The U.S. Food and Drug Administration issued new final guidance on September 11, 2025, establishing updated requirements for the development of therapeutic protein biosimilars. The guidance, titled "Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry," replaces a draft guidance from May 22, 2019, and outlines the FDA's recommendations for demonstrating biosimilarity to reference products licensed under section 351(a) of the Public Health Service Act.
Regulatory Framework and Abbreviated Pathway
The guidance addresses the abbreviated licensure pathway under section 351(k) of the PHS Act, which allows biosimilar 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 PHS Act 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) application.
The FDA retains discretion to waive certain studies if justified by robust analytical data, emphasizing the critical importance of comprehensive analytical characterization in the biosimilar development process.
Enhanced Analytical Requirements
The updated guidance places significant emphasis on the use of advanced analytical technologies. According to the FDA, "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 product."
The comparative analytical assessment must address multiple critical factors including expression systems, manufacturing processes, physicochemical properties, functional activities, impurities, reference materials, and stability. Any observed differences between the proposed biosimilar and reference product must be scientifically justified, with sponsors required to document their rationale thoroughly.
Risk Assessment and Data Analysis
The guidance recommends a stepwise approach to risk assessment, requiring sponsors to rank quality attributes by their potential impact on clinical performance. Both quantitative and qualitative analyses are required, with acceptance criteria based on reference product data. The FDA emphasizes that the comparative analytical assessment serves as the cornerstone of biosimilar approval.
Failure to adequately address differences may result in delays or rejection of applications, making comprehensive documentation and defensible submissions essential for regulatory success.
Implications for Industry
The updated guidance sets a high bar for biosimilar development, particularly regarding analytical capabilities and documentation standards. The emphasis on "state-of-the-art" technologies raises questions about resource requirements and accessibility for smaller biotech companies.
The guidance indicates that adequate capitalization is fundamental for biotech startups undertaking biosimilar development, as state-of-the-art equipment, appropriate product lot sizes, and rigorous testing require significant financial resources. This may necessitate evaluation of capital strategies through private placements or debt market participation.
Strategic Considerations
The FDA encourages early engagement with sponsors to address specific scientific and regulatory questions during the development process. Companies must maintain comprehensive documentation covering all aspects of product development, from manufacturing to analytical testing.
Additionally, biosimilar sponsors must navigate potential intellectual property barriers, including patents and exclusivity periods associated with reference products, requiring strategic planning to avoid costly delays in the regulatory process.
