Received: 20 March 2019 Revised: 22 July 2019 Accepted: 30 July 2019 DOI: 10.1111/bcp.14089 COMMENTARY Biosimilar and interchangeable: Inseparable scientific concepts? As defined by the European Commission, the term interchangeability doping in sports. Indeed, the differentiation between an endogenously refers to “the possibility of exchanging one medicine for another that produced protein, such as erythropoietin, and an externally adminis- is expected to have the same clinical effect.”1 In the context of tered version, such as epoetin alfa or beta, requires extremely sophisti- biosimilars the term interchangeability has caused confusion. Likely cated laboratory techniques.5,6 The experience in analysing differences due to specific regulatory requirements in the United States, physicians among batches of original biological agents has shown that no clinical sometimes interpret interchangeability as the potential for a biologic to comparison of efficacy and safety can match the accuracy and sensitiv- be substituted by a biosimilar at the pharmacy level, without the involve- ity of a stringent physicochemical and functional comparability. The rig- ment of a physician. However, interchangeability between a biological orous regulation applied to the intrinsic variability of original biologics reference medicine and a corresponding biosimilar medicine should has thus been extended to the pioneering guidance regarding not be defined by its practical application; whether physician‐driven biosimilar‐to‐originator comparability put forth by the European Medi- switch or pharmacist‐driven substitution. Interchangeability, ie, the pos- cines Agency (EMA).7 The magnitude of acceptable physicochemical sibility of safely and effectively changing a reference medicine by its differences between biosimilars and their corresponding reference bio- biosimilar, or vice‐versa, in a given patient, should be rather recognized logics can confidently be assessed in the laboratory, where the differ- as a scientific concept. In this paper, we review the evidence supporting ences in critical quality attributes must be shown not to exceed the the assertion that interchangeability is inherent to biosimilarity. batch‐to‐batch variability of the reference biologic. In science, a conclusion is reached when a hypothesis is tested by In addition to analytical comparability, biosimilarity is further sup- the use of an appropriate experimental approach. The aim of biosimilar ported by the demonstration of comparable pharmacokinetic, and pos- development is to replicate an existing biomedicine. Biosimilarity must sibly pharmacodynamic, clinical data.8 Furthermore, although clinicians be substantiated by robust scientific evidence. To generate such evi- are primarily familiar with the traditional benefit‐to‐risk balance dence, a hypothesis of high similarity between a biosimilar candidate assessment in patients for new medicines, the paradigm changes when and the original reference medicine should be verified through well‐ assessing comparability, rather than therapeutic benefit per se. Indeed, established and validated methodologies that aim to identify all the when a biosimilar designation is to be granted, patient trials are con- potential relevant physicochemical differences, but are also capable of sidered to be confirmatory because of the superior value of analytical detecting even clinically meaningless differences. The acceptable dif- studies for comparative purposes.9 Accordingly, the necessity of ference level between the biosimilar candidate and the reference med- patient trials has been a matter of debate for a number of years.10 In icine is determined to a qreat extent by a thorough assessment of light of current practical evidence, the issue is being raised again.11 multiple batches of the reference biologic. Indeed, no approved biolog- In fact, the EMA already allows efficacy trials in patients to be waived ical medicine, whether original or not, is structurally identical to itself, for insulin biosimilar candidates,12 and it introduced the possibility of due to an intrinsic batch‐to‐batch variability that can be enhanced by bypassing patient trials for filgrastim biosimilar candidates.13 The total- manufacturing changes. Although different batches of reference bio- ity of the evidence generated under a stringent regulatory framework, logical compounds are not identical to each other, they may be consid- such as EMA's, indicates that biosimilars and their reference medicines ered essentially equal and therapeutically indistinguishable. Therefore, essentially overlap structurally, thus clinically. Under these circum- there is a clinically acceptable range of inherent structural heterogene- stances, if two versions of any given biologic