Interchangeability of biosimilar and biological reference product: updated regulatory positions and pre- and post-marketing evidence

ABSTRACT

Introduction: Since 2006, biosimilars have been available in several countries worldwide, thus allowing for potential savings in pharmaceutical expenditure. However, there have been numerous debates about the interchangeability of biosimilars and reference products based on concerns of immunogenicity by switching between biological products, which may cause lack of effect and toxicity.

Areas covered: The authors provide the reader with an overview of the different positions of regulatory authorities on the interchangeability and automatic substitution of biosimilars and reference products. Presently, the FDA allows automatic substitution without prescriber intervention if the biosimilar is interchangeable with reference products, while the European Medicines Agency delegate to each single EU member state.

Expert opinion: Different approaches in defining interchangeability and automatic substitution call for harmonization to increase confidence of healthcare professionals and patients about the clinical impact of switching. Networks of electronic healthcare records and administrative databases, potentially linkable to clinical charts and registries may rapidly assess frequency and benefit-risk profile of different switching patterns in routine care at different levels, thus integrating and strengthening pre-marketing evidence.

KEYWORDS:

• Switch
• immunogenicity
• biosimilars
• real world evidence

Article highlights

• Biosimilars are approved once biosimilarity has been evaluated based on a comparability exercise, which has been used for decades to grant similarity of a biological product after a manufacturing change

• Concerns have raised about immunogenicity of switching between biological products, which may cause lack of effect and toxicity

• Regulatory agencies have different positions on defining interchangeability and automatic substitution between biosimilars and reference products

• Data from both clinical trials and real-world setting suggest that switching from reference product to biosimilar is not expected to trigger or enhance immunogenicity

• Given the limitations of pre-marketing randomized clinical studies, post-marketing monitoring is necessary to address residual uncertainty regarding a demonstration of interchangeability and the safety of the switch

• Networks of administrative databases, potentially linkable to clinical charts and registries, may assess frequency and benefit-risk profile of different switching patterns in routine care, thus integrating and strengthening pre-marketing evidence

This box summarizes key points contained in the article.

Declaration of interest

G Trifirò is on the advisory board for biosimilars organized by Hospira and Sandoz. They were also on the coordination of research teams for the conduction of studies funded by Amgen Inc, Novartis, Teva Pharmaceuticals and Daiichi Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. One referee discloses receiving a consultancy fee from Celltrion.

Additional information

Funding

This manuscript has not been funded.