet regulatory standards and are positioned for successful approval. As the biosimilars market continues to grow, proactive legal and regulatory strategies will be essential for biotech companies seeking to bring new therapies to market.
For further details, consult the full FDA guidance:
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
Footnotes
1. https://www.regulations.gov/docket/FDA-2019-D-2102 (September 11, 2025)
2. Id. at page 4, citing PHA Act, Section 351(i)(4)
3. Id. at page 2.
4. Id. at page 6.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.