were unable to be safely 2,3 ity for any biological product. As a consequence, many patients have interchanged, whether that refers to two batches of any given biologic likely been treated with structurally slightly different versions of any or to a biosimilar and its reference product, which treatments could? given reference biomedicine, which constitutes a de facto switch of Hence, because batches of an original biologic can be deemed to be insignificant therapeutic concern. The approach used to substantiate interchangeable, biosimilars and their corresponding reference medi- biosimilarity represents a refinement of the procedures that have been cines may also be safely reciprocally interchanged, as endorsed by securely applied for decades to batches of biologics that are subject to EMA regulators.14 Indeed, the best scientific claim for interchangeabil- 4 manufacturing changes, but also to the very precise discrimination ity is the demonstration of essential sameness, ie, biosimilarity, based between native and non‐native proteins during the monitoring of on a robust comparability programme. --------------------------------------------------------------------------------------------------------------------------------- This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. 2460 wileyonlinelibrary.com/journal/bcp Br J Clin Pharmacol. 2019;85:2460–2463. COMMENTARY 2461 Beyond the exhaustive pre‐registration requisites that support intra‐ and inter‐patient variability in response to treatment, and the biosimilarity, more than thirteen years of clinical experience have been minute molecular differences found among biosimilars and the corre- amassed while biosimilars have been available on the market, including sponding reference medicines, trials performed in patients would very extensive switching practice, which has provided overwhelming evi- unlikely provide the level of sensitivity required to confidently reflect dence to sustain the safety of interchanging. Indeed, post‐marketing the safety of a switching decision. Moreover, requesting such clinical studies and real‐world evidence may help physicians more switching studies would question the foundation of the comparability accurately calibrate the extent of the safety net when facing a model that has been applied successfully for decades to pre‐ and post‐ switching decision. The NorSwitch study, fostered by Norwegian manufacturing versions of original biopharmaceuticals. health care authorities, was the first independent, phase IV, random- Despite the strength of the science supporting interchangeability, ized clinical trial to investigate switching as a primary endpoint.15 The when two medicines are deemed to be interchangeable, physicians study confirmed the safety of switching a given patient from being should be relevant players in any switching decision. The use of treated with a reference product containing infliximab to being treated biosimilars should not constitute an exception to this general rule of with a biosimilar version of the medicine. Moreover, a recent meta‐ the medical practice,particularly because there are several factors analysis of more than 90 studies, involving over 14 000 patients, con- beyond active ingredients that could impact the therapeutic outcome, firmed that no specific risks can be attributed to the replacement of a such as delivery device‐related issues, or the nocebo effect caused by reference medicine with a biosimilar.16 As highlighted in the meta‐anal- a patient's misperception, or expectation, of the treatment. This posi- ysis, immunogenicity is a common matter of concern for prescribers tion is advocated by several medical associations, sometimes in a more when making a switching decision. However, the stringent scientific cautious manner, like the European Society of Medical Oncology proof of physicochemical and functional comparability is also key to (ESMO), or the Spanish Society of Rheumatology (SER), that support substantiating the conclusion of equivalent immunogenicity. Conclu- interchangeability in stable patients as long as the switch is decided sive molecular overlap between biosimilars and reference medicines by the physician in an individualized assessment, and in agreement is well‐illustrated by the finding that anti‐drug antibodies (ADA) with the patient.25,26 cross‐react equally with both products.17 Although analytical compara- An in‐depth understanding of the scientific background supporting bility is reassuring on its own, reference regulatory bodies require case‐ biosimilarity/interchangeability, combined with an appropriate level of by‐case, pre‐ and post‐authorization immunogenicity‐targeted assess- communication with patients, can contribute to the maximization of ment plans.18 