Biological agents and biosimilars: Essential information for the internist


      • Biologics are a wide range of substances synthesized by cells or living organisms.
      • A biosimilar is a copy of an authorized original biological medicinal product.
      • Safety and efficacy of biosimilars are comparable to the originator's.
      • The post-marketing safety evaluation is stringent as for any new biological product.


      Biologics embrace a wide range of substances synthesized by cells or living organisms by means of different biological processes, including recombinant DNA technology, controlled gene expression, or antibody technologies. A biosimilar establishes similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise. Minimizing development costs and accelerating their market access create a convergence of interests between health services, worried about sustainability, and generic manufacturers. While the demonstration of bioequivalence is sufficient for small synthetic molecules, this approach is not scientifically applicable to a copy of biological drug constituted by large and complex molecules, which are similar but not identical to the originator and are also subject to different post-translational processes. Internists should be confident that the development process of biosimilars ensures a comparable risk-to-benefit balance with the originators. On the basis of available evidence and pharmacovigilance network, there are no grounds to believe that the use of a biosimilar carries more risks for the patient than the use of an originator. Since the first biosimilar was authorized in Europe in 2006, no clinical alerts have raised red flags about the established EMA biosimilar pathway. In this article, we discuss some of the most frequent concerns raised by clinicians about biosimilars and try to explains the scientific principles underlying the biosimilar concept established in the EU in order to license biosimilar drugs.


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        • Mellstedt H.
        Clinical considerations for biosimilar antibodies.
        EJC Suppl. Dec 2013; 11: 1-11
        • Isaacs J.D.
        • Cutolo M.
        • Keystone E.C.
        • et al.
        Biosimilars in immune-mediated inflammatory diseases: initial lessons from the first approved biosimilar anti-tumour necrosis factor monoclonal antibody.
        J Intern Med. 2016; 279: 41-59
        • Dranitsaris G.
        • Dorward K.
        • Hatzimichael E.
        • Amir E.
        Clinical trial design in biosimilar drug development.
        Invest New Drugs. 2013; 31: 479-487
        • Bennett C.L.
        • Chen B.
        • Hermanson T.
        • et al.
        Regulatory and clinical considerations for biosimilar oncology drugs.
        Lancet Oncol. 2014; 15: e594-e605
        • Schneider C.K.
        • Vleminckx C.
        • Gravanis I.
        • et al.
        Setting the stage for biosimilar monoclonal antibodies.
        Nat Biotechnol. Dec 2012; 30: 1179-1185
        • Sekhon B.S.
        • Saluja V.
        Biosimilars: an overview.
        Biosimilars. 2011; 1: 1-11
        • Ramanan S.
        • Grampp G.
        Drift, evolution, and divergence in biologics and biosimilars manufacturing.
        BioDrugs. 2014; 28: 363-372
        • US Food and Drug Administration
        Information for consumers (biosimilars).
        ([Accessed on May 20, 2016])
        • Rathore A.S.
        Roadmap for implementation of quality by design (QbD) for biotechnology products.
        Trends Biotechnol. 2009; 27: 546-553
        • European Medicines Agency
        Scientific guidelines on biosimilar medicines.
        ([Accessed on May, 2016])
        • U.S. Food and Drug Administration
        Demonstration of comparability of human biological products, including therapeutic biotechnology-derived products.
        ([Accessed on May 20, 2016])
        • European Medicines Agency
        Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: quality issues.
        Date: December 2003
        (CPMP/BWP/3207/00/Rev 1) ([Accessed on May 20, 2016])
      1. European Medicines Agency. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. December 2003. (CPMP/3097/02). This guideline has been superseded in November 2007 by the following revised version: (Accessed on May 20, 2016).

        • Weise M.
        • Bielsky M.C.
        • De Smet K.
        • et al.
        Biosimilars: what clinicians should know.
        Blood. Dec 2012 20; 120: 5111-5117
        • Schneider C.K.
        Biosimilars in rheumatology: the wind of change.
        Ann Rheum Dis. Mar 2013; 72: 315-318
        • Schiestl M.
        • Stangler T.
        • Torella C.
        • Cepeljnik T.
        • Toll H.
        • Grau R.
        Acceptable changes in quality attributes of glycosylated biopharmaceuticals.
        Nat Biotechnol. Apr 2011; 29: 310-312
        • Vezér B.
        • Buzás Z.
        • Sebeszta M.
        • Zrubka Z.
        Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents.
        Curr Med Res Opin. 2016 May; 32: 829-834
        • European Medicines Agency
        Concept paper on extrapolation of efficacy and safety in medicine development.
        ([Accessed on May 20, 2016])
        • European Medicines Agency
        CHMP assessment report.
        ([Accessed on May 20, 2016])
        • European Medicines Agency
        Assessment report for Aranesp.
        ([Accessed on May 20, 2016])
        • Finnish Medicines Agency
        Are biosimilars interchangeable?.
        ([Accessed on May 20, 2016])
        • Seidl A.
        • Hainzl O.
        • Richter M.
        • et al.
        Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity.
        Pharm Res. 2012; 29: 1454-1467
        • Heinemann L.
        • Khatami H.
        • McKinnon R.
        • Home P.
        An overview of current regulatory requirements for approval of biosimilar insulins.
        Diabetes Technol Ther. 2015; 17: 510-526
      2. INN for biological and biotechnological substances.
        ([Accessed on May 20, 2016])
      3. Nonproprietary naming of biological products guidance for industry. USA Food and Drug Administration. [ [Accessed on May 20, 2016]].

        • Federal Trade Commission FTC
        Emerging health care issues: follow-on biologic drug competition.
        • IMS Institute for Healthcare Informatics
        Delivering on the potential of biosimilar medicines. The role of functioning competitive markets.
        ([Accessed on May 20, 2016])