European regulatory guidelines for biosimilarsAndrzej Wiecek 1and Ashraf Mikhail 21Department of Nephrology,Endocrinology and Metabolic Diseases,Medical University of Silesia,Katowice,Poland and 2Department of Renal Medicine,Morriston Hospital,Swansea,UKAbstract The impending arrival en masse of biosimilars on Western markets is placing drug regulatory agencies under pressure to realign their policies.Biosimilars require more rigorous assessments than traditional chemical generics.This is because of the molecular complexity of recombinant proteins,and the complex-ity of biological manufacturing processes.Small differences can arise in a recombinant protein product which are hard or impossible to detect with even state-of-the-art analytical techniques.Yet,these differences can have significant impact on the safety and efficacy of the drug.The European Medicines Agency (EMEA)has taken the lead in issuing guidelines,most of whichare still under review.The guidelines advocate pre-clinical and clinical testing of biosimilars priorto market authorization,complemented by tailoredpharmacovigilance plans.These guidelines provide a valuable base from which to develop in this evolving regulatory environment.Keywords:biopharmaceuticals;biosimilars;EMEA;regulatory guidelines Introduction A generation of biotechnology-derived therapeutic agents are reaching the end of their patent lives,heralding the market entry of biosimilars.However,recombinant proteins are associated with a number of issues which distinguish them from traditional chemical drugs and their generics.Recombinant proteins are highly complex at the molecular level,and biological manufacturing processes are highly elaborate:they involve cloning,selection of a suitable cell line,fermentation,purification and formulation.In addition,the therapeutic properties of recombinant proteins are highly dependent on each step of the manufacturing process.The result is that different manufacturing processes yield a unique product,which may have a distinctive safety and efficacy profile (hence the name ‘biosimilar’instead of ‘biogeneric’,which implies identity).A biosimilar may differ significantly from a reference brand product.Furthermore,such differences may not be detectable with even state-of-the-art analytical techniques.The only certain way to assess the safety and efficacy of a biosimilar is to conduct pre-clinical and clinical tests.Are current regulations adequate?Current European Union (EU)legislation is embodied in three documents,dating from 2001onwards.The first covers items such as blood-derived productsand vaccines [1],without referring specifically tobiotechnology-derived drugs.Article 10contains a paragraph which remains the object of contention:‘The applicant shall not be required to provide theresults of toxicological and pharmacological tests orthe results of clinical trials if he can demonstrate:(i)either that the medicinal product is essentially similarto a medicinal product authorised in the MemberState ...(ii)or that the constituent or constituents of the medicinal product have a well established medicinal use,with recognised efficacy and an acceptable level of safety,by means of a detailed scientific bibliography’.The first point importantly lacks a precise definition of ‘essentially similar’,while the second ignores the significant differences that can occur between manufac-turing processes.An amendment in 2003[2]describes recombinant proteins as a ‘new class of biological medicinal product’,but provides no further guidance.The last update,in 2004[3],begins to broach the topicof biosimilars,stating ‘Biological medicinal productssimilar to a reference medicinal product do not usuallymeet all the conditions to be considered as a generic medicinal product mainly due to manufacturing process characteristics.When a biological medicinal product does not meet all the conditions to be considered as a Correspondence and offprint requests to : A.Wiecek,Department of Nephrology,Endocrinology and Metabolic Disease,Medical University of Silesia,Francuscka St 20-40,40-027Katowice,Poland.Email:awiecek@spskm.katowice.pl Nephrol Dial Transplant (2006)21[Suppl 5]:v17–v20doi:10.1093/ndt/gfl477ßThe Author [2006].Published by Oxford University Press on behalf of ERA-EDTA.All rights reserved.For Permissions,please email:journals.permissions@oxfordjournals.org by guest on October 18, 2013http://ndt.oxfordjournals.org/Downloaded from 谭阳2013.10.18

欧盟关于生物仿制药的法规文件European regulatory guidelines for biosimilars