EMA Issues Draft Reflection Paper On Accelerating Biosimilar Approval

By Tim Sandle, Ph.D.

Biosimilar medicines are becoming more sought after as a way to tackle rising healthcare costs, especially for relatively expensive biologics (as such anti-cancer treatments).¹ This process began in Europe in 2006 with the approval of Omnitrope (somatropin). This paved the way for non-innovator versions of biologicals (as biosimilars) to enter the market once patents expire or when pharmaceutical companies agree to a partnership following regulatory approval. Currently, the process for bringing a biosimilar to market requires detailed pharmacokinetic studies to demonstrate drug efficacy. As knowledge of biologic active substances increases, there is potential scope for streamlining aspects of experimental data required for the supporting dossier. To pave the way for this, defining which types of data need to be included and what can be excluded requires clear regulatory guidance.

Within Europe, a potential approach was recently mapped out. In April 2025, the European Medicines Agency issued a draft of a new guidance document titled Reflection paper on a tailored clinical approach in biosimilar development.² The public consultation runs until September 30, 2025.

The reflection paper looks at biosimilars where similar clinical efficacy and safety can be inferred from a conclusion of physicochemical and biological similarity and comparable pharmacokinetics.³ This is based on the principle that biological activity, and ultimately the therapeutic effects, are dictated by the structure of the pharmacologically active substance. This means, for example, if the structure of two proteins is the same, or at least highly similar (“biosimilar”), then these two proteins will bind to the same receptors in the same quantitative manner and will therefore have the same pharmacological properties. Consequently, the two proteins will exert the same clinical efficacy.⁴

Biosimilars And Harmonization

The EMA guidance, together with the definition produced in 2015⁵ aligns the definition of a biosimilar to the development requirements set out in ICH Q5E.⁶ Unlike the U.S. FDA draft guidance,⁷ the EMA guidance does not have a specific “interchangeable” designation for biosimilars. Instead, each member state is required to set their own decision-making framework for either interchanging or substitution a biosimilar for a reference product.

Objectives For The Reflection Paper

The draft EMA guidance is evidence-based, drawing on the biosimilar development process since the first biosimilar drug was approved in Europe in 2006. This is presented as a streamlined framework for developers to follow to aid the eventual approval process.

Comparability

A level of comparability remains essential, not least because biologicals are inherently variable. The scope of this should be developed in a similarity assessment protocol to enable the final assessment of similarity at the end of the development process. The protocol determines the number of batches that will be needed to demonstrate consistency as well as establishes the quality parameters and assays required to measure batch data, along with the statistical methods to be used. The aim is to establish if there are any clinically meaningful differences between the biosimilar and the reference medicine in terms of safety, quality and efficacy.

While comparability is important, there is scope for streamlining, given that minor differences in quality attributes can be clinically irrelevant. The concept of comparability, for biosimilars, enables scientists and regulators to take into consideration quality differences (the principle of biosimilars is that products do not need to be identical as long as they achieve the same clinical effect, i.e., “highly similar”). This introduces the scope for modifying the current comparability requirements.

Comparative Efficacy Studies

Comparative efficacy studies (CESs) are normally conducted to assess residual differences with quality attributes, between the biosimilar and the reference product (significant differences between quality attributes would be a sign that the medicines are not sufficiently similar).

The central argument in the reflection paper is that CESs (in which safety and immunogenicity data are captured) do not, in specific circumstances, add relevant additional information to the biosimilarity exercise.⁷ As an alternative, clinical efficacy and safety can be inferred from a conclusion of physicochemical and biological similarity and comparable pharmacokinetics, including:

• absorption,
• disposition,
• time dependence, and
• binding to blood components,

together with equivalent pharmacodynamics (assessing the efficacy of the biosimilar at the target tissue and its mechanism of action).

Hence, the reflection paper presents the regulatory option that, under certain prerequisites, authorization for a biosimilar could be given for use within the European Union where comparability can be presented with a limited (tailored) clinical data package (based on a comparative pharmacokinetic trial). In doing so, biosimilar medicines would reach the market faster without compromising quality.

