The scientific foundations of today’s lean biosimilar development model were established over the past two decades through accumulated regulatory, clinical, and real-world experience. Omnitrope® (somatropin) became the first biosimilar authorized in the European Union in 2006, and the FDA approved Zarxio® (filgrastim-sndz), the first U.S. biosimilar, in 2015. Building on this growing body of evidence, the MHRA pioneered the regulatory acceptance of comparative efficacy study (CES) waivers1 , an approach that has subsequently been reflected in evolving FDA2 and EMA3 guidance.
As a result, the lean biosimilar development model has evolved from an emerging concept into an increasingly accepted paradigm. Characterized by fewer clinical studies, deeper analytical characterization, and integrated process design, this approach expands market access to more competitors while bringing additional treatment options to patients faster.
This model also raises the stakes for development execution. Sponsors must generate a scientifically robust biosimilar candidate quickly enough to compete as reference products lose exclusivity while simultaneously designing a commercially viable manufacturing process. As biosimilar competition intensifies, manufacturing economics becomes a key differentiator.
Consequently, costs of goods sold (COGS) optimization should be considered a core development objective, as it directly influences pricing flexibility, supply chain resilience, and the overall value proposition for payers and healthcare systems. With more than 85 biosimilar molecules currently approved in the US and more than 160 approved in the EU, ample precedent exists to help new and existing biosimilar sponsors successfully navigate the evolving development landscape.
Upstream Diligence Dictates Downstream Requirements
One of the defining objectives of the lean biosimilar model is negotiating a Phase 3 waiver with regulatory authorities, which potentially eliminates the need to conduct a CES, significantly reducing development timelines and costs. In practice, this requires building a scientifically robust biosimilarity evidence package4,5 early in development through thorough characterization of reference product variability, structural and physicochemical characterization of the candidate molecule, and functional evidence supporting its mechanism of action (MoA).
Linking how structure translates into function requires a highly sensitive analytical panel, employing orthogonal methods capable of confirming the biosimilar’s attributes and MoA are not meaningfully different from the reference product. Additionally, since monoclonal antibodies (mAbs) typically feature multiple approved indications, developers must demonstrate how the MoAs can be directly translated into the clinical performance across each indication.
The process begins with identifying the molecule’s critical quality attributes (CQAs) using a risk-based framework to define the analytical similarity assessment strategy. Equally important is comprehensive characterization of both product- and process-related impurities, as these may influence pharmacokinetics, immunogenicity, and ultimately clinical performance. These analytical findings must also be supported by strong process knowledge that links manufacturing parameters directly to the CQAs. Throughout development, early and ongoing engagement with regulatory authorities remains essential to align the analytical strategy and evidence required to demonstrate biosimilarity.
Retrospective evaluation of post approval changes implemented for the reference products and on-market biosimilars reinforces the idea that any well-understood biosimilar candidate — supported by thorough CQA understanding, robust structural and functional assessment, and a sufficient immunogenicity risk assessment — provides a strong scientific basis for regulatory agencies to consider granting a Phase 3 waiver.
This shift is already reflected in regulatory practice, with several agencies approving biosimilars based on streamlined clinical development programs. Examples include the MHRA’s approval of a ranibizumab biosimilar, Health Canada’s approval of an ustekinumab biosimilar, and Australia’s approval of a trastuzumab biosimilar without requiring a CES. These precedents demonstrate that, where analytical and functional evidence provides sufficient confidence in biosimilarity, regulators are increasingly willing to reduce reliance on confirmatory Phase 3 trials.
The Model Continues To Evolve
Although regulators increasingly agree on reducing unnecessary clinical studies, expectations for Phase 1 clinical study still vary among sponsors. In response, there is an industry push to embrace more standardized Phase 1 study designs, drawing from the precedent of previous biosimilar molecules that an extensive Phase 1 is not always necessary. For monoclonal antibodies, recent regulatory thinking increasingly supports streamlined clinical programs paired with routine pharmacovigilance, rather than expanded post-approval monitoring requirements.
Consequently, a CES may be reserved for molecules that are not well-characterized, in the sense that the MoA is poorly understood, or where regulators continue to mandate a local Phase 3 study, like locally acting biologics. Outside of those scenarios, the lean biosimilar model is likely to drive the progress of analytical capabilities, prompting the industry to invest in a more precise, faster, and more platform-based approach to analytical strategy. This initiative is supported by the rapid improvement in existing technologies, as well as collaboration between regulators, industry, and academic institutions to advance next-generation analytical methodologies.
Regulators increasingly recognize that comprehensive analytical characterization may be more sensitive than a CES for detecting clinically meaningful differences between a biosimilar candidate and its reference product. In the longer term, these advances may also influence the development of New Biological Entities (NBEs), where enhanced analytical characterization, integrated with other evidence-generation tools, could streamline development and strengthen decision-making throughout the product lifecycle.
