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.

Source:

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).