Accordingly, over many years of pharmaceutical surveil- the value of biosimilars.27 Their contribution to sustainability and lance of biosimilar safety and efficacy in European countries, including patient access is the main driver for biosimilars development, and clini- switching scenarios in Nordic countries15,19 and more recently in the cians are being increasingly involved in the management of resources United Kingdom,20 no unexpected alerts or warnings have been raised freed up by their use. This has recently been advocated by a decree regarding the development of ADA, or any other adverse effect, as a issued in France that experimentally encourages biosimilars prescrip- result of the presence of biosimilars on the market. Interestingly, the tion partly based on a redistribution towards the hospital, or the med- British Society of Gastroenterology21 recommends to switch to the ical department, of the extra budget resulting from an increased biosimilar version patients stabilized, or in remission, with the refer- biosimilars utilization.28 Similar initiatives are being progressively gen- ence product containing infliximab. Other learned societies also back eralized in the United Kingdom.29 Despite the economic grounds that the safety of switching stable patients to biosimilars.22 Although the primarily promote the development of biosimilars, their therapeutic scope of this article does not cover this issue, it is worth mentioning use should rely on scientific principles. A science‐based understanding that as new biosimilars for a given reference medicine reach the mar- of interchangeability may raise confidence among physicians that cur- ket, interchangeability among biosimilars is also being debated. Given rently prescribe biosimilars only in naïve patients, and may make them the stringency of the EMA regulatory framework, patients subject to more comfortable switching from the reference medicine to a any biosimilar‐to‐biosimilar switch are unlikely to face a non‐accept- biosimilar, to further foster the positive impact of biosimilars. able risk. As experience continues to accumulate, registries of patients who undergo switching may be created to generate supporting evi- dence, which, in turn, may allow for new clinical guidance to be issued. COMPETING INTERESTS Based on the facts reviewed, the demonstration of biosimilarity under strict regulatory standards, such as the EMA's, parallels the claim M.C‐S. has worked as a speaker for Roche, Sanofi, and Astra Zeneca in of interchangeability, and interchangeability therefore represents a sci- the previous 5 years and no other relationships or activities that could entific concept that is inseparable from the biosimilar nature. There- appear to have influenced the submitted work. M‐A.A. works, or has fore, in contrast to some public positions,23,24 there does not appear worked, as a speaker and/or consultant for Biogen, Novartis, Kern to be any scientific basis for requiring clinical switching studies before Pharma, Lilly, Amgen, Sanofi, Celgene, MSD, Pfizer, Amgen, and Roche a biosimilar can be granted the designation of “interchangeable.” The in the previous 5 years and no other relationships or activities that interpretation of such studies would be far less conclusive and reliable could appear to have influenced the submitted work. J.G. has served than the data provided by the current totality of the evidence built pri- as a speaker, a consultant, and advisory member for or has received marily on the analytical comparability. Indeed, given the degree of research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, 2462 COMMENTARY 2 Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Hospital La paz, Rheumatology Unit, Instituto de Investigación Sani- Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen taria IdiPAZ, Madrid, Spain 3 Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma. F.M. Medical Oncology, Hospital General de Segovia, Segovia, Spain 4 works, or has worked, as a speaker and/or consultant for Amgen, Dermatology, Hospital Universitari Germans Trias i Pujol, Barcelona, Adium, Asofarma, Biogen, Finox, Gebro, Hikma, Hospira, KernPharma, Spain 5 Lilly, Merck Serono, Mylan, Oli Med, Sandoz, Stada, Theramex, and Rheumatology Department, Hospital Universitari Vall d'Hebron, Barce- Roche, in the last 5 years, and there are no other relationships or activ- lona, Spain 6 ities that could appear to have influenced the submitted work. A.B. has Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de received honoraria as an advisor and speaker and grants from Pfizer, Investigación Sanitaria Princesa (IIS‐IP), Universidad Autónoma de Madrid, Abbvie, Roche, UCB, Gilead, Sandoz, Novartis, Lilly, Nordic, Sanofi Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y