Submitted: 27 November 2021; Revised: 15 December 2021; Accepted: 15 December 2021; Published online first: 28 December 2021

Biosimilars have been used for 15 years in the European Union (EU). They are able to trigger price competition and reduce costs as well as to increase access to important biological medicines [1]. In spite of the long experience and excellent safety record, many prescribers and other healthcare professionals still have concerns about the quality, safety, efficacy, and especially interchangeability of biosimilars [2]. Systematic clinical switch studies to demonstrate interchangeability of biosimilars are required in some jurisdictions while theoretical considerations and current clinical data question the feasibility and relevance of such studies.

Differences in terminology and regulatory approach hurt biosimilars

In the EU, interchangeability is a scientific and clinical concept meaning that switching between a biosimilar and its reference product does not change the efficacy or safety [3]. Interchangeable products can be switched under the control of the prescriber (physician-led switch) or at the pharmacy without consultation of the prescriber (automatic substitution). Both scenarios are practical applications of interchangeability. Several European national regulatory authorities have issued position papers that endorse physician-led switching [4]. Automatic substitution is a political, administrative, and practical measure that may require changes to the legislation and needs to be adapted to local circumstances.

In the US, interchangeability is regarded as a higher level of biosimilarity that allows automatic substitution. The US Food and Drug Administration (FDA) may grant interchangeable status to already licensed biosimilars if they fulfill the requirements of its interchangeability guideline [5]. The main hurdle is the conduct of a controlled clinical trial consisting of three switches. The switch studies constitute a significant burden to developers and patients. In addition, the results may not give a definite answer [6]. Thus far, the interchangeable status has been granted to only two products by FDA; Semglee (insulin glargine-yfgn) in July 2021 and Cyltezo (adalimumab-adbm) in November 2021.

In spite the fact that switch studies are not required in the EU, the concept a clinical switch study is deeply rooted in the minds of prescribers and policymakers also in the EU, as seen in some position papers of national regulatory authorities and learned societies [4] and in the hesitance among prescribers [2]. Manufacturers whose old blockbuster products are threatened by biosimilars support requirements for systematic multiple switch studies and even switch studies between biosimilars and repeated demonstration of interchangeability [7-9] – obviously because extensive switch studies discourage biosimilar development. The feasibility of conducting extensive switch studies has been questioned [6, 10]. Moreover, it is difficult to find detailed theoretical justifications and clinical data to support systematic switch studies. Thus, the crucial question is not what kind of comparative switch studies should be done but whether these studies are justified and feasible at all.

The hypothesis of switch-related immunogenicity

Immunogenicity is presented as the risk of switching between a biosimilar and its reference product. The FDA interchangeability guideline states,‘in the context of switching between the products, multiple exposures to each product may potentially prime the immune system to recognize subtle differences in structural features between products’ and‘the overall immune response could be increased under these conditions’ [5]. Some proponents of switch studies explain this hypothesis by the discontinuation theory [7]. Thus,‘subtle’ differences in the structure, notably the glycosylation profiles of active substances of biosimilars and their reference product seem to be a cornerstone for the immunogenicity hypothesis [8]. This theory may be relevant to vaccines that are designed to be‘foreign’ to human immune system and immune response is amplified by adjuvants ― a completely different situation compared to therapeutic proteins that are made highly similar. Thus, this possibility is also highly unlikely after switching between a biosimilar and its reference product that have already been shown to be highly similar and which are expected to have some degree of immunological tolerance due to their resemblance to human proteins [11].

It is also suggested that exposure to different sets of antigenic epitopes upon switching might enhance anti-drug immunity by epitope spreading. This situation has been observed in epoetin alpha (epoetin-α) products where a poor product formulation or inappropriate storage may lead to cross-reacting neutralizing antibodies to endogenous erythropoietin. The root cause of the induction of neutralizing erythropoietin antibodies is aggregation of proteins in a poor formulation [12]. Thus far, there is no clinical data to support above-mentioned immunogenicity theories in the context of switching between a reference product and its licensed biosimilar version.

