EMA’s concept paper on confirmatory clinical studies a welcome step for industry

In Vitro EU regulation

The European Medicines Agency has taken an important step toward adapting requirements for comparative efficacy studies (CES) for biosimilars.

Earlier this year, the agency released a Concept Paper for the development of a Reflection Paper on the way forward for biosimilar studies[1]. This is the start of the journey to adapt the approach to biosimilar development in Europe established in the EMA’s biosimilars guideline published in 2014[2].

It follows a workshop held by the US Food and Drug Administration (FDA) in September 2023, in which EMA, other regulatory agencies and other stakeholders participated[3]. During the workshop, some stakeholders asked EMA on why they still required confirmatory trials. Questions over the need for CES and other ways to support comparability were raised in a recent panel discussion that I moderated, where experts highlighted the importance of regulators being willing to let the science and experience guide what is right for each product[4].

So, what does the EMA communication mean for biosimilars developers?

A Concept Paper is a short document that announces a larger paper, in this case one that establishes the agency’s current thinking on an issue (a Reflection Paper). EMA opened the paper to public consultation, which ends on 30 April 2024. It is highly likely the agency will receive significant supportive feedback, given ongoing questions as to whether such studies are really necessary.

After the agency has reviewed that feedback, they can begin drafting the Reflection Paper. This is less binding than Guidelines, but it does clarify the agency’s thinking on the issue and establishes greater flexibility for industry when developing biosimilars.

As EMA notes in the Concept Paper, since regulators have gained extensive experience with biosimilars  “the importance of dedicated clinical efficacy and safety data should be re-evaluated1.” As experience has shown, biosimilars have been proven to be equally safe and efficacious as the reference product and are a real alternative, improving patient access to treatment. There is significant experience and data with monoclonal antibodies (mAbs), as well as advances in analytical science to study a biologic’s physicochemical and functional properties[5]. This combination has given regulators a three-dimensional perspective on biosimilars.

While the Concept Paper does suggest CES could be reconsidered for less complex biosimilars, it goes on to note that the Committee for Medicinal Products for Human Use (CHMP) has gained considerable experience with more complex mAbs, which begs the question: is it the complexity that drives the shift in thinking or is it the methodology? My view is that it is the methodology, given how experienced the industry has become with analytical and functional characterization.

The paper also suggests the need for clinical data may depend on the clinical profile of the reference medical product (RMP), such as the potential impact of immunogenicity. This raises some other interesting questions. Sometimes biosimilar companies use other expression systems for several reasons – either because the RMP’s expression system is patent protected or, increasingly, because there are now newer expression systems available.

There have been concerns raised that biosimilars could be more immunogenic, which would neutralize the product or raise safety issues[6]. We have sometimes seen seemingly slightly higher immunogenicity with biosimilars as compared to historical results, but not because of any real clinical relevance, rather because the assays have become much more sensitive to detecting an immune response. In fact, the comparator group with the reference product in  these cases had a similarly higher immunogenicity. The data indicates that there has not been a big problem with immunogenicity[7]. And, in fact, an information guide from the EMA and European Commission indicates that “there is no reason to believe that harmful immunogenicity should be expected after switching between highly similar biological medicines5”.

With this in mind, it is fair to suggest that the safety database from the RMP can be relied upon and that immunogenicity is under control when you have the pharmaceutical quality under control, unless there is inherently a high risk to immunogenicity (described for the reference product) as per its consequences for the patient which has to be elucidated (an often-quoted example is erythropoietin).


Paving the way for future biosimilar development

EMA was the first jurisdiction in the world to have a biosimilar framework in place, and, as of April 2023, the agency had approved 93 biosimilars compared with 40 in the United States[8]. The agency has taken a more conservative approach to CES than some other jurisdictions – it was the first agency to draw up guidelines, at the time for the right reasons more toward the conservative end of the spectrum.

The UK’s MHRA, for example, adopted a progressive step on biosimilar development in 2021, when it updated its guidelines to note that “…in most cases, a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach[9].”

However, with the publication of the Concept Paper, EMA has flagged their thinking on CES to industry. While biosimilar developers would still need to get scientific advice from the agency on comparator studies, they can point to the concept paper in their discussions with the regulator.

This paper is a welcome step and a measured approach by an agency that has been at the forefront of biosimilars.

What challenges, if any, have you had with comparative efficacy study requirements for biosimilar development? And what does the EMA’s Concept Paper mean for your development? We would be interested in hearing your perspective and experience.


Download the Science Huddle white paper to gain more insights from the panel of biosimilars experts.


About the author:

Christian K Schneider, M.D., is Chief Medical Officer, Strategic Product Development Consulting, and Vice President & Head of Biopharma Excellence at Cencora PharmaLex. Before joining PharmaLex, Christian was interim Chief Scientific Officer at the UK’s medical products regulator, the MHRA. Christian was the Chairman of the European Medicines Agency’s Biosimilar Working Party for nine years and one of the architects of the European biosimilar framework. Christian has broad global regulatory authority experience, having served in many capacities at different regulatory authorities.



[1] Concept paper for the development of a Reflection Paper on a tailored clinical approach in Biosimilar development, EMA.

[2] Guideline on similar biological medicinal products, EMA. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf

[3] Increasing the Efficiency of Biosimilar Development Programs–Reevaluating the Need for Comparative Clinical Efficacy Studies, FDA. https://www.fda.gov/drugs/news-events-human-drugs/increasing-efficiency-biosimilar-development-programs-reevaluating-need-comparative-clinical

[4] 20 years of biosimilars: Are we on the right track? PharmaLex. https://www.biopharma-excellence.com/the-science-huddle/20-years-of-biosimilars-are-we-on-the-right-track/

[5] Biosimilars in the EU, Information guide for healthcare professionals, EMA and European Commission. https://www.ema.europa.eu/system/files/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en_1.pdf

[6] The Efficacy, Safety, and Immunogenicity of Switching Between Reference Biopharmaceuticals and Biosimilars: A Systematic Review, Clin Pharmacol Ther. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540323/

[7] Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective, Drugs. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578115/

[8] Biosimilars approved in Europe, Generics and Biosimilars Initiative. May 2023. https://www.gabionline.net/biosimilars/general/biosimilars-approved-in-europe

[9] Guidance on the licensing of biosimilar products, MHRA. https://www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products/guidance-on-the-licensing-of-biosimilar-products



This blog is intended to communicate PharmaLex’s capabilities which are backed by the author’s expertise. However, PharmaLex US Corporation and its parent, Cencora, Inc., strongly encourage readers to review the references provided with this article and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto as the article may contain certain marketing statements and does not constitute legal advice. 

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