study programme of the original drugs, where the focus is the comparison of clinically relevant efficacy and safety profiles of two therapeutic regimens. In clinical studies, pre-existing pharmacovigilance data on the reference product help validate the safety data obtained from biosimilar studies, and are compared with historical data or in direct head-to-head comparability studies. Therefore, bridging studies correlating critical attributes of the antibody and pharmacovigilance data are required to support the use of biosimilars, irrespective of the source of the drug. Also, not only should patient data in the market be followed up over time (for example, safety data collection after approval), but data on the quality of the biosimilar should also be generated. Confidence in biosimilars will thus depend on how transparent this assessment is. Norway, Finland or Hungary). Data show that similar immunogenicity and safety exist between the biosimilar and the original infliximab, and these results have resulted in some regulatory bodies in the EU supporting interchangeability. 26,27 Data from an independent study sponsored by the Norwegian government (NOR-SWITCH) designed to assess the efficacy, safety and immunogenicity of biosimilar Remsima have added to the real-world evidence that supports switching patients from reference infliximab to biosimilar infliximab. The biosimilar was non-inferior to its reference product in adult patients who had been switched to receive treatment with the biosimilar for 54 weeks; all participants had been on stable treatment with the reference product for at least six months prior to switching to the biosimilar. 28 Risks associated with switching Development programmes of several biosimilars have included studies in which the reference product has been switched to the biosimilar and, occasionally, back to the reference drug. Epoetin (EPO) is a highly glycosylated protein that depends on post-translational modification for its mechanism of action and is one of the few therapeutic proteins to induce severe immunogenicity reactions; however, no serious adverse events based on immunogenicity have been reported in regard to switching from EPO reference products to biosimilars. Results regarding use of infliximab have not raised concerns either. Transition data from the PLANETAS and PLANETRA extension studies showed comparable rates of serious treatment-emergent adverse events between the maintenance and transition groups. The anti-drug antibody positivity and hypersensitivity reactions during the second year of both studies did not differ significantly between patients exposed to the reference product or biosimilar as compared with those who received only the biosimilar over two years. 24,25 This view is supported by the fact that switches between these reference products and biosimilars have been accepted in some EU Member States (Poland, Development timelines It is the general perception that biosimilars can progress from bench to shelves in a shorter period of time than conventional biologics and small- molecule drugs. The stages of comparative analysis, process development, scale-up and validation, clinical trials, and review and approval of the biosimilar by regulatory agencies might in fact take 5–9 years, and the main challenge is conducting long and expensive studies, in particular because in many cases the study designs are not sensitive enough to detect differences between the reference product. 29 Another challenge in terms of timelines for development concerns the degree of protection conferred by patents for the original biologics, which have a period of exclusivity that varies per country once the agent receives approval for commercialisation, during which a biosimilar cannot be marketed. References 1 European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London, UK. 3 June 2013. www.ema.europa.eu/ docs/en_GB/document_library/ Scientific_guideline/2013/06/ WC500144124.pdf (accessed September 2018). 2 European Medicines Agency. Guideline on similar biological medicinal products. London, UK. 23 October 2014. www. ema.europa.eu/docs/en_GB/ document_library/Scientific_ guideline/2014/10/WC500176768. pdf (accessed September 2018). 