Switch-related immunogenicity: a remote risk

Switch-related immunogenicity is often seen as an unpredictable reaction of the immune system. However, the factors triggering of anti-drug immunity are well known. Immune recognition is essential for identifying proteins as‘self’ or‘non-self’. Recognition of the protein as‘non-self’ may be associated with transient or persistent immune reactions. The switching between highly similar versions of the same active substance is not sufficient to break tolerance and to raise persisting and strong T cell-dependent immunogenicity such as affinity maturation, isotype switch or strong recall response due to the identical amino acid sequence and highly similar secondary structure. Differences in glycosylation profiles have never triggered immunogenicity of different versions of therapeutic proteins [10]. Such differences are found after changes in manufacturing process and even between different batches of therapeutic proteins without immunological problems [13]. Studies of originator and biosimilar infliximab and adalimumab support the similarity of important antigenic epitopes in biosimilars and their reference products [14-16].

B cells may be stimulated independently by impurities, such as bacterial endotoxins as well as by degraded and aggregated proteins [11]. Such problems may be due to inappropriate storage or poor formulations, i.e. not due to‘subtle differences’ in the active substances of highly similar products in normal use. These cases, such as the formulation change of originator epoetin-α or one of its biosimilar versions have made developers and regulators very careful in assessing formulations and stability studies of biosimilars [17]. Therefore, it is unlikely that licensed biological products will have immunogenicity triggered by impurities [13].

The clinical evidence

Review of 178 clinical switch studies of biosimilars and their reference products found no evidence of switch-related adverse effects, including harmful immunogenicity [18]. More recent reviews of newer biosimilars confirm the lack of switch-related adverse effects [19, 20]. From a theoretical perspective, the lack of adverse effects is the expected outcome whereas the hypothesis of switch-related adverse effects is not supported by current evidence [6, 11, 21]. Furthermore, clinical switch studies will not be able to detect potential rare adverse effects. Thus, the risk management of switching should be based on pharmacovigilance and pharmaco-epidemiological studies.

Clinical switch studies: time for a re-evaluation

The concept of systematic switch studies is becoming obsolete, but FDA keeps requiring extensive studies due to US legislation. The innovative industry is promoting even more extensive switch studies due to their commercial interests, experts do not dare to challenge FDA and the existing dogma, and prescribers are confused. Ironically, a similar situation has been described in the old tale‘The Emperor’s New Clothes’ [22].

The moral of the tale of systematic switch studies is that EU regulators should have the courage to issuing a common position in interchangeability of biosimilars [23]. The message should be that EU-licensed biosimilars are interchangeable with its reference product without systematic clinical switch studies.

Funding sources

No financial support was received for conducting this research.

Disclaimer

The opinions expressed in this article are personal views of the author and should not be understood being made on behalf of or reflecting the position of the agencies or organizations with which the author is or has been affiliated.

