New biosimilar pathways – key takeaways from the EMA’s draft reflection paper

The European Medicines Agency (EMA) has published a draft reflection paper that signals a potential evolution in the regulatory landscape for biosimilar development within the EU.¹ Rather than representing a radical break from established practice, the document builds on decades of scientific and regulatory experience, proposing that – under certain well-defined conditions – the demonstration of bio-similarity might rely more heavily on advanced analytical characterisation and pharmacokinetic (PK) data, with a reduced emphasis on comparative efficacy studies (CES).

This approach is not intended to lower the EU’s rigorous standards for safety and efficacy, but rather to reflect the increasing sensitivity and reliability of modern analytical techniques, as well as the growing body of evidence suggesting that, in many cases, traditional efficacy trials may offer limited additional value.^1,2,3 The reflection paper is currently open for public consultation, inviting feedback from stakeholders across the pharmaceutical sector until 30 September 2025.

Scientific rationale and regulatory context

The foundation of the EMA’s tailored approach is the well-established scientific principle that the structure of a biological molecule determines its function. If a biosimilar candidate can be shown – using state-of-the-art analytical methods – to be highly similar to its reference medicinal product (RMP) in all critical quality attributes (CQAs), and if comparable PK profiles are demonstrated, then clinical efficacy and safety can be inferred. This concept has long been accepted in the context of manufacturing changes for biologics, where regulatory authorities have approved significant process changes based on analytical comparability, without requiring new clinical efficacy data.^1,2

The reflection paper also highlights the limitations and diminishing value of CES in many biosimilar development programmes. Advances in analytical science, combined with the EMA’s regulatory experience, have shown that CES often do not provide additional meaningful information when the biosimilar and RMP are already well-characterised. Furthermore, the feasibility of conducting CES is increasingly limited for certain biologics, such as those with narrow indications or those used in complex combination therapies.^1,4,5,6

EMA’s draft reflection paper

Key elements of the proposed tailored clinical approach

Central to the EMA’s proposal is the idea that, under specific prerequisites, a robust analytical comparability exercise, supported by a comparative PK trial, may be sufficient for biosimilar approval. The prerequisites for this approach are outlined in the reflection paper. First, the mechanism of action (MoA) of the biosimilar must be well understood, and all functionally relevant CQAs must be identified and characterised using orthogonal, state-of-the-art analytical methods.^1,2 Functional assays, such as potency and receptor binding tests, must confirm that the biosimilar mirrors the RMP in biological activity. The manufacturing process must be validated to ensure batch-to-batch consistency, and a pre-established similarity assessment protocol should guide the development process.

A sufficient quantity of RMP and biosimilar batches – typically 15 to 30 for the RMP – should be tested to capture the full range of variability and ensure robust statistical assessment. The similarity assessment protocol should include clear criteria for similarity, a plan for addressing any observed differences, and a discussion of why a tailored clinical approach is appropriate for the product in question.¹

Rethinking the role of Comparative Efficacy Studies

Traditionally, CES have played a central role in biosimilar development, intended to address any residual uncertainties after analytical and non-clinical comparison.^1,2 However, the reflection paper argues that, for many products, these studies are no longer scientifically necessary. Instead, comparative PK studies, possibly supplemented by pharmacodynamic endpoints if relevant, become the pivotal clinical requirement. PK studies should be designed to include immunogenicity monitoring, particularly for products where anti-drug antibodies may develop over time. The EMA emphasises the importance of aligning protein content and other critical parameters between the biosimilar and RMP batches used in PK trials.

CES will still be required in certain scenarios, such as when the MoA or structure-function relationship is not fully understood, when analytical methods lack sufficient sensitivity, or for products with negligible systemic absorption. In these cases, traditional clinical trials remain indispensable for ensuring patient safety and product efficacy.^1,2

EMA’s draft reflection paper – implications for drug developers and manufacturers

The proposed tailored approach offers opportunities for developers and manufacturers. By potentially waiving the requirement for CES, companies could reduce development costs significantly per product and potentially accelerate timelines to market by several months.^4,5,6 However, these benefits are contingent on the ability to generate comprehensive, high-quality analytical and PK data packages. Robust manufacturing control systems and real-time release testing become even more critical, as any inconsistencies in quality could undermine the case for waiving clinical trials.