and Amgen. R.M. is currently working at Sandoz Iberia. M.W. is cur- Digestivas (CIBEREHD), Madrid, Spain 7 rently working at Sandoz Biopharmaceuticals c/o Hexal AG. R.D. has FEA Reumatología, Hospital Virgen del Puerto, Plasencia, Spain 8 received honoraria as a consultant and/or speaker for Amgen, Astellas, Hematology Department, Hospital Universitario Puerta de Hierro Bristol Myers‐Squibb, Celgene, Genzyme, Gilead Sciences, Incyte, Jazz Majadahonda, Majadahonda, Spain 9 Pharmaceuticals, Kiadis Pharma, Merck Sharp and Dohme, Novartis, Global Medical Affairs, Sandoz Biopharmaceutical, Holzkirchen, Omeros, Pfizer, Sanofi Oncology and Therakos‐Mallinckrodt in the Germany 10 previous five years, and no other relationships or activities that could Medical Affairs Department, Sandoz Iberia, Madrid, Spain appear to have influenced the submitted work. J‐M.C. has received consulting/speaker fees and/or has acted as a board member and/or Correspondence Fernando de Mora, Department of Pharmacology, Therapeutics and Toxicology, has acted as PI/SI for Novartis, Janssen, Eli Lily, Celgene, Almirall, UAB, Campus UAB‐Edificio V, Universidad Autónoma de Barcelona, Bellaterra Leo Pharma, Abbvie, Sandoz, Mylan and Pfizer, and no other relation- 08193, Spain. ships or activities that could appear to have influenced the submitted Email: fernando.demora@uab.cat work.The other authors have no competing interests to declare. REFE RENCES None of the authors has received funding in the form of honoraria, 1. European Medicines Agency and the European Commission. or any other compensation, for the writing of this paper. The views, Biosimilars in the EU Information guide for healthcare professionals. thoughts, and opinions expressed in this Commentary belong solely 2017. Available from: https://www.ema.europa.eu/documents/leaf- to the authors. They do not intend to reflect necessarily the position let/biosimilars‐eu‐information‐guide‐healthcare‐professionals_es.pdf. of the authors' employer, organization, or learned society to which Accessed February 19, 2019. they belong. 2. Lamanna WC, Mayer RE, Rupprechter A, et al. The structure‐function relationship of disulfide bonds in etanercept. Nat Sci Rep. 2017;7 (1):3951. Keywords 3. Kim S, Song J, Park S, et al. Drifts in ADCC‐related quality attributes of Herceptin: impact on development of a trastuzumab biosimilar. MAbs. biological, biosimilar, biosimilarity, interchangeability, interchangeable, 2017;9(4):704‐714. switch 4. Lamanna WC, Holzmann J, Cohen HP, et al. Maintaining consistent quality and clinical performance of biopharmaceuticals. Expert Opinion OR CI D Biol Ther. 2018;18(4):369‐379. 5. Reichel C. Differences in sialic acid O‐acetylation between human uri- Fernando de Mora https://orcid.org/0000-0002-3002-6004 nary and recombinant erythropoietins: a possible mass spectrometric Alejandro Balsa https://orcid.org/0000-0001-8070-7062 marker for doping control. Drug Test Anal. 2013;5(11–12):877‐889. Jose‐Manuel Carrascosa https://orcid.org/0000-0003-4266-0771 6. Jelkmann W. Erythropoiesis stimulating agents and techniques: a chal- Javier P. Gisbert https://orcid.org/0000-0003-2090-3445 lenge for doping analysts. Curr Med Chem. 2009;16(10):1236‐1247. 7. EMA (European Medicines Agency), 2014. Guideline on similar biolog- Fernando de Mora1 ical medicinal products. Committee for Medicinal Products for Human Alejandro Balsa2 Use (CHMP), CHMP/437/04 Rev 1. Available from: http://www.ema. europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/ María Cornide‐Santos3 10/WC500176768.pdf. Accessed August 15, 2019. Jose‐Manuel Carrascosa4 8. EMA (European Medicines Agency), 2014. Guideline on similar biolog- Sara Marsal5 ical medicinal products containing biotechnology‐derived proteins as 6 Javier P. Gisbert active substance: non‐clinical and clinical issues. Committee for Medic- Miguel‐Angel Abad7 inal Products for Human Use (CHMP) EMEA/CHMP/BMWP/42832/ Rafael F. Duarte8 2005 Rev1. Available from: https://www.ema.europa.eu/en/docu- ments/scientific-guideline/guideline-similar-biological-medicinal-prod- Michael Wiechmann9 ucts-containing-biotechnology-derived-proteins-active_en-2.pdf. Rafael Martínez10 Accessed August 15, 2019. 1 Department of Pharmacology, Therapeutics and Toxicology, Universidad 9. Weise M, Bielsky MC, de Smet K, et al. Biosimilars: the science of Autónoma de Barcelona, Barcelona, Spain extrapolation. Blood. 2012;120(26):5111‐5117. COMMENTARY 2463 10. Warren JB. Generics, chemisimilars and biosimilars: is clinical testing fit 21. IBD Section Committee. BSG Guidance on the Use of Biosimilar for purpose? Brit J Clin Pharmacology. 2013;75(1):7‐14. Infliximab CT‐P13 in IBD February 2016. Available from: https:// 11. Frapaise FX. The end of phase 3 clinical trials in biosimilars develop- www.bsg.org.uk/resource/bsg‐guidance‐on‐the‐use‐of‐biosimilar‐ ment? BioDrugs. 