3 Committee for Medicinal Products for Human Use, European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies − non- clinical and clinical issues. EMA/ CHMP/BMWP/403543/2010. London, UK. 30 May 2012. www. ema.europa.eu/docs/en_GB/ document_library/Scientific_ guideline/2012/06/WC500128686. pdf (accessed September 2018). 4 Health Products and Food Branch, Health Canada. Information and submission requirements for biosimilar biologic drugs. Ottawa, Canada. 14 November 2016. www.canada. ca/content/dam/hc-sc/migration/ hc-sc/dhp-mps/alt_formats/ pdf/brgtherap/applic-demande/ guides/seb-pbu/seb-pbu-2016- eng.pdf (accessed September 2018). 5 Feagan BG et al. The challenge of indication extrapolation for inﬂiximab biosimilars. Biologicals 2014;42(4):177–83. 6 Weise M et al. Biosimilars: why terminology matters. Nat Biotechnol 2011;29(8):690–3. 7 Nick C. The US Biosimilars act challenges facing regulatory approval. Pharm Med 2012;26(3):145–52. 8 Zalai D et al. Risk-based process development of biosimilars as part of the quality by design paradigm. J Pharm Sci Technol 2013;67(6):569–80. 9 Martin-Moe S et al. A new roadmap for biopharmaceutical drug product development: integrating development, validation, and quality by design. J Pharm Sci 2011;100(8): 3031–43. 10 Cook J et al. Quality-by- design: are we there yet? AAPS Pharm Sci Tech 2014;15(1): 140–8. 11 Kuhlmann M, Covic A. The protein science of biosimilars. Nephrol Dial Transplant 2006;21(Suppl 5):v4-8. 12 | 2019 | hospitalpharmacyeurope.com Conclusions Taking all this into account, prescribers, pharmacists, payers and patients should feel confident in the sound, scientific approaches taken to evaluate and approve biosimilars, including switching and interchangeability and indications granted via extrapolation. 12 Beck A, Reichert JM. Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry. mAbs 2013;5(5):621–3. 13 Flynn GC et al. Naturally occurring glycan forms of human immunoglobulins G1 and G2. Mol Immunol 2010;47(11- 12):2074–82. 14 Declerk P et al. The language of biosimilars: Clarification, definitions, and regulatory aspects. Drugs 2017;77(6): 671–77. 15 McCamish M, Woollett G. The continuum of comparability extends to biosimilarity: how much is enough and what clinical data are necessary? Clin Pharmacol Ther 2013;93(4): 315–17. 16 Moroi R et al. FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn’s disease through affecting the ADCC activity. Immunogenetics 2013;65(4): 265–71. 17 Biologics Price Competition and Innovation Act. Title VII – improving access to innovative medical therapies. Subtitle A – Biologics Price Competition and Innovation. Sec. 7002. Approval pathway for biosimilar biological products. 2009. www. fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/UCM216146.pdf (accessed September 2018). 18 Ebbers HC. Biosimilars: in support of extrapolation of indications. J Crohns Colitis 2014;8(5):431–5. 19 Afif W et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105(5):1133–9. 20 Gonçalves J et al. Biosimilar monoclonal antibodies: preclinical and clinical development aspects. Clin Exp Rheumatol 2016;34(4):698–705. 21 Araújo F, Gonçalves J, Fonseca JE. Biosimilar DMARDs: What does the future hold? Drugs 2016;76(6):629–37. 22 Ryff JC. Clinical investigation of the immunogenicity of interferon-alpha 2a. J Interferon Cytokine Res 1997;17(Suppl. 1):S29e33. 23 Derbyshire M. Interchangeability of biosimilars in the US and around the world. GaBI Journal 2017;6(2):97−8. 24 Pan H et al. Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn. Protein Sci 2009;18(2):424–33. 25 McCamish M, Woollett G. The continuum of comparability extends to biosimilarity: how much is enough and what clinical data are necessary? Clin Pharmacol Ther 2013;93(4): 315–17. 26 FDA. FDA Briefing Document: Arthritis Advisory Committee Meeting. BLA 125544 CT-P13, a proposed biosimilar to Remicade® (infliximab). 9 February 2016. www.fda.gov/ downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/ Drugs/ArthritisAdvisory Committee/UCM484859.pdf (accessed September 2018). 27 Park SH et al. Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea. Expert Rev Gastroenterol Hepatol 2015;(S1):35–44. 28 Farkas K et al. Infliximab biosimilar CT-P13 therapy is effective and safe in maintaining remission in Crohn’s disease and ulcerative colitis – experiences from a single center. Expert Opin Biol Ther 2017;17(11):1325-332. 29 Generics and Biosimilars Initiative (GABI). http://www. gabionline.net/ (accessed September 2018).