Interchangeability of Biosimilars: A European Perspective
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Many of the best-selling ‘blockbuster’ biological medicinal products are, or will soon be, facing competition from similar biological medicinal products (biosimilars) in the EU. Biosimilarity is based on the comparability concept, which has been used successfully for several decades to ensure close similarity of a biological product before and after a manufacturing change. Over the last 10 years, experience with biosimilars has shown that even complex biotechnology-derived proteins can be copied successfully. Most best-selling biologicals are used for chronic treatment. This has triggered intensive discussion on the interchangeability of a biosimilar with its reference product, with the main concern being immunogenicity. We explore the theoretical basis of the presumed risks of switching between a biosimilar and its reference product and the available data on switches. Our conclusion is that a switch between comparable versions of the same active substance approved in accordance with EU legislation is not expected to trigger or enhance immunogenicity. On the basis of current knowledge, it is unlikely and very difficult to substantiate that two products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch. Our conclusion is that biosimilars licensed in the EU are interchangeable.
KeywordsInsulin Glargine Reference Product Insulin Lispro Biosimilar Product Biological Medicinal Product
The authors thank Drs. Meenu Wadhwa and Christian Schneider for their valuable expert comments during the preparation of the manuscript. The generous help of Ms. Mira Juppi is also gratefully acknowledged.
PK conceptualized the idea for the study. The manuscript was written by PK, LvA, EW-H, TG, VS, and MW.
Compliance with Ethical Standards
Conflict of interest
PK, LvA, EW-H, TG, VS, and MW have no conflicts of interest. They are employees of national regulatory agencies. However, the opinions expressed in this article represent the personal opinions of the authors.
No funding was received for the preparation of this manuscript.
- 1.European Commission, DG Enterprise and industry. What you Need to Know about Biosimilar Medicinal Products. Process on Corporate Responsibility in the Field of Pharmaceuticals Access to Medicines in Europe. A Consensus Information Document, 2013. http://europa.eu/geninfo/query/resultaction.jsp?query_source=GROWTH&QueryText=biosimilars&op=Search&swlang=en&form_build_id=form-CA4kk1hS9th2Qw_AyEvYWFKAUUlCNvY6kFflINvXlD4&form_id=nexteuropa_europa_search_search_form. Accessed 30 Sept 2016.
- 3.Ebbers HC, Chamberlain P. Interchangeability. An insurmountable fifth hurdle? GaBI J 2014;3:88–93.Google Scholar
- 6.The Alliance for Safe Biologic Medicines (ASBM). Interchangeability and Physician Notification. http://safebiologics.org/resources/in-the-states/. Accessed 30 Sept 2016.
- 12.European Medicines Agency (EMA). ICH Q5E, CPMP/ICH/5721/03. Comparability of Biotechnological/Biological Products: Note for guidance on biotechnological/biological products subject to changes in their manufacturing process. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000888.jsp&mid=WC0b01ac058002956b. Accessed 30 Sept 2016.
- 13.European Medicines Agency (EMA): Guideline on Similar Biological Medicinal Products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf. Accessed 30 Sept 2016.
- 17.European Medicines Agency (EMA). European Public Assessment reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124. Accessed 30 Sept 2016.
- 19.European Medicines Agency (EMA). Immunogenicity assessment of biotechnology-derived therapeutic proteins, rev1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001391.jsp&mid=WC0b01ac058002958c. Accessed 1 Sept 2019.
- 37.European Medicines Agency (EMA). CHMP assessment report: herceptin subcutaneous formulation. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000278/WC500153233.pdf. Accessed 30 Sept 2016.
- 38.Smits LJ, Derikx LA, de Jong DJ, Boshuizen RS, van Esch AA, Drenth JP, Hoentjen F. Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohns Colitis. 2016;10(11):1287–93. doi: 10.1093/ecco-jcc/jjw087.CrossRefPubMedGoogle Scholar
- 39.Benucci M, Gobbi FL, Bandinelli F, Damiani A Infantino M, Grossi V, et al. Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: a 6-month real-life observational study. Immunol Res. 2016. doi: 10.1007/s12026-016-8843-5 (Epub 23 Jul 2016).
- 40.Buer LC, Moum BA, Cvancarova M, Warren DJ, Medhus AW, Høivik ML. Switching from Remicade® to Remsima® is safe and feasible: a prospective, open-label study. J Crohns Colitis. 2016. doi: 10.1093/ecco-jcc/jjw166 (Epub 22 September 2016).