2018;32(4):319‐324. infliximab‐ct‐p13‐in‐ibd.html. Accessed February 19, 2019 12. European Medicines Agency (EMA), 2015. Guideline on non‐clinical 22. Franchimont D, Ferrante M, Louis E, et al. Belgian IBD research group and clinical development of similar biological medicinal products con- (BIRD) position statement 2017 on the use of biosimilars in inflamma- taining recombinant human insulin and insulin analogues. Committee tory bowel diseases (IBD). Acta Gastroenterol Belg. 2018;LXXXI:49‐53. for Medicinal Products for Human Use (CHMP) EMEA/CHMP/ 23. Araújo FC, Sepriano A, Teixeira F, et al. The Portuguese Society of BMWP/32775/2005_Rev.1. Available from: https://www.ema. Rheumatology position paper on the use of biosimilars‐2017 update. europa.eu/en/documents/scientificguideline/guideline-non-clinical- Acta Reumatol Port. 2017;42(3):219‐228. clinical-development-similar-biological-medicinal-products-containing_ 24. Faccin F, Tebbey P, Alexander E, Wang X, Cui L, Albuquerque T. The en-0.pdf. Accessed August 15, 2019. design of clinical trials to support the switching and alternation of 13. European Medicines Agency (EMA), 2018. Guideline on similar biolog- biosimilars. Expert Opin Biol Ther. 2016;16(12):1445‐1453. ical medicinal products containing recombinant granulocyte‐colony 25. Abad‐Hernández M, Andreu JL, Balsa AC, et al. Update of the posi- stimulating 5 factor (rG‐CSF). Committee for Medicinal Products for tion paper of the Spanish Society of Rheumatology on Biosimilar Human Use (CHMP) EMEA/CHMP/BMWP/31329/2005_Rev.1. Avail- Drugs. Reumatología Clínica. 2019. https://doi.org/10.1016/j. able from: https://www.ema.europa.eu/en/documents/scientific- reuma.2019.03.007 guideline/draft-guideline-similar-biological-medicinal-products-con- 26. Tabernero J, Vyas M, Giuliani R, et al. Biosimilars: a position paper of taining-recombinant-granulocyte-colony_en.pdf. Accessed August the European Society for Medical Oncology, with particular reference 15, 2019. to oncology prescribers. ESMO Open. 2016;1(6):e000142. https://doi. 14. Kurki P, van Aerts L, Wolff‐Holz E, Giezen T, Skibeli V, Weise M. Inter- org/10.1136/esmoopen‐2016‐000142 changeability: a European perspective. BioDrugs. 2017;31(2):83‐91. 27. de Mora F. Biosimilars: a value proposition. BioDrugs. 2019;33 15. Jørgensen KK, Olsen IC, Goll GL, et al. Switching from originator (4):353‐356. https://doi.org/10.1007/s40259‐019‐00360‐7 infliximab to biosimilar CT‐P13 compared with maintained treatment 28. Legifrance. Arrêté du 3 août 2018 relatif à l'expérimentation pour l'inci- with originator infliximab (NOR‐SWITCH): a 52‐week, randomised, tation à la prescription hospitalière de médicaments biologiques double‐blind, non‐inferiority trial. Lancet. 2017;389 similaires délivrés en ville. In: JORF n°0188 du 17 août 2018, texte n (10086):2304‐2316. ° 9. Available from: https://www.legifrance.gouv.fr/eli/arrete/2018/ 16. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. 8/3/SSAS1821431A/jo/texte. Accessed August 15, 2019. Switching reference medicines to Biosimilars: a systematic literature 29. South West London (SWL) Arrangements for Introduction of new review of clinical outcomes. Drugs. 2018;78(4):463‐478. Biosimilars (Rituximab, Etanercept 25mg and Adalimumab)—Gainshare 17. Reinisch W, Jahnsen J, Schreiber S, et al. Evaluation of the cross‐reac- and QIPP agreements. Available from: https://www.gov.uk/govern- tivity of antidrug antibodies to CT‐P13 and infliximab reference ment/uploads/system/uploads/attachment_data/file/499229/Opera- product (Remicade): an analysis using immunoassays tagged with both tional_productivity_A.pdf. Accessed August 15, 2019. agents. BioDrugs. 2017 Jun;31(3):223‐237. 18. Gerdes S, Thaçi D, Griffiths CEM, et al. Multiple switches between GP2015, an etanercept biosimilar, with originator product do not How to cite this article: de Mora F, Balsa A, Cornide‐Santos impact efficacy, safety and immunogenicity in patients with chronic M, et al. Biosimilar and interchangeable: Inseparable scientific plaque‐type psoriasis: 30‐week results from the phase 3, confirmatory concepts?. Br J Clin Pharmacol. 2019;85:2460–2463. https:// EGALITY study. J Eur Acad Dermatol Venereol. 2018;32(3):420‐427. doi.org/10.1111/bcp.14089 19. Glintborg B, Sørensen IJ, Loft AGet al.A nationwidenon‐medical switch from originator infliximab to biosimilar CT‐P13 in 802patients with inflammatory arthritis: 1‐year clinical outcomes from the DANBIOregistry. Ann Rheum Dis. 2017;76(8):1726‐1431. 20. NHS Business Services Authority: medicines Optimization Dashboard. Available from: https://apps.nhsbsa.nhs.uk/MOD/ AtlasTrustsMedsOp/atlas.html. Accessed February 19, 2019.