Drug Res (Stuttg) 2016; 66(01): 1-6
DOI: 10.1055/s-0035-1548911
© Georg Thieme Verlag KG Stuttgart · New York

From Bioequivalence to Biosimilarity: The Rise of a Novel Regulatory Framework

V. D. Karalis
1  Laboratory of Biopharmaceutics – Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
› Author Affiliations
Further Information

Publication History

received 13 February 2015

accepted 26 March 2015

Publication Date:
20 April 2015 (online)


One of the most crucial issues in pharmacotherapy is to address the query if a patient can be switched from one product to another of the same active substance. For the conventional small-molecule drugs, there is a consensus on the required bioequivalence criteria. However, proving equivalence in the field of biologicals is an issue with no clear harmony. The aim of this review is to highlight the differences between the biologicals and the conventional chemical drugs, as well as, to present the different regulatory requirements for the placement of biosimilars on the market.

Biologicals are substantially larger than chemical compounds, their manufacturing process is very complex, and their protein structure may trigger immune reactions. For this reason, the conventional bioequivalence approach is not adequate, but further emphasis should be placed on the quality of the manufacturing process and the risks of immunogenicity. The assessment procedure of biosimilars should encompass their comparison with the innovator product using all available evidence derived from the development process. The latter includes analytical and animal studies, pharmacokinetic and pharmacodynamic data, as well as, clinical trials focusing on immunogenicity. The US FDA has established a step-wise approach to demonstrate biosimilarity, while the EMA has already issued many guidelines referring either to all biosimilars or to specific products/classes. Overall, a case-by-case assessment procedure is considered by the regulatory authorities. In any case the placement of a biosimilar on the market does not necessarily imply interchangeability with the innovator drug.