Biosimilar clinical efficacy studies: are they still necessary?

A paper published in Drugs, explores the evolution in biosimilars regulatory thinking which is now moving away from the default requirement for clinical efficacy studies (CES) for approval [1]. This follows the release of European Medicines Agency's ‘draft reflection paper on a tailored clinical approach in biosimilar development’ [2] published on 1 April 2025.

‘The Tailored Biosimilar Approach: Expectations and Requirements’, co-authored by researchers from across Europe, outlines that the regulatory framework for biosimilars is evolving toward a tailored approach, where CES are no longer required by default. It reviews growing evidence that robust analytical, functional, and pharmacokinetic data are sufficient to demonstrate biosimilarity, particularly for monoclonal antibodies and fusion proteins. The authors argue that CES often add little scientific value and may fail to resolve uncertainties that stem from quality or functional discrepancies.

Drawing from retrospective analyses of biosimilar approvals, they show that decisions to approve have consistently aligned with quality data, not CES outcomes. The paper also discusses how CES may lack the sensitivity to detect clinically meaningful differences and can introduce inconsistent results. The authors propose that biosimilar development should be based on a case-by-case evaluation, reserving CES only for scenarios where they are essential, thereby ensuring scientific rigour while avoiding unnecessary clinical trials.

The paper outlines that, in the context of tailored biosimilar development, where CES may no longer be required, demonstrating biosimilarity relies on a robust analytical comparability exercise supported by pharmacokinetic and immunogenicity data. Advances in analytical techniques and decades of regulatory experience have led to global consensus that CES are often not sensitive enough to detect subtle differences relevant to biosimilarity, prompting regulators to re-evaluate their necessity. The removal of the necessity for CES from the biosimilarity assessment has been explored in other recent publications and is being investigated by regulatory authorities in some regions [3, 4].

A biosimilar’s development is now centered on detailed physicochemical and functional characterization, with assays designed around the known mechanism of action. These assays identify critical quality attributes (CQAs) that must match the reference product’s established variability range. If differences are observed, they must be justified with evidence demonstrating no clinical impact. This model reflects longstanding regulatory practices for approving manufacturing changes in originator biologicals, where analytical comparability, not clinical trials, is typically sufficient.

The paper also emphasizes that analytical variability is inherent in biologicals, and similarity ranges are established using multiple reference product batches. The goal is to assure that any differences fall within clinically irrelevant thresholds. Complementary pharmacokinetic studies in healthy volunteers or patients further support biosimilarity, often capturing safety and immunogenicity data more sensitively than CES. These studies can be tailored, e.g., multi-dose, extended duration, to detect delayed immune responses.

In most cases, a combination of state-of-the-art physicochemical, functional, and pharmacokinetic evidence is sufficient to demonstrate biosimilarity without CES. Post-marketing pharmacovigilance continues to confirm comparable safety profiles between biosimilars and reference products. Ultimately, the tailored approach maintains high scientific standards while eliminating unnecessary clinical trials, provided that analytical and pharmacokinetic data offer clear evidence of biosimilarity.

The paper stresses that CES may still be needed in specific cases, such as when the mechanism of action is unknown or poorly understood, as with antibody–drug conjugates or cell therapies. CES may also be required for highly heterogeneous or insufficiently characterized products where analytical methods cannot fully assess similarity. Additionally, for locally administered biologicals or those with known safety/immunogenicity concerns, CES may be necessary when pharmacokinetic studies cannot provide adequate safety or efficacy insights.

In conclusion, the authors note that biosimilarity can generally be confirmed without CES by using a totality-of-evidence approach focused on advanced analytical and functional testing, supported by pharmacokinetic studies. CES should only be used to address unresolved uncertainties. Aligning manufacturing processes with the reference product is often more effective than clinical trials. Global regulatory harmonization and stakeholder education are essential to ensure trust and clarity in biosimilar development.

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References
1. The Tailored Biosimilar Approach: Expectations and Requirements. https://pubmed.ncbi.nlm.nih.gov/40169518/
2. GaBI Online - Generics and Biosimilars Initiative. Advances in EMA plans to streamline biosimilar assessment[www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 May 27]. Available from: www.gabionline.net/guidelines/advances-in-ema-plans-to-streamline-biosimilar-assessment
3. GaBI Online - Generics and Biosimilars Initiative. Comparative efficacy studies: where are we now? [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 May 27]. Available from: www.gabionline.net/biosimilars/research/comparative-efficacy-studies-where-are-we-now
4. Kurki P. Comparative efficacy studies of biosimilars: data versus theoretical risks, beliefs, and comfort. Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(1):23-6. doi:10.5639/gabij.2024.1301.004

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