- 45.Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 2017;76(2):355–63. doi: 10.1136/annrheumdis-2015-208786.CrossRefPubMedGoogle Scholar
- 47.Nikiphorou E, Kautiainen H, Hannonen P, Asikainen J, Kokko A, Rannio T, Sokka T. Clinical effectiveness of CT-P13 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data. Expert Opin Biol Ther. 2015;15(12):1677–83.CrossRefPubMedGoogle Scholar
- 49.Sieczkowska J, Jarzebicka D, Banaszkiewicz A, Plocek A, Gawronska A, Toporowska-Kowalska E, et al. Switching between infliximab originator and biosimilar in paediatric patients with inflammatory bowel disease. Preliminary observations. J Crohns Colitis. 2016;10(2):127–32.CrossRefPubMedGoogle Scholar
- 51.Kolar M, et al. ‘P1410—switching of patients with inflammatory bowel disease from original infliximab (Remicade®) to biosimilar infliximab (Remsima®) is effective and safe—one-year follow-up.’ In: Abstract presented at the United European Gastroenterology (UEG) Week meeting, 15–19 October 2016, Vienna, Austria.Google Scholar
- 52.Jørgensen K, et al. ‘LB15—biosimilar infliximab (CT-P13) is not inferior to originator infliximab: results from the 52-week randomized NOR-SWITCH trial.’ In: Abstract presented at the United European Gastroenterology (UEG) Week meeting, 15–19 October 2016, Vienna, Austria. https://cslide.ctimeetingtech.com/ueg2016/confcal/switch. Accessed 27 Oct 2016.
- 53.Smolen JS, Choe J-Y, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, et al. (FRI0162) comparable safety and immunogenicity and sustained efficacy after transition To SB2 (an infliximab biosimilar) vs ongoing infliximab reference product in patients with rheumatoid arthritis: results of phase III transition study (a poster. Ann Rheum Dis. 2016;75:488.Google Scholar
- 54.US Department of Health and Human Services. US Food and Drug Administration. 2016 Meeting materials, arthritis advisory committee. Briefing Information for the July 12–13, 2016, Meeting of the Arthritis Advisory Committee (AAC). http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ucm481975.htm. Accessed 30 Dec 2016.
- 57.Vermeer N, Straus S, Mantel-Teeuwisse A, Domergue F, Egberts ACG, Leufkens HGM, de Bruin ML. Traceability of biopharmaceuticals in spontaneous reporting systems: a cross-sectional study in the FDA adverse event reporting system (FAERS) and EudraVigilance data bases. Drug Saf. 2013;36:617–25.CrossRefPubMedGoogle Scholar
- 58.Valensi P, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. Initiating insulin therapy with, or switching existing insulin therapy to, insulin aspart 30/70 (Novomix 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study. Int J Clin Pract. 2009;63:522–31.CrossRefPubMedGoogle Scholar
- 60.D’Haens GR, Panaccione R, Higgins PD, et al. The London position statement of the world congress of gastroenterology on biological therapy for IBD with the European Crohn’s and colitis organisation: when to start, when to stop, which drug to choose and how to predict response? Am J Gastroenterol. 2011;106:199–212.CrossRefPubMedGoogle Scholar
- 62.Medicines Evaluation Board (MEB). Are biosimilar medicinal products interchangeable? https://english.cbg-meb.nl/latest/news/2015/08/17/clarification-of-stance-on-biological-and-biosimilarmedicines. Accessed 19 Jan 2017.
- 63.Finnish Medicines Agency Fimea. Are biosimilars interchangeable? https://www.fimea.fi/documents/542809/838272/29197_Biosimilaarien_vaihtokelpoisuus_EN.pdf. Accessed 19 Jan 2017.
- 64.Healthcare Improvement Scotland and NHS. Biosimilar medicines: a national prescribing framework. May 2015. http://www.healthcareimprovementscotland.org/our_work/technologies_and_medicines/programme_resources/biosimilar_medicines_framework.aspx. Accessed 2 Oct 2016.
- 65.Health Products Regulatory Agency (Ireland). Guide to biosimilars for healthcare professionals and patients. December 2015. https://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-biosimilars-for-healthcare-professionals-and-patients-v2.pdf?sfvrsn=18. Accessed 2 Oct 2016.
- 66.Position of Paul-Ehrlich-Institute regarding the use of biosimilars. Update December 2015. http://www.pei.de/EN/medicinal-products/antibodies-immunoglobulins-fusion-proteins/monoclonal-antibodies/biosimilars/position-pei-interchangebility-biosimilars-content.html. Accessed 13 Oct 2016.