To eliminate the efficacy study, a risk assessment would be required. This process should begin with an identification of the quality attributes. Following this, the risk assessment should draw upon prior scientific knowledge in order to make a sound justification as to why CESs do not need to be performed. The scientific assessment would need to detail how the critical quality attributes impact the interaction with receptor(s) (such as membrane receptors, ligands, substrates, and other targets). This is important since these interactions form the basis of subsequent biological effects. The risk assessment should assess pharmacology, toxicology, and pharmacokinetic/pharmacodynamic modeling. In outlining the requirements for the risk assessment, the reflection paper advises that the risk assessment should be conducted as an initial criticality assessment and updated as knowledge accumulates as the biosimilar is developed.

There will be cases where, even in the event of residual differences with quality attributes, a CES is still required. This could occur, for instance, when the mechanism of action of the active and structure-function relationship are not sufficiently understood.

Comparative Clinical Pharmacokinetic Studies

Although there is scope to reduce or to eliminate CESs, as set out in the reflection paper, comparative clinical pharmacokinetic studies remain an essential requirement (including human clinical trials). Such studies not only prove biosimilarity, but they also provide essential safety and immunogenicity data. What the reflection paper ensures is the avoidance of unnecessarily repeating the animal-based clinical trials required during the initial developmental phases of the reference medicine.  

While comparative clinical pharmacokinetic studies remain necessary for understanding if the developed drug is truly a “biosimilar” and for gaining approval for the medicine, there is scope for reform. The reflection paper sets out how specific adjustments to the data requirements can help to accelerate this process. Examples given include the inclusion of immunogenicity parameters and/or modifying the study design (such as one-dose vs. multiple-dose).

Manufacturing Development

The reflection paper additionally discusses the commercial manufacturing process and the need for manufacturing process controls so that a biosimilar product that is highly similar to the reference product can be consistently produced. This requires a robust manufacturing control system and sufficient data to demonstrate batch-to-batch consistency. There must be a high similarity between the quality attributes of the biosimilar and the reference product.

To support manufacturing and to provide the necessary evidence of similarity, the accuracy and precision of the analytical methods need to be robust.⁸ This is to show:

• comparable molecular structure of a biosimilar and the reference product
• protein content
• biological activity
• glycosylation / protein folding (the attachment of sugar moieties to proteins. This is critical for a wide range of biological processes, including cell attachment to the extracellular matrix and protein-ligand interactions in the cell.)
• tests for impurities.

Producing and gaining approval for a biosimilar remains challenging. However, the reflection paper provides an opportunity for the process timelines to be reduced. The basis for this is by providing similar clinical efficacy and safety pharmacology through a stringent evaluation of analytical comparability, in vitro pharmacology, and a comparative clinical pharmacokinetic study.

References

1. Rémuzat C, Dorey J, Cristeau O, et al. Key drivers for market penetration of biosimilars in Europe. J Mark Access Health Policy. 2017;5(1):1272308.
2. EMA. Reflection paper on a tailored clinical approach in biosimilar development, European Medicines Agency, April 2025; EMA/CHMP/BMWP/60916/2025: https://www.ema.europa.eu/en/documents/other/reflection-paper-tailored-clinical-approach-biosimilar-development_en.pdf
3. Schellekens, H. Biosimilar therapeutics—what do we need to consider?, NDT Plus, 2009; 2 (1): 27–i36, https://doi.org/10.1093/ndtplus/sfn177
4. De Mora, F. Biosimilar: what it is not, British Journal of Clinical Pharmacology, 2015; 80 (5): 949-956
5. EMA. Guideline on similar biological medicinal products, April 2015; CHMP/437/04 Rev 1: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf
6. ICH Q5E Biotechnological/biological products subject to changes in their manufacturing process: comparability of biotechnological/biological products - Scientific guideline, June 2005, CPMP/ICH/5721/03: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-e-comparability-biotechnologicalbiological-products-step-5_en.pdf
7. FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Update, Draft Guidance for Industry, June 2024: https://www.fda.gov/media/179456/download
8. Kurki, P., Barry, S., Bourges, I. et al. Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective. Drugs. 2021; 81(16): 1881–1896
9. Guillen, E., Ekman, N., Barry, S., et al. A Data Driven Approach to Support Tailored Clinical Programs for Biosimilar Monoclonal Antibodies. Clin Pharmacol Ther, 2023; 113: 108-123. https://doi.org/10.1002/cpt.2785

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.