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

References
1. Troein P, Newton M, Scott K. The impact of biosimilar competition in Europe. December 2020 [homepage on the Internet]. [cited 2021 Dec 15]. Available from: https://ec.europa.eu/health/sites/health/files/human-use/docs/biosimilar_competition_en.pdf
2. Barbier L, Simoens S, Vulto AG, Huys I. European stakeholder learnings regarding biosimilars: Part I—improving biosimilar understanding and adoption. BioDrugs 2020;34:783-96.
3. European Medicines Agency and European Commission. Biosimilars in the EU. Information guide for healthcare professionals [homepage on the Internet]. [cited 2021 Dec 15]. Available from: https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf
4. Medicines for Europe. Positioning statements on physician-led switching for biosimilar medicines. 2020 [homepage on the Internet]. [cited 2021 Dec 15]. Available from: https://www.medicinesforeurope.com/docs/M-Biosimilars-Overview-of-positions-on-physician-led-switching.pdf
5. U.S. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product. Guidance for Industry. May 2019 [homepage on the Internet]. [cited 2021 Dec 15]. Available from: https://www.fda.gov/media/124907/download
6. Alvarez DF, Wolbink G, Cronenberger C, Orazem J, Kay J. Interchangeability of biosimilars: what level of clinical evidence is needed to support the interchangeability designation in the United States? BioDrugs. 2020;34(6):723-32.
7. Faccin F, Tebbey P, Alexander E, Wang X, Cui L, Albuquerque T. The design of clinical trials to support the switching and alternation of biosimilars. Expert Opin Biol Ther. 2016;16(12):1445-53.
8. Feagan BG, Marabani M, Wu JJ, Freddy Faccin F, Spronk C, Castañeda-Hernández G. The challenges of switching therapies in an evolving multiple biosimilars landscape: a narrative review of current evidence. Adv Ther. 2020;37(11):4491-518.
9. Afzali A, Furtner D, Melsheimer R, Molloy PJ. The automatic substitution of biosimilars: definitions of interchangeability are not interchangeable. Adv Ther. 2021;38(5):2077-93.
10. Mysler E, Azevedo VF, Danese S, Alvarez D, Iikuni N, Ingram B, et al. Biosimilar-to-biosimilar switching: what is the rationale and current experience? Drugs. 2021;81(16):1859-79.
11. Doevendans E, Schellekens H. Immunogenicity of innovative and biosimilar monoclonal antibodies. Antibodies (Basel). 2019;8(1):21.
12. Rubic-Schneider T, Kuwana M, Christen B, Aßenmacher M, Hainzl O, Zimmermann F, et al. T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia. Blood Adv. 2017;1(6):367-79.
13. Lamanna WC, Holzmann J, Cohen HP, Guo X, Schweigler M, Stangler T, et al. Maintaining consistent quality and clinical performance of biopharmaceuticals. Expert Opin Biol Ther. 2018;18(4):369-79.
14. Reinisch W, Jahnsen J, Schreiber S, Danese S, Panés J, Alejandro Balsa A, et al.  Evaluation of the cross-reactivity of antidrug antibodies to CT-P13 and infliximab reference product (Remicade): an analysis using immunoassays tagged with both agents. BioDrugs. 2017;31(3):223-37.
15. Ben-Horin S. Yavzori M, Benhar I, Fudim E, Picard O. Ungar B, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patient with IBD similarly recognise the biosimilar Remsima. Gut. 2016;65(7):1132-8.
16. Goncalves J, Myung G, Park M, Jeong D, Ghil J. SB5 shows cross-immunogenicity to adalimumab but not infliximab: results in patients with inflammatory bowel disease or rheumatoid arthritis. Therap Adv Gastroenterol. 2019;12:1756284819891081.
17. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). 22 May 2014 [homepage on the Internet]. [cited 2021 Dec 15]. Available from:https://www.ema.europa.eu/en/documents/ scientific-guideline/guideline-similar-biologicalmedicinal- products-containing-biotechnologyderived- proteins-active_en-0.pdf
18. Barbier L, Ebbers H, Declerck P, Simoens S, Vulto A, Huys I. The effi cacy, safety, and immunogenicity of switching between reference biopharmaceuticals and biosimilars: a systematic review. Clin Pharmacol Ther. 2020;108(4):734-5.
19. Strand V, Gonçalves J, Hickling TP, Jones HE, Marshall L, Isaacs JD. Immunogenicity of biosimilars for rheumatic diseases, plaque psoriasis, and infammatory bowel disease: a review from clinical trials and regulatory documents. BioDrugs. 2020;34(1):27-37.
20. 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;81(16):1881-96.
21. Chamberlain P. Multidisciplinary approach to evaluating immunogenicity of biosimilars: lessons learnt and open questions based on 10 years’ experience of the European Union regulatory pathway. Biosimilars. 2014;4:23-43.
22. Andersen HC. The emperor’s new clothes (“Kejserens nye klæder”). In: Reitzel CA. Fairy tales told for children. Third Booklet. 1837.
23. Ebbers HC, Schellekens H. Are we ready to close the discussion on the interchangeability of biosimilars? Drug Discov Today. 2019;24(10):1963-7.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2022 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.