I NTRODUCTION The first therapeutic, recombinant, biological molecules (biopharmaceuticals) were introduced in the 1980s, and the patents for these have either expired (e.g. recombinant insulin, human growth hormone, and interferons alfa and beta) or are about to expire (epoetin alfa in 2004, granulocyte colony- stimulating factor in 2006, and follicle-stimulating hormone in 2007). Contact for correspondence: Prof. Dr. Daan J .A. Crommelin, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht,The Netherlands Tel:+31 30-253-6973/7306 Fax:+31 30-251-7839 – E-mail:d.j.a.crommelin@pharm.uu.nl 1 Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht,The Netherlands 2 Servicio de Farmacia, Hospital Ramón y Cajal, Madrid, Spain 3 Farmacia, Ospedale Civico Lugano, Lugano, Switzerland 4 Pharmacy Department,Virga Jesse Hospital, Hasselt, Belgium 5 Pharmacy Department,JohannesGutenberg-University Hospital,Mainz,Germany 6 Pharmacie Saint-Eloi, CHU de Montpellier, Montpellier, France 7 Farmacia Ospedale Civile Maggiore,Verona, Italy 8 Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia 9 Pharmacy Department, St George’s Hospital, London, UK Received:15th December 2004,Revised manuscript received:25th January 2005 Accepted:26th January 2005 As with traditional (low-molecular-weight) pharmaceuticals, this is likely to stimulate development of new versions of these products, which may increase competition and reduce prices. This immediately raises the question of how such new versions of biopharmaceuticals can be evaluated, both by the regulators and by those prescribing and dispensing them. Traditional generic pharmaceutical products are relatively easy to develop, and gain market approval by demonstrating physicochemical similarity and bioequivalence in studies in healthy volunteers [1]. Biopharmaceuticals pose unique pro- blems because of their high molecular weights, their complex three-dimensional structures, the dependence of biological acti- vity on structural integrity, the complexity of their manufactu- ring processes, and the inadequacy of current analytical methods to fully characterize these complex proteins [2]. For these reasons, the established concept of low-molecular-weight generic drugs cannot be applied to biopharmaceuticals, and this leaves regulators with the challenge of defining therapeutic equivalence for these products, and hospital pharmacists with the challenge of deciding whether or not to switch to these products. In April 2004, an international working group of practising hospital pharmacists and pharmaceutical scientists met to discuss how best to advise hospital pharmacists on the evaluation of Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals Daan Crommelin, PhD 1 ,Teresa Bermejo, PhD 2 , Marco Bissig, PhD 3 , Jaak Damiaans, PhD 4 , Irene Krämer, PhD 5 , Patrick Rambourg, PhD 6 , Giovanna Scroccaro, PhD 7 , Borut Strukelj, PhD 8 , and Roger Tredree, BPharm 9 Biosimilars are structurally more complex and inherently less stable than ‘classic’ low-molecular-weight generics: their efficacy and safety can only be assessed thoroughly on the basis of clinical (including post-marketing) data. ABST RACT The patents for several established biopharmaceuticals have either expired or are about to expire, opening the way for new ver- sions of these products, referred to as‘biosimilars’ in Europe and ‘follow-on biologics’ in the USA. However, biopharmaceuticals and biosimilars pose unique problems because of their high molecular weights, their complex three-dimensional structures, the depen- dence of biological activity on structural integrity, and the complexity of their manufacturing processes. Current analytical methods are inadequate to characterize these productscompletely.Therefore,the established concept of low-molecular-weight generic drugs cannot be applied to biopharmaceuticals, which leaves regulators with the challenge of defining therapeutic equivalence for these products, and hospital pharmacists with the challenge of deciding whether to switch to these products.This review presents back- ground information on the differences between biosimilars and low-molecular-weight generic drugs and the current regulatory situation, and provides a checklist to aid hospital pharmacists in their evaluation of biosimilars. KEY W O RD S biosimilars, follow-on biologics, evaluation, immunogenicity, safety www.ejhp.org The European Journal of Hospital Pharmacy Science Volume 11 • 2005 • Issue 1 • P. 11 - 17 © 2005 The European Association of Hospital Pharmacists. All rights reserved 1378-1537 €20 EJHP-S • Volume 11 • 2005/1• www.ejhp.org • 11