Building confidence in biosimilars

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The third Multi-stakeholder Workshop on Biosimilar Medicinal Products included a session on ‘Building Stakeholder Confidence in Biosimilar Medicines through Evidence-Based Information Sharing’ [1]. The session focused on clinical experience of switching and clarifying definitions of ‘interchangeability’ between the US and the European Union (EU).

Review committee V15a16

Dr Sol Ruiz, Head of Biologics, Biotechnology and Advanced Therapies at the Agency of Medicinal Products and Medical Devices, Spain, and Chair of the Biologicals Working Party at the European Medicines Agency (EMA), chaired the session. She said that ‘the evidence base for biosimilar use is continuously increasing, allowing for improved knowledge sharing and identification of best practices to support the appropriate use of biologicals, including biosimilar medicines’.

Dr Hans Ebbers, Regulatory Project Leader of the Pharmacotherapeutic Group III at the Medicines Evaluation Board (MEB/CBG) in The Netherlands discussed how to establish interchangeability [2]. The European Commission has defined interchangeability in a consensus information document on biosimilars [3]. The US Food and Drug Administration (FDA) released draft guidance on the interchangeability of biosimilars with their reference biologicals in January 2017 [4]. But what should studies investigating switching to biosimilars look like? Dr Ebbers discussed possible study designs for switching studies and how this might differ in Europe and the US [5, 6].

Dr Gianluca Trifirò, Assistant Professor, Department of Clinical and Experimental Medicine and Pharmacology at the University of Messina, Italy presented the Italian experience of switching epoetin and granulocyte colony-stimulating factor (G-CSF) between 2009-2014 in an observational study covering 25% of the Italian population [7]. The study showed large variability in the use of biologicals, both originators and biosimilars, in regions across Italy, which is not surprising, since the health service in Italy is managed at the regional level [8]. The study showed that switches occur frequently in clinical practice, either between originators or switching to a biosimilar, with no identifiable pattern in switching between products. Professor Trifirò concluded that ‘more information is needed regarding the long-term effects of switching, not just from an originator to a biosimilar, but also between originators’. He added that ‘utilizing existing databases for post-marketing surveillance to assess these population impacts could be very useful’.

Dr Benedicte Lunddahl Rasmussen, Head of Section at the Danish Medicines Agency (Laegemiddelstyrelsen, DKMA), Denmark, shared a case study of infliximab uptake in Denmark following a 2015 recommendation establishing equivalence between originator and biosimilar infliximab and recommending switching [9]. As a result of the tender system, nearly the entire infliximab market switched to biosimilar infliximab in 2016. Coinciding with this switch, an Executive Order in December 2015 mandated traceability, requiring physicians to record the brand name and batch number in patient records and in adverse drug event reports [10]. A review of the reports received following implementation of this law shows that batch numbers are included in reports for biosimilars more often than with reference products. Of the 294 reports received, 20 could possibly be related to switching. No correlation between batches and reported events was observed, supporting equivalence in safety profiles between products. The Danish Government continues to be engaged with patients and healthcare professionals through a variety of educational formats to ensure understanding and confidence in biosimilars.

There are some major differences between Europe and the US when it comes to how they view interchangeability of biosimilars. Dr Pekka Kurki, Adjunct Professor of Clinical Immunology at the University of Helsinki and expert of the Finnish Medicines Agency, FIMEA, Finland and Sue Lim, Team Leader Therapeutic Biologics and Biosimilar medicines, Office of New Drugs, FDA, USA, explained the differences in nomenclature related to ‘interchangeability’ between the EU and US. They pointed out that although EMA and FDA are aligned in most aspects of the concept of biosimilarity; the difference related to ‘interchangeability’ is due to a discrepancy in terminology and legal definition. In Europe, interchangeability is a scientific and medical term that refers to the medical practice of changing one medicine for another that is expected to achieve the same clinical outcome. In Europe, the administrative practice of switching or substituting is a national decision. In the US, however, the legal definition of ‘interchangeability’ allows for substitution of the biosimilar for the reference product without the intervention of the prescriber [11].

The session ended with a clarification that immunogenicity is a product-related risk that exists for all products irrespective of switching. Because pharmacovigilance systems are robust and each patient is monitored as an individual, the question of whether a product has higher or lower theoretical immunogenicity profile when switching could be considered irrelevant. Regulators from the US and EU also re-affirmed their commitment to the global development of biosimilars and to minimizing duplicate studies between ICH-member countries where possible.

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1. European Commission Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs. Multi-stakeholder Workshop on Biosimilar Medicinal Products; 5 May 2017; Brussels, Belgium.
2. GaBI Online - Generics and Biosimilars Initiative. Establishing interchangeability for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 16]. Available from:
3. GaBI Online – Generics and Biosimilars Initiative. Integrating biosimilars into clinical practice []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 15]. Available from:
4. GaBI Online - Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilar interchangeability []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 15]. Available from:
5. GaBI Online - Generics and Biosimilars Initiative. Interchangeability and switching study designs for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 15]. Available from:
6. GaBI Online - Generics and Biosimilars Initiative. Establishing interchangeability for biosimilars in the US []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 15]. Available from:
7. Trifirò G. Building stakeholder confidence in biosimilar medicines through evidence-based information sharing. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(4):181-2. doi:10.5639/gabij.2017.0604.038
8. Genazzani A, Trifirò G, Marcianò I, Ingrasciotta Y. Biosimilars in Italy: what do real-world data reveal? Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(3):114-9. doi:10.5639/gabij.2017.0603.023
9. Lunddahl B. Pharmacovigilance on biologicals and biosimilars: a Danish perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(3):123-4. doi:10.5639/gabij.2016.0503.030
10.   GaBI Online - Generics and Biosimilars Initiative. Building trust in biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 15]. Available from:
11. Derbyshire M. USA and Europe differ in interchangeability of biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(4):183-4. doi:10.5639/gabij.2017.0604.039

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