Dr Andrew Baron
Scientific Director of Biosimilars, Product Characterisation and Biophysics
Insights|
October 20, 2026
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6 min read
When the European Medicines Agency (EMA) adopted its tailored clinical approach to biosimilar development in March 2026, much of the discussion focused on comparative efficacy studies (CES) and whether they would become a thing of the past. Several months on, that debate has largely settled. The industry now accepts that, for many biosimilars, large comparative efficacy studies are no longer the centrepiece of demonstrating biosimilarity. Instead, attention has shifted to a more practical question: what evidence are regulators now relying on to establish biosimilarity with confidence?
The answer is increasingly clear; the future of biosimilar development will be built on strong analytical characterisation, robust pharmacokinetic data and, critically, functional evidence that demonstrates a biosimilar behaves like its reference product in biologically meaningful ways.
One of the most common misconceptions surrounding the EMA's tailored clinical approach is that biosimilar development has somehow become less demanding. In reality, the scientific expectations remain as high as ever.
What has changed is the type of evidence regulators consider most informative. Over two decades of biosimilar experience, regulators have accumulated substantial evidence that comparative efficacy studies rarely identify clinically meaningful differences that were not already apparent from analytical, functional and pharmacokinetic data. At the same time, advances in analytical technologies have dramatically increased our ability to detect subtle differences between biological products.
As a result, the focus has shifted away from asking whether two products perform similarly in a large patient population and towards understanding whether there is any scientific basis to expect them to perform differently in the first place.
The foundation of biosimilarity remains a detailed understanding of a molecule's structure and critical quality attributes. However, structure alone is only part of the story.
Ultimately, biological medicines exert their clinical effects through specific biological interactions. Monoclonal antibodies bind targets, engage receptors, activate signalling pathways and, in some cases, recruit immune effector mechanisms. Demonstrating that a biosimilar reproduces these functions is therefore central to demonstrating biosimilarity.
This is where functional characterisation plays a critical role.
Modern biosimilar programmes typically include a range of functional assessments designed to evaluate the mechanisms that are relevant to clinical activity. Depending on the molecule, these may include:
Ligand neutralisation and target blockade.
Receptor agonism or antagonism.
Modulation of downstream signalling pathways.
Induction or inhibition of cell proliferation, activation or apoptosis.
Fc-mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC).
Other mechanism-specific biological activities that contribute to the therapeutic effect
These studies help answer one of the most important questions in biosimilar development: does the biosimilar perform the same biological functions in a manner that is highly similar to the reference product?
If there is one lesson the industry has learned since the EMA's new framework was introduced, it is that reduced reliance on comparative efficacy studies does not reduce the need for sensitive functional data.
In many respects, it has the opposite effect.
As comparative efficacy studies become less central to biosimilarity assessments, greater emphasis is being placed on understanding the mechanism of action, identifying clinically relevant quality attributes and selecting assays with sufficient sensitivity, capable of detecting meaningful differences.
This places functional assays at the heart of the biosimilarity exercise. The question is no longer whether functional characterisation is required, but whether the chosen assays are sufficiently relevant and sensitive to provide confidence that the biosimilar and reference product will behave similarly in patients.
The increasing importance of functional characterisation is closely linked to another trend: a greater focus on understanding mechanism of action.
Not all quality attributes are equally important, and not all biological functions contribute equally to clinical activity. While all therapeutic antibodies rely on target recognition, the relative importance of individual mechanisms can vary considerably between products. For some molecules, demonstrating equivalent target binding and biological potency may be most critical. For others, Fc-mediated activities such as ADCC or CDC also play an important role and therefore warrant detailed characterisation.
The challenge for developers is demonstrating that they understand these relationships and can justify why particular assays and attributes are relevant to biosimilarity.
As regulators continue to embrace a totality-of-evidence approach, a scientifically coherent understanding of mechanism of action becomes increasingly important in determining which studies are required and how residual uncertainty is addressed.
Several months after implementation of the EMA's tailored clinical approach, the practical implications for developers are becoming apparent.
Successful biosimilar programmes are increasingly characterised by:
Comprehensive analytical characterisation.
Strong understanding of mechanism of action.
Scientifically justified critical quality attribute selection.
Robust, biologically relevant functional assay packages.
Well-designed pharmacokinetic comparability studies.
Early identification and management of residual uncertainty.
In other words, the industry is moving towards a model where success depends less on generating large volumes of clinical data and more on generating highly informative scientific data.
The regulatory conversation around comparative efficacy studies has already evolved. The more interesting discussion now concerns the evidence framework replacing them.
For biosimilar developers, the message is clear. The future of biosimilarity assessment will be shaped by the ability to characterise molecules deeply, understand how they work and demonstrate functional similarity using sensitive, scientifically relevant assays.
The result is not less science, but smarter science. By focusing on the studies most capable of detecting meaningful differences between a biosimilar and its reference product, developers can improve the efficiency of biosimilar development while maintaining the rigorous standards of quality, safety and efficacy that patients and regulators rightly expect.
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