In short Read article

Interchangeability of biosimilars

Over the last 15 years, a large number of so-called ‘biosimilars’ have been marketed. Biosimilars are biological drugs that have been copied from the biological reference drug after the period of market protection had ended. They are comparable to the original biologicals, but not identical. Care providers and patients have doubts about the effectiveness and safety of biosimilars compared to the original biologicals. Can the original biologicals be exchanged for the comparable biosimilars without problems? And are the various biosimilars interchangeable? 

  • Biosimilars are generally cheaper that the original biologicals.
  • For the purpose of registration, the manufacturer is obliged to show that the biosimilar is equivalent, by means of research involving direct comparison with the reference drug. In that case, exchanging a biosimilar for the reference drug will yield equal effectiveness and safety.
  • If there are multiple biosimilars of the same reference drug, these are not compared with each other. Evidence for their interchangeabiliy is then obtained by analysing the various direct comparisons with the reference drug. 
  • Since direct comparative research among biosimilars is lacking, it cannot be fully excluded that switching between biosimilars leads to undesirable immunogenicity. This risk appears small, but vigilance is warranted.

  1. Barbier L, Vulto AG. Interchangeability of Biosimilars: Overcoming the Final Hurdles. Drugs. 2021 Nov;81(16):1897-1903. doi: 10.1007/s40265-021-01629-4. Erratum in: Drugs. 2022 Apr;82(6):717. PMID: 34727332; PMCID: PMC8578114.
  2. Vulto AG, de Vos Burchart H. Worden de biosimilar-beloften in Nederland waargemaakt? Een gedetailleerde 5-jaar analyse van de Nederlandse markt van een selectie van biologische geneesmiddelen (2014-2018). Available at: Accessed 26-10-2022
  3. Information guide for healthcare professionals: Biosimilars in the EU. Available at: Accessed 11-09-2022
  4. EMA list centrally authorized biosimilars. Available at: Accessed 21-11-2022
  5. Biosimilar medicines authorised via the EMA Table last updated on 17/09/2022 based on last CHMP meeting highlights: 12-15 September 2022. Available at: Accessed 26-10-2022
  6. KNMP. Biosimilars in de eerste lijn. Available at: Last modification 10 februari 2022. Accessed 11-09-2022.
  7. de Vink X, Adhien P. Onderzoeken tonen equivalentie insuline en biosimilar Insuline. Pharmaceutisch Weekblad. 2022;157:22-4 
  8. EMA. Statement on the scientific rationale supporting interchangeability of biosimilar medicines in the EU. 19-09-2022 Available at: Accessed 29-09-2022.
  9. Sarnola K, Merikoski M, Jyrkkä J, Hämeen-Anttila K. Physicians' perceptions of the uptake of biosimilars: a systematic review. BMJ Open. 2020 May 5;10(5):e034183. doi: 10.1136/bmjopen-2019-034183. PMID: 32371511; PMCID: PMC7228507.
  10. Barbier L, Ebbers HC, Declerck P, Simoens S, Vulto AG, Huys I. The Efficacy, Safety, and Immunogenicity of Switching Between Reference Biopharmaceuticals and Biosimilars: A Systematic Review. Clin Pharmacol Ther. 2020 Oct;108(4):734-755. doi: 10.1002/cpt.1836. Epub 2020 Apr 30. PMID: 32236956; PMCID: PMC7540323.
  11. Kurki P, Barry S, Bourges I, Tsantili P, Wolff-Holz E. Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective. Drugs. 2021 Nov;81(16):1881-1896. doi: 10.1007/s40265-021-01601-2. Epub 2021 Oct 1. PMID: 34596876; PMCID: PMC8578115.
  12. Mysler E, Azevedo VF, Danese S, Alvarez D, Iikuni N, Ingram B, Mueller M, Peyrin-Biroulet L. Biosimilar-to-Biosimilar Switching: What is the Rationale and Current Experience? Drugs. 2021 Nov;81(16):1859-1879. doi: 10.1007/s40265-021-01610-1. Epub 2021 Oct 27. PMID: 34705255; PMCID: PMC8578069.
  13. van Puijenbroek EP. Geneesmiddelen en bijwerkingen. Gebu. 2017;51(7):59-64 
  14. Boone NW, Liu L, Romberg-Camps MJ, Duijsens L, Houwen C, van der Kuy PHM, Janknegt R, Peeters R, Landewé RBM, Winkens B, van Bodegraven AA. The nocebo effect challenges the non-medical infliximab switch in practice. Eur J Clin Pharmacol. 2018 May;74(5):655-661. doi: 10.1007/s00228-018-2418-4. Epub 2018 Jan 24. PMID: 29368188; PMCID: PMC5893662.
  15. Zaal J, Bogaard L. Placebo’s en placebo-effecten – II. Gebu. 2017;51(2):13-20
  16. Kay J, Isaacs JD. Clinical trials of biosimilars should become more similar. Ann Rheum Dis. 2017 Jan;76(1):4-6. doi: 10.1136/annrheumdis-2015-208113. Epub 2016 Aug 25. PMID: 27566795.
  17. Pagnini C, Di Paolo MC, De Angelis G, Torcolacci F, Milano M, Trinca D, Porciello R, Graziani MG. Similar But Not Identical: Plaque Psoriasis Exacerbation in a Patient With Crohn's Disease After Switching From CT-P13 to SB2 Infliximab Biosimilar. Inflamm Bowel Dis. 2020 Jul 17;26(8):e83-e84. doi: 10.1093/ibd/izaa128. PMID: 32458993.
  18. Fiorino G, Ruiz-Argüello MB, Maguregui A, Nagore D, Correale C, Radice S, Gilardi D, Allocca M, Furfaro F, Martínez A, Danese S. Full Interchangeability in Regard to Immunogenicity Between the Infliximab Reference Biologic and Biosimilars CT-P13 and SB2 in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2018 Feb 15;24(3):601-606. doi: 10.1093/ibd/izx086. PMID: 29462398.
  19. EMA. European public assessment reports: background and context. Available at: Accessed 11-09-2022.
  20. EMA. Scientific Guideline: Immunogenicity assessment of biotechnology-derived therapeutic proteins. Available at: Accessed 01-10-2022.
  21. Druedahl LC, Kälvemark Sporrong S, Minssen T, Hoogland H, De Bruin ML, van de Weert M, Almarsdóttir AB. Interchangeability of biosimilars: A study of expert views and visions regarding the science and substitution. PLoS One. 2022 Jan 11;17(1):e0262537. doi: 10.1371/journal.pone.0262537. PMID: 35015783; PMCID: PMC8751983.
  22. FDA. Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry. FDA-2017-D-0154, mei 2019. Available at: Accessed 01-10-2022.
  23. CBG. Available at:,betreft%20kwaliteit%2C%20veiligheid%20en%20effectivitei. Accessed 30-11-2022.


  • Leo M.L. Stolk, dr