Developers are encouraged to engage proactively with regulators, submitting well-justified similarity assessment protocols and addressing any uncertainties through interdisciplinary risk assessment. The EMA also recommends that applicants seek scientific advice early in development to ensure alignment on the similarity assessment protocol.¹

Broader alignment

The EMA’s draft paper is consistent with the EU’s ongoing efforts to support the development and availability of biosimilar medicines within a harmonised regulatory framework. Since establishing a dedicated pathway for biosimilars in 2004, the EU has aimed to balance rigorous evaluation with the practicalities of fostering competition and improving patient access to biologics.^7,8 The regulatory framework, coordinated through the EMA, requires that biosimilars meet the same standards of quality, safety, and efficacy as all biological medicines.⁷ The current proposals reflect an adaptive stance, acknowledging advances in analytical technologies and accumulated regulatory experience that may, in some cases, allow clinical efficacy and safety to be inferred from robust physicochemical and PK comparability.¹

EU pharmaceutical policy increasingly recognises the importance of sustainable healthcare systems by facilitating access to effective and affordable treatments, supporting innovation, and ensuring timely market entry for biosimilars.⁹ The ongoing public consultation exemplifies the EU’s commitment to transparent, evidence-based policymaking, inviting stakeholder input to refine regulatory approaches in line with scientific and public health developments.

It will also be important to observe how the EMA’s evolving approach to biosimilar development will interact with the forthcoming EU Pharma Package, especially as the Council of the EU has only recently agreed its position on this major legislative reform.¹⁰ The package, once adopted, is expected to introduce changes to regulatory exclusivity, market access, and competition rules for medicines, including biosimilars, across the EU. How these new provisions will align with or influence the implementation of a tailored clinical approach for biosimilars remains to be seen and will likely be an area of close attention for both regulators and industry stakeholders as the legislative process moves forward.

Conclusion

While the EMA’s draft reflection paper sets out a potentially significant evolution in the regulatory approach to biosimilar development, it is best viewed as a considered response to both scientific advances and accumulated regulatory experience, rather than a wholesale transformation. By proposing that, under certain well-defined conditions, robust analytical and PK evidence may be sufficient to demonstrate bio-similarity, the agency is seeking to streamline aspects of development where the science supports such a move, all while maintaining established standards for safety and efficacy.

For those involved in late-stage drug development and manufacturing, this tailored approach could present both efficiencies and new technical expectations, particularly in the areas of analytical characterisation and data justification. However, the reflection paper also makes clear that this is not a one-size-fits-all solution: CES will remain necessary in cases where uncertainties persist or where the mechanism of action is not fully understood. As the consultation process continues, stakeholders have opportunity to engage with the EMA and help shape a regulatory framework that balances innovation, scientific rigour, and patient safety.

References

1. European Medicines Agency. Reflection Paper on A Tailored Clinical Approach In Biosimilar Development. EMA/CHMP/BMWP/60916/2025. 2025.
2. European Medicines Agency. Guideline On Similar Biological Medicinal Products, CHMP/437/04 Rev 1. 2014.
3. European Medicines Agency. Guideline On Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins As Active Substance: Non-Clinical and Clinical Issues, EMEA/CHMP/BMWP/42832/2005 Rev1. 2014.
4. Guillen E, Ekman N, Barry S, et al. A Data Driven Approach to Support Tailored Clinical Programs for Biosimilar Monoclonal Antibodies. Pharmacol. Ther. 2023;113:108-123.
5. Kirsch-Stefan N, Guillen E, Ekman N, et al. Do the Outcomes of Clinical Efficacy Trials Matter in Regulatory Decision-Making for Biosimilars? BioDrugs. 2023;37:855–871.
6. Bielsky MC, Cook A, Wallington A, et al. Streamlined Approval of Biosimilars: Moving On From The Confirmatory Efficacy Trial. Discov. Today. 2020;25(11):1910-1918.
7. Biosimilar Medicines: Overview. European Medicines Agency. 2024. Available from: https://www.ema.europa.eu/en/human-regulatory-overview/biosimilar-medicines-overview
8. European Commission. Pharmaceutical Strategy for Europe. COM(2020) 761 final. 2020.
9. Streamlining Development And Assessment Of Biosimilar Medicines. European Medicines Agency. 2025. Available from: https://www.ema.europa.eu/en/news/streamlining-development-assessment-biosimilar-medicines
10. Council of the European Union. Proposal For a Regulation Of The European Parliament And Of The Council Laying Down Union Procedures For The Authorisation And Supervision Of Medicinal Products For Human Use And Establishing Rules Governing The European Medicines Agency – Mandate For Negotiations With The European Parliament. Brussels: Council of the European Union; 2 June 2025. Document 9286/25. Interinstitutional File: 2023/0131 (COD).