Skip to main content
Log in

Interchangeability of Biosimilars: A European Perspective

BioDrugs Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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.

  2. Rak Tkaczuk K, Jacobs I. Biosimilars in oncology: from development to clinical practice. Semin Oncol. 2014;41(Suppl 3):S3–12.

    Article  PubMed  Google Scholar 

  3. Ebbers HC, Chamberlain P. Interchangeability. An insurmountable fifth hurdle? GaBI J 2014;3:88–93.

  4. Ebbers H, Crow S, Vulto A, Schellekens H. Interchangeability, immunogenicity and biosimilars. Nat Biotechnol. 2012;30:1186–90.

    Article  CAS  PubMed  Google Scholar 

  5. Hlavaty T, Letkovsky J. Biosimilars in the therapy of inflammatory bowel diseases. Eur J Gastroenterol Hepatol. 2014;26:581–687.

    CAS  PubMed  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.

  7. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies: regulatory, clinical and commercial considerations. Drugs. 2011;71:1527–36.

    Article  CAS  PubMed  Google Scholar 

  8. Declerck P. Biologicals and biosimilars: a review of the science and its implications. GaBI J. 2012;1:13–6.

    Article  Google Scholar 

  9. Cortes J, Curigliano G, Dieras V. Expert perspectives on biosimilar monoclonal antibodies in breast cancer. Breast Cancer Res Treat. 2014;144:233–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. No authors listed. Building a wall against biosimilars. Nat Biotechnol. 2013;31:264.

    Article  Google Scholar 

  11. 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;32:829–34.

    Article  PubMed  Google Scholar 

  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.

  14. Ebbers H, Münzenberg M, Schellekens H. The safety of switching between therapeutic proteins. Expert Opin Biol Ther. 2012;12:1473–85.

    Article  CAS  PubMed  Google Scholar 

  15. Jelkmann W. The ESA scenario gets complex: from biosimilar epoetins to activin traps. Nephrol Dial Transplant. 2015;30:553–9.

    Article  PubMed  Google Scholar 

  16. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: why terminology matters. Nat Biotechnol. 2011;29(8):690–3.

    Article  CAS  PubMed  Google Scholar 

  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.

  18. Yu Y, Teerenstra S, Neef C, Burger D, Maliepaard M. A comparison of the intrasubject variation in drug exposure between generic and brand-name drugs: a retrospective analysis of replicate design trials. Br J Clin Pharmacol. 2016;81(4):667–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  20. Stephens S, Emtage S, Vetterlein O, Chaplin L, Bebbington C, Nesbitt A, et al. Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology. 1995;85:668–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chamberlain P. Multidisciplinary approach to evaluating immunogenicity of biosimilars: lessons learned and open questions based on 10 years’ experience of the European Union regulatory pathway. Biosimilars. 2014;4:23–43.

    Article  Google Scholar 

  22. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Casadevall N, Nataf JM, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–75.

    Article  CAS  PubMed  Google Scholar 

  24. Ruiz-Argüello MB, Maguregui A, Ruiz Del Agua A, Pascual-Salcedo D, Martínez-Feito A, Jurado T, et al. Antibodies to infliximab in Remicade-treated rheumatic patients show identical reactivity towards biosimilars. Ann Rheum Dis. 2016;75(9):1693–6.

    Article  PubMed  Google Scholar 

  25. Ben-Horin S, Yavzori M, Benhar I, Fudim E, Picard O, Ungar B, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut. 2016;65(7):1132–8.

    Article  PubMed  Google Scholar 

  26. Pate M, Kelly Smith J, Chi D, Krishnaswamy G. Regulation and dysregulation of immunoglobulin E: a molecular and clinical perspective. Clin Mol Allergy. 2010;8:3.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Smith-Garvin J, Koretzky G, Jordan M. T Cell Activation. Annu Rev Immunol. 2009;27:591–619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol. 2001;13:114–9.

    Article  CAS  PubMed  Google Scholar 

  29. Wolfert MA, Boons G-J. Adaptive immune activation: glycosylation does matter. Nat Chem Biol. 2013;9:776–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schneider C. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013;72:315–8.

    Article  CAS  PubMed  Google Scholar 

  31. Haag-Weber M, Vetter A, Thyroff-Friesinger U, INJ-study group. Therapeutic equivalence, long-term and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis. Clin Nephrol. 2009;72:380–9.

