European regulatory pathways for biosimilars

The European regulatory pathways for biosimilars were discussed in a review of biosimilars in rheumatology by author José M Serra López-Matencio and colleagues from the Universidad Autónoma, Madrid, Spain*.

The European Union (EU) has led the way in establishing regulations for biosimilars. In 2005, the European Medicines Agency (EMA) established the first regulatory pathway for biosimilars that is distinct from the generics pathway [1]. The biosimilar manufacturer should assemble all available knowledge of the reference product with respect to the type of host cell, formulation and container closure system. The manufacturer must also submit a complete description and data package information showing the whole manufacturing process, including obtaining and expression of target genes, optimization and fermentation of gene engineering cells, clarification and purification of the products, formulation and testing, and aseptic filling and packaging.

Furthermore, non-clinical evaluations should be undertaken both in vitro and in vivo. In terms of the clinical evaluation, the comparability exercise should begin with pharmacokinetic (PK) and pharmacodynamic (PD) studies followed by pivotal clinical trials. PK studies should be designed to enable detection of potential differences between a biosimilar and the reference product. Also, single dose, crossover PK studies in a homogenous population are recommended.

The manufacturer should justify the choice of single dose studies, steady-state studies, or repeated determination of PK parameters and the study population. PD studies and confirmatory PK/PD studies may be appropriate if there are clinically relevant PD markers, but if there is lack of them, the traditional 80‒125% equivalence range is often used [2].

In addition, similar efficacy of the biosimilar and the reference product has to be demonstrated in randomized and well-controlled clinical trials, which should preferably be double blind or at least observer blind. The pre-licensing safety data and the immunogenicity data should be obtained from comparative efficacy trials. Finally, applicants also need to present an ongoing risk-management and pharmacovigilance plan, since data from pre-authorized clinical studies are usually too limited to identify all potential side effects of the biosimilar.

Generics may be approved at the country level or using a decentralized procedure. However, all medicines for human and animal use derived from biotechnology and other high-tech processes (including biosimilars) must be approved via the centralized EMA procedure [1].

This article is prepared based on the paper entitled ‘Biosimilars: a new challenge in the current pharmacology’ by Serra-Matencio JM, Ramirez-Herraiz E, Morell-Baladron A, Castañeda S.Hospital de La Princesa, IIS-IP, Madrid, Universidad Autónoma, Madrid, Spain.

Editor’s comment
Readers interested to learn more about the regulatory pathways for biosimilars in Europe are invited to visit to view the following manuscript published in GaBI Journal:

The EU regulatory approach to generics and biosimilars is essentially similar

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal – please send us your submission here.

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Biosimilars: a new challenge in the current pharmacology

1. GaBI Online – Generics and Biosimilars Initiative. EU guidelines for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from:
2. GaBI Online – Generics and Biosimilars Initiative. Quantitative evaluation of bioequivalence []. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from:


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