The U.S. Food and Drug Administration (FDA) has finalized its long-awaited guidance on comparative analytical studies for therapeutic protein biosimilars, providing much-needed clarity for developers navigating the complex biosimilar approval process. This final document replaces an earlier 2015 version and updates the 2019 draft guidance, reflecting how far the science and regulatory framework have advanced in recent years.
Why Biosimilars Matter
Biosimilars are highly similar to existing, FDA-approved biologic therapies and have no clinically meaningful differences in safety, purity, or potency. These products are designed to expand patient access to critical treatments—particularly for conditions like cancer, autoimmune disorders, and diabetes—while helping to reduce healthcare costs. Because therapeutic proteins are more complex than small-molecule drugs, developing biosimilars requires rigorous testing to ensure they perform consistently with their reference products.
Key Updates in the Final Guidance
The finalized guidance outlines FDA’s recommendations for designing and evaluating comparative analytical studies, which are a cornerstone of biosimilar applications submitted under section 351(k) of the Public Health Service Act. Several notable changes stand out:
- Functional Activity Over Target Binding Alone: Instead of treating target binding as a stand-alone section, FDA has incorporated it under broader functional activity considerations. Methods such as ELISA or surface plasmon resonance remain acceptable, but sponsors are encouraged to discuss these approaches with FDA early in development.
- Distinction Between Reference Products and Reference Materials: Unlike the draft version, the final guidance separates these two categories. Sponsors may rely not only on existing scientific knowledge but also on FDA’s own findings of safety, purity, and potency as described in product labeling.
- Removal of Glossary and Cross-References: The final document no longer includes a glossary of definitions or a list of related guidance’s. This reflects FDA’s expectation that sponsors already be familiar with existing terminology and related documents.
- Shift Away From Animal Studies: References to animal data have been removed, signaling FDA’s broader movement toward alternative scientific approaches. Toxicity assessments may still be required, but animal studies are no longer explicitly recommended.
Implications for Sponsors
For companies developing biosimilars, these updates clarify the FDA’s expectations around analytical comparisons. The emphasis on functional activity and removal of animal study references aligns with the industry’s push toward modern, scientifically robust, and more humane approaches to product evaluation. At the same time, the absence of a glossary or cross-references means that sponsors will need to be proactive in identifying the most relevant companion documents to ensure compliance.
Ultimately, the new guidance highlights FDA’s goal of balancing rigorous scientific standards with the need to streamline biosimilar development. This balance is essential as biosimilars continue to play a greater role in the U.S. healthcare system, where cost savings and expanded treatment options remain critical priorities.
The Role of Regulatory Partners
For life science companies, understanding and applying FDA’s evolving guidance is not just about meeting compliance requirements—it is about accelerating the availability of safe, effective, and affordable therapies for patients. Firms that can integrate these expectations into their development programs early on will be better positioned for efficient review and successful product launches.
At EMMA International, we work closely with biopharmaceutical companies to navigate complex regulatory landscapes like this one. Our expertise in compliance, quality systems, and global regulatory strategy ensures that organizations can bring biosimilars and other innovative therapies to market with confidence. By supporting sponsors through every stage—from study design to FDA submission—EMMA International helps bridge the gap between innovation and patient access.
For more information on how EMMA International can assist, visit www.emmainternational.com. Contact EMMA International at (248) 987-4497 or by email at info@emmainternational.com to learn more.
References
U.S. Food and Drug Administration. (2025, September 8). Comparative Analytical Studies for Therapeutic Protein Biosimilars: Final Guidance. https://www.fda.gov
Regulatory Affairs Professionals Society. (2025, September 8). FDA finalizes guidance on therapeutic protein biosimilars.