    CAS  PubMed  Google Scholar 

  32. Seidl A, Hainzl O, Richter M, Fischer R, Böhm S, Deutel B, et al. Tungsten-induced denaturation and aggregation of epoetin-alfa during primary packaging as a cause of immunogenicity. Pharm Res. 2012;29:1454–67.

    Article  CAS  PubMed  Google Scholar 

  33. Fotiou F, Aravind S, Wang PP, Nerapusee O. Impact of illegal trade on the quality of epoetin alfa in Thailand. Clin Ther. 2009;31:336–46.

    Article  CAS  PubMed  Google Scholar 

  34. Gouw S, van der Born J, Ljung R, Escuriola C, Cid AR, Claeyssens-Donadel S, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med. 2013;368:231–9.

    Article  CAS  PubMed  Google Scholar 

  35. Santagostino E, Auerswald G, Benson G, Dolan G, Jiménez-Yuste V, Lambert T, et al. Switching treatments in haemophilia: is there a risk of inhibitor development? Eur J Haematol. 2015;94:284–9.

    Article  PubMed  Google Scholar 

  36. Gneiss C, Koudouovoh-Tripp PM, Ropele S, Gotwald T, Ehling R, Lutterotti A, et al. Influence of interferon-beta therapy switching on neutralizing antibody titres: results from the Austrian Switch Study. Mult Scler. 2009;15:1481–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google 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).

  41. Flodmark C-E, Lilja K, Woehling H, Järvholm K. Switching from originator to biosimilar human growth hormone using dialogue teamwork: single-center experience from Sweden. Biol Ther. 2013;3:35–43.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Romer T, Zabransky M, Walczak M, Szalecki M, Balzer S. Effect of switching recombinant human growth hormone: comparative analysis of phase 3 clinical data. Biol Ther. 2011;1:005.

    Article  Google Scholar 

  43. Rashid N, Saenger P, Wu YL, et al. Switching to Omnitrope® from other recombinant human growth hormone therapies: retrospective study in an integrated healthcare system. Biol Ther. 2014;4:27–39.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hörbrand F, Bramlage P, Fischaleck J, Hasford J, Brunkhorst R. A population-based study comparing biosimilar versus originator erythropoiesis-stimulating agent consumption in 6,117 patients with renal anaemia. Eur J Clin Pharmacol. 2013;69:929–36.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  46. McKeage K. A review of CT-P13: an infliximab biosimilar. BioDrugs. 2014;28:313–21.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  48. Dapavo P, Vujic I, Fierro MT, Pietro Q, Sanlorenzo M. The infliximab biosimilar in the treatment of moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75(4):736–9. doi:10.1016/j.jaad.2016.04.068.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  50. Park SH, Kim YH, Lee JH, Kwon HJ, Lee SH, Park DI, et al. Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea. Expert Rev Gastroenterol Hepatol. 2015;9(Suppl 1):35–44.

    Article  PubMed  Google 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.

  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.

  55. Declerck P, Mellstedt H, Danese S. Biosimilars: terms of use. Curr Med Res Opin. 2015;31:2325–30.

    Article  CAS  PubMed  Google Scholar 

  56. Minghetti P, Rocco P, Schellekens H. The constrained prescription interchangeability and substitution of biosimilars. Nat Biotechnol. 2015;33:688–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  59. Ormerod AD. Switching biologicals for psoriasis. Br J Dermatol. 2010;163:667–9.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  61. Annese V, Avendaño-Solá C, Breedveld F, Ekman N, Giezen TJ, Gomollón F, et al. Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, 12 January 2016. GaBI J. 2016;5(2):74–83.

    Article  Google 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.

Download references

Acknowledgements

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.

Author contributions

PK conceptualized the idea for the study. The manuscript was written by PK, LvA, EW-H, TG, VS, and MW.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pekka Kurki.

Ethics declarations

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.

Funding

No funding was received for the preparation of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kurki, P., van Aerts, L., Wolff-Holz, E. et al. Interchangeability of Biosimilars: A European Perspective. BioDrugs 31, 83–91 (2017). https://doi.org/10.1007/s40259-017-0210-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-017-0210-0

Keywords

Navigation