BioRationality: EMA Accepts Waiver of Clinical Efficacy Testing of Biosimilars

The European Medicines Agency (EMA) has finally delivered on their promise. I have filed a petition to the US FDA to follow it. FDA has a strategy wherein they can issue a guideline, as they did for the interchangeability, instead of waiting for the amendments to the Biologics Price Competition and Innovation Act (BPCIA). I am working closely with the US Senate now in case the FDA decides to delay this decision-making. Below is the text of the Citizen’s petition I’ve penned to the FDA.

Executive Summary

This policy document proposes an update to the Biologics Price Competition and Innovation Act (BPCIA) of 2009, recommending that the U.S. Food and Drug Administration (FDA) adopt a tailored clinical approach for biosimilar development. The proposal is aligned with the European Medicines Agency's (EMA) 2025 Reflection Paper (EMA/CHMP/BMWP/60916/2025), which supports a shift away from mandatory comparative efficacy trials (CES) under specific scientific conditions.1 The aim is to modernize regulatory requirements for biosimilars in the United States by reducing unnecessary clinical testing, accelerating market access, and preserving high standards of patient safety and therapeutic equivalence.

Background and Rationale

The BPCIA mandates a demonstration of biosimilarity to an FDA-licensed reference product, including analytical, animal, and clinical studies.2 However, advances in analytical technologies and international regulatory experience indicate that comparative efficacy trials often fail to provide added value when molecular similarity is well-characterized.

In its 2025 draft guidance, the EMA emphasizes the principle that structure determines function and proposes that biosimilarity may be established based on:

1. Robust analytical comparability
2. In vitro functional assays
3. Comparative pharmacokinetics (PK)

Immunogenicity and safety assessments are embedded in PK studies.

The FDA’s own 2019 guidance acknowledges that CES may be waived but does not go as far as the EMA in recommending a default tailored approach when specific prerequisites are met.

Proposal for BPCIA Modification and FDA Guidance Update

1. Eliminate the Default Expectation of Comparative Efficacy Studies (CES)

Replace the current BPCIA default assumption requiring CES with a principle aligned with EMA: CES should only be mandated when justified by molecular uncertainty or insufficient analytical resolution.

2. Codify Tailored Clinical Requirements Based on Molecular Understanding

• Incorporate language requiring demonstration that:
• The mechanism of action (MoA) and structure-function relationships are well understood
• A comprehensive quality attribute (QA) comparison is completed using orthogonal analytical methods
• Functional assays correlate with clinical activity.

3. Formalize Comparative PK Studies as the Primary Clinical Requirement

Accept comparative PK studies as sufficient for biosimilar approval when supported by strong quality and in vitro pharmacology data. Include immunogenicity assessments in the PK study design.

4. Expand Use of Pharmacodynamic (PD) Surrogates

Encourage integration of validated PD markers into PK studies when available but clarify that PD data are not mandatory if analytical and PK evidence is sufficient.

5. Require Similarity Assessment Protocols

Mandate pre-submission of a similarity protocol defining critical QAs, similarity criteria, batch numbers, and statistical methods.

Regulatory Impact and Benefits

Scientific Integrity: Advances a totality-of-evidence approach grounded in structural biology.

Regulatory Efficiency: Streamlines development timelines, lowers costs, and reduces unnecessary human exposure.

Global Harmonization: Aligns U.S. policy with EMA, WHO, and ICH Q5E principles.3-5

Public Health Access: Accelerates time to market for safe and effective biosimilars.

Conclusion

Modern biosimilar science supports regulatory convergence. By updating the BPCIA and associated FDA guidance to align with EMA’s 2025 reflection paper, the U.S. can promote innovation, reduce barriers to biosimilar entry, and ensure sustainable access to biologic therapies. We recommend urgent regulatory consideration and legislative support for these amendments.

References

1. Reflection paper on a tailored clinical approach in biosimilar development. EMA. January 4, 2025. Accessed April 18, 2025. https://www.ema.europa.eu/en/reflection-paper-tailored-clinical-approach-biosimilar-development
2. Development of therapeutic protein biosimilars: comparative analytical assessment and other quality-related considerations guidance for industry. FDA. June 15, 2022. Accessed April 18, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-therapeutic-protein-biosimilars-comparative-analytical-assessment-and-other-quality
3. Implementation of the Biologics Price Competition and Innovation Act of 2009. FDA. Updated February 12, 2016. Accessed April 18, 2025. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/implementation-biologics-price-competition-and-innovation-act-2009
4. ICH Q5E Biotechnological/biological products subject to changes in their manufacturing process: comparability of biotechnological/biological products - Scientific guideline. EMA. November 12, 2003. Updated November 12, 2003. Accessed April 18, 2025. https://www.ema.europa.eu/en/ich-q5e-biotechnological-biological-products-subject-changes-their-manufacturing-process-comparability-biotechnological-biological-products-scientific-guideline
5. Guidelines on evaluation of biosimilars. World Health Organization. April 22, 2022. Accessed April 18, 2025. https://www.who.int/publications/m/item/guidelines-on-evaluation-of-biosimilars