Biosimilar regulation in the EU

Abstract

In the EU, the EMA has been working with biosimilars since 1998. This experience is crystallized in the extensive set of guidelines, which range from basic principles to details of clinical trials. While the guidance may appear complicated, it has enabled the development of biosimilars, of which 21 have managed to get marketing authorization. Currently marketed biosimilars in the EU have a good track record in safety and traceability. No biosimilars have been withdrawn from the market because of safety concerns. The most controversial issues with biosimilars are immunogenicity and extrapolation of therapeutic indications. The available data for these topics do not raise concerns among EU regulators. Interchangeability and substitution are regulated by individual EU member states.

Keywords:

• biosimilars
• clinical trials
• comparability
• extrapolation
• immunogenicity
• interchangeability
• regulatory

Financial & competing interests

P Kurki and is an employees of the Finnish Medicines Agency and an expert of the biosimilar medicinal product working party of the European Medicines Agency. N Ekman is an employee of the Finnish Medicines Agency and a member of the biosimilar medicinal product working party of the European Medicines Agency. 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.

Key issues

• EU was the first well-developed regulatory region to establish a pathway for licensing biosimilars.

• The licensing of a biosimilar requires that the comparability to the reference product is demonstrated by extensive head-to-head physicochemical, structural and in vitro functional tests complemented with tailored clinical studies.

• In order to be approved as a biosimilar, the active substances of the biosimilar and the reference product must be highly similar.

• In vivo animal studies are usually not feasible in the development biosimilars.

• In clinical studies, the selection of the target population and the clinical endpoints is based on the sensitivity of the test system to detect differences.

• Before licensing, immunogenicity of the biosimilar must be compared to the immunogenicity of the reference product.

• Extrapolation of efficacy and safety data from a studied therapeutic indication/patient population to those not studied is based on scientific criteria.

• Twenty one biosimilars have been granted marketing authorization by 2014; somatropins, filgrastims, follitropin alfas, infliximabs and an insulin glargine.

• The marketed biosimilars have the same efficacy and safety profiles as their reference products.

• All biosimilars have a risk management plan for the detection of unexpected rare adverse effects.