Step-wise approach to develop biosimilar focusing on quality and clinical efficacy

By William Chin, PhD, Scientific Coordinator, EUCRAF

Recently, European regulators from EMA, Medicines Evaluation Board (CBG-MEB), Netherlands, Paul Ehrlich Institute (PEI), Germany, and the Danish Health and Medicines Authority (DHMA) have published 2 review articles addressing the use of animal studies in demonstrating similarity of biosimilar. The consensus is that biosimilar should be developed based on a stepwise approach to demonstrating biosimilarity.

The stepwise approach involves: (1) extensive structural and functional characterization of the biosimilar and reference products; (2) animal studies; (3) comparative human pharmacokinetics/pharmacodynamics studies; (4) clinical data of immunogenicity; and (5) clinical studies of safety and efficacy.

Here are the highlights of the 2 recent review articles:

  • The functional properties of the biosimilar can be tested and compared in vitro and these assays are generally more sensitive than animal studies.
  • A physicochemically and biologically well-characterized biological for which close similarity with a well-known reference product has been demonstrated based on extensive analytical and in vitro data are highly unlikely to pose a safety concern different from the reference product, with the exception of immunogenicity issues.
  • To minimize any risk associated with the presence of impurities, these impurities should be kept to a minimum instead of setting up a non-clinical evaluation program.
  • Animal studies are recommended in EU overarching guidelines to establish biosimilarity.
  • Animal studies support similarity despite known quality differences.
  • When differences were detected, these were not considered clinically relevant.
  • A step-wise, risk based approach to develop biosimilars may not need animal studies.
  • For the PK comparability, human data will be more informative and hence these data would supersede the animal data. 
  • The need for in vivo studies for biosimilar candidates will be driven by what level of evidence one can feasibly generate to inform the biosimilar comparability exercise.
  • The absence of sufficiently powered studies in humans could increase the relative weight of non-clinical pharmacodynamic and PK data in the totality of evidence when biosimilarity needs to be established for this kind of products.


1. Contribution of animal studies to evaluate the similarity of biosimilars to reference products. Peter J.K. van Meer, Hans C. Ebbers, Marlous Kooijman, Christine C. Gispen-de Wied, Beatriz Silva-Lima, Ellen H.M. Moors, Huub Schellekens. Drug Discov Today. 2014 Nov 20. pii: S1359-6446(14)00446-2. doi: 10.1016/j.drudis.2014.11.009.

2. Biosimilars entering the clinic without animal studies: A paradigm shift in the European Union.Leon AGJM van Aerts, Karen De Smet, Gabriele Reichmann, Jan Willem van der Laan & Christian K Schneider. MAbs. 2014 Aug 5;6(5).