Comparative efficacy studies: where are we now?

In an article published in GaBI Journal titled ‘Comparative efficacy studies of biosimilars: data versus theoretical risks, beliefs, and comfort’ [1], Professor Pekka Kurki, a Clinical Immunology Professor at University of Helsinki, Finland and a member of the Finnish Medicines Agency (Fimea), explores the current position on biosimilar efficacy studies held by medicines agencies across the globe.

Biosimilars have potential to mitigate treatment costs associated with biological medicines and improve access to products worldwide. However, current stringent and non-harmonized regulatory practices hinder competition and contribute to relatively high biosimilar prices.

Professor Kurki highlights that biological therapies, including gene and cell therapies, are advancing rapidly but face significant challenges due to their high costs, which limit patient access. Biosimilars could reduce treatment costs and improve access to medicines. However, their market growth has been impeded by various factors, including prescriber reluctance to adopt them, despite evidence supporting their safety and efficacy. This hesitance is often fuelled by misinformation, administrative burdens, concerns about physician autonomy, and a lack of incentives. To address these issues, some countries have implemented automatic substitution policies to encourage biosimilar use.

Another significant factor contributing to high biosimilar prices is limited competition, exacerbated by anti-competitive practices from innovators and stringent regulatory requirements. Biosimilar development is costly, often requiring the purchase of reference products and large-scale clinical trials to demonstrate equivalence. These regulatory hurdles particularly affect the development of biosimilars for rare diseases.

Current guidelines from the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) allow some flexibility in biosimilar clinical development but typically require comparative efficacy trials unless pharmacodynamic studies using established efficacy surrogates are conducted. Unfortunately, suitable pharmacodynamic markers are often unavailable for most biosimilars, particularly monoclonal antibodies [2].

This scenario is likely to lead to increased reliance on costly efficacy studies, straining clinical resources and potentially delaying the development of new innovative medicines, especially in oncology.

The long-term safety and efficacy of biosimilars have been validated through widespread use, with no significant post-licensing issues related to immunogenicity or extrapolated therapeutic indications. However, the necessity of large clinical efficacy studies remains contentious. Retrospective analyses suggest that these studies have limited impact on regulatory approvals, as many biosimilars gain approval based on analytical and functional comparability, regardless of efficacy trial outcomes.

Recent regulatory changes in the UK and by the World Health Organization (WHO) suggest a shift toward waiving the requirement for comparative efficacy studies under specific circumstances. EMA has initiated a re-evaluation of its guidelines, acknowledging that the historical reliance on comparative efficacy studies may be outdated [3]. While the FDA remains more conservative, it has shown openness to revisiting its stance, particularly regarding immunogenicity concerns.

Pharmaceutical regulation should prioritize public health while fostering industry growth. Some regulatory agencies are streamlining requirements, reflecting the need for harmonization in guidance. Legislative initiatives in the US aim to eliminate distinctions between biosimilar and interchangeable products, potentially easing the burden of comparative efficacy studies [3].

As more biologicals lose exclusivity, regulators are encouraged to simplify and accelerate biosimilar development to enhance competition and improve access to essential medicines. Professor Kurki notes that coordinated efforts among regulatory agencies can facilitate better alignment on the necessity of comparative efficacy studies, ultimately benefiting public health and expanding treatment options for patients.

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References
1. 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
2. GaBI Online - Generics and Biosimilars Initiative. Advancing biosimilar drug development with pharmacodynamic biomarkers [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 Jan 7]. Available from: www.gabionline.net/biosimilars/general/advancing-biosimilar-drug-development-with-pharmacodynamic-biomarkers
3. GaBI Online - Generics and Biosimilars Initiative. EMA concept paper towards a tailored clinical approach in biosimilar development [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 Jan 7]. Available from: www.gabionline.net/policies-legislation/ema-concept-paper-towards-a-tailored-clinical-approach-in-biosimilar-development

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