Further, the industry and its partners are exploring how computational tools like machine learning and AI may facilitate integration and interpretation of multidimensional analytical datasets more efficiently, drawing scientifically sound conclusions earlier in development. AI-assisted data analysis, in particular, is well-suited to parsing through the massive datasets generated during analytical development. Researchers continue to examine how a Quality-by-Design (QbD) framework could provide the structured process understanding and validated datasets needed to develop, qualify, and continuously refine AI-assisted analytical models, enabling faster knowledge generation and more robust interpretation of complex analytical data.
The Lean Biosimilar Development Future Is Here
The current industry reality is that biosimilar developers should evaluate whether a lean development model is appropriate for their molecule and regulatory strategy. Acknowledging that the evidentiary burden has shifted upstream, these companies and their CDMOs need to be able to show regulators a biosimilar molecule whose attributes are thoroughly characterized and whose MoA is supported by a robust structural and functional assessment. However, the possibility that a lean approach will support a Phase 3 study waiver varies from country to country based on the supporting data.
Regulatory harmonization efforts must now keep pace with advances in analytical science and development methodologies. For example, markets like Japan, China, and South Korea comprise diverse patient populations and significant revenue streams, so it is in the interest of drug developers and patients that regulators quickly find common ground on comparability, rather than requiring a local CES in every market.
Achieving greater harmonization will not be simple. Regulators must adapt country-specific regulatory frameworks while addressing differences in reference product requirements, intellectual property (IP) considerations, and local legislation. But it remains feasible and scientifically justified since both academic study and real-world evidence support the lean biosimilar model’s safety, efficiency, and market benefits.
Rezon Bio has proven experience helping biosimilar programs in developing and establishing similarity which will help sponsors to redirect investment from confirmatory clinical studies toward generating high-quality analytical evidence earlier in development, as well as successfully negotiating CES waivers.
This post is for informational and educational purposes only and does not constitute legal, professional or regulatory advice of any kind. No warranties are given regarding completeness or accuracy.
About The Experts
Dr. Anna Ducka is Analytical Development Senior Director at Rezon Bio, where she leads analytical strategies supporting development and characterization of biopharmaceutical products. She works closely with cross-functional teams to generate robust analytical data, supporting successful regulatory submissions for biologics, including biosimilars. Anna has 20 years of experience spanning scientific research and the biopharmaceutical industry, with deep expertise in analytical development, protein characterization, and project leadership. Her work has focused on advancing complex biologics and biosimilars through all stages of development. Prior to joining Rezon Bio, Anna was an investigator in the Structure Research Group at the Max Planck Institute of Biochemistry and worked in Analytical Development at Polpharma Biologics. She holds a PhD in Natural Sciences from the Technical University of Munich and an Executive MBA from the University of Gdańsk.
Krishna Mohan Sarikonda is Senior Director, Product Quality & Regulatory CMC, at Rezon Bio, where he works closely with clients to develop effective global regulatory strategies, navigate complex CMC requirements, and accelerate product development from early-stage programs through commercialization. Krishna has 20+ years of industry experience, guiding the development, approval, and lifecycle management of complex biopharmaceutical products. His expertise spans biologics, biosimilars, combination products, and medical devices across key global markets, including the United States, Europe, Australia, and Canada. Prior to joining Rezon Bio, Krishna held senior regulatory roles at Sanofi, Lupin Limited and Biocon Biologics, where he contributed to the development and registration of biologic therapeutics.
About Rezon Bio
Rezon Bio is a science-driven, integrated CDMO specializing in the development and manufacturing of mammalian biologics. Headquartered in Poland, Rezon Bio offers integrated solutions spanning cell line, process and analytical development, clinical and commercial drug substance manufacturing, and drug product development. The company operates with state-of-the-art facilities, world-class teams, and a proven track record of regulatory and commercial success. Drawing on a legacy of biosimilars development and global commercialization expertise with proven capabilities in achieving CES study waiver for the client programs, Rezon Bio combines experience, digital transparency, and cost-to-value efficiency to help clients move from concept to market with confidence.
References
- Medicines and Healthcare products Regulatory Agency. Guidance on the Licensing of Biosimilar Products. GOV.UK, 6 May 2021, www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products
- United States, Department of Health and Human Services, Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies. Draft Guidance for Industry, Oct. 2025, www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product-updated-recommendations
- European Union, European Medicines Agency. Reflection Paper on a Tailored Clinical Approach in Biosimilar Development. Document EMA/CHMP/BMWP/60916/2025, 1 Apr. 2025, www.ema.europa.eu/en/reflection-paper-tailored-clinical-approach-biosimilar-development
- United States, Department of Health and Human Services, Food and Drug Administration. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality – Related Considerations. Final Guidance for Industry, Sep. 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-therapeutic-protein-biosimilars-comparative-analytical-assessment-and-other-quality
- European Union, European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology – derived proteins as active substance: quality issues (revision 1). Draft guideline, EMA/CHMP/BWP/247713/2012, (March 2014). https://www.ema.europa.eu/en/similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active-substance-quality-issues-scientific-guideline
