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The use of biosimilars in immune-mediated disease: A joint ItalianSociety of Rheumatology (SIR), Italian Society of Dermatology(SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD)position paper

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OGionata Fiorino a,⁎, Giampiero Girolomoni b, Giovanni Lapadula c, Ambrogio Orlando d,Silvio Danese a, Ignazio Olivieri e,f,⁎⁎, on behalf of SIR, SIDeMaST, and IG-IBDa IBD Center, IRCCS Humanitas, Rozzano, Milan, Italyb Department of Medicine, Section of Dermatology and Venereology, University of Verona, Verona, Italyc Interdisciplinary Department of Medicine, University of Bari, Bari, Italyd Internal Medicine, “Cervello” Hospital, Palermo, Italye Rheumatology Deparment of Lucania, San Carlo Hospital of Potenza, Italyf Madonna delle Grazie Hospital of Matera, Italy

⁎ Correspondence to: G. Fiorino, IBD Unit, Departmentfax: +39 0282242591.⁎⁎ Correspondence to: I. Olivieri, Rheumatology Unit, D85100 Potenza, Italy. Tel.: +39 0971613039; fax: +39 09

E-mail addresses: gionataf@gmail.com (G. Fiorino), i.o

http://dx.doi.org/10.1016/j.autrev.2014.02.0041568-9972/© 2014 Elsevier B.V. All rights reserved.

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CTEBiological agents are widely used in rheumatology, dermatology and inflammatory bowel disease. Evidence

about their efficacy and safety has been strengthened for all those therapeutic indications over the last decade.Biosimilar agents are monoclonal antibodies similar to previously approved biologics. In the European Union,they have been approved for all the indications in the management of immune-mediated inflammatory diseases(IMIDs), although data only in rheumatoid arthritis and ankylosing spondylitis are currently available. Directevidence on efficacy, safety, and immunogenicity of biosimilars is mandatory in psoriasis, psoriatic arthritis,and inflammatory bowel disease, as well as in children. Based on the current evidence in the literature, wepresent the joint official position of the Italian Society of Rheumatology, Dermatology and Inflammatory BowelDisease on the use of biosimilars in IMIDs.

© 2014 Elsevier B.V. All rights reserved.

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. General aspects of biosimilars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03. Traceability and interchangeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04. Biosimilars in rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05. Biosimilars in dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06. Biosimilars in inflammatory bowel disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 07. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. Tel.: +39 0282245555;

eparment of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Contrada Macchia Romana,71613036.livieri@ospedalesancarlo.it (I. Olivieri).

use of biosimilars in immune-mediated disease: A joint Italian Society of Rheumatology (SIR), Italian(2014), http://dx.doi.org/10.1016/j.autrev.2014.02.004

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1. Introduction

The introduction of monoclonal antibodies, commonly known asbiologics and fusion proteins has dramatically changed the clinicalman-agement and the course of immune mediated inflammatory diseases(IMIDs), such as rheumatoid arthritis (RA), ankylosing spondylitis(AS), psoriatic arthritis (PsA), psoriasis (Pso), Crohn's disease (CD)andulcerative colitis (UC) [1–3]. The use of anti TNFs, such as infliximab,etanercept, adalimumab, certolizumab, and golimumab, and newmolecules, such as ustekinumab, an anti-IL-12/23monoclonal antibody,represents important therapeutic options in patients refractory toconventional immunosuppressive treatments, or that need prolongedand frequent courses of steroids. In addition, prolonged maintenancetherapy with anti TNFs may avoid severe complications and improvespatients' quality of life.

The main limitation of biologics is related to their costs [4]. Biologicsare very complex and large molecules (about 1000 times the size ofchemically synthesized drugs) produced by living cell cultures, thusrequiring large investments. In spite of a better control of immune-mediated inflammatory diseases, their use may result very expensiveovertime [4–6], especially for National Healthcare Systems. In times ofexpense reduction, this issue becomes highly important, and maylimit their use.

2. General aspects of biosimilars

The concomitant patent's expiration of some biologics, such asinfliximab, and the development of their biosimilars have raised animportant debate on their use to save resource for the treatment ofchronic inflammatory diseases [7]. Although the strictly controlledmanufacturing process makes biosimilars very similar to originators,the lack of solid data on their long-term safety and effectiveness raisessome concerns.

The European Medical Agency (EMA) defines a biosimilar as abiological medicinal product, which is similar to a biological medicinethat has already been authorized, the so-called “reference medicinalproduct”. A biosimilar and its reference product are expected to havethe same safety and efficacy profile, and are generally used to treat thesame conditions. The reference product is defined as a medicinal prod-uct which has been granted a marketing authorization by a MemberState or by the European Commission on the basis of a complete dossier,i.e. with the submission of quality, pre-clinical and clinical data [8]. Asfar as the biosimilar product is concerned, such comparability must beclearly supported by scientific evidence. Between 2003 and 2005, theEMA has addressed this challenge by establishing that the developmentof biosimilars should satisfy the so-called “comparability exercise”. Asfar as comparability is concerned, however, some issues have raised.Because of the complexity of the molecule itself and the diversity ofmanufacturing processes, it is generally clear that an identical copy ofa biological agent cannot be made. Even minor differences may resultand their clinical relevance could be potentially very challenging.Thus, clinicians may be reluctant to switch to a biosimilar agent whichhas not been tested enough [9,10]. Moreover, the clinical comparabilityexercise is the least sensitive method to detect differences. Even if pres-ent, disparities may not be revealed in clinical studies with a limitedsample size, particularly when the biosimilar differs from the referenceproduct mostly for safety, immunogenicity or rare adverse events. Thescientific principles underlying the required comparability for changesin the manufacturing process (also known as microheterogeneity) of agiven biological drug and for the development of a biosimilar medicinalproduct are the same. However, data requirements for biosimilars mustbe higher than those imposed to assess themicroheterogeneity [11–14].Therefore, in 2012, the European Commission changed its position onthe use of the reference medicinal product in the comparability exer-cise [15]. Previous requirements of an exclusive use of products licensedin the European Economic Area (EEA) were changed in accepting

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critical data for comparisons from reference products authorized inregulated markets outside EEA. This new position left the applicantthe responsibility to establish the equivalence from the non-EU to theEU reference product, and to demonstrate that the former is representa-tive of the latter with additional comparisons of both originators.

Based on current published data, which report some differences interms of pharmacokinetics and dosing properties [16], the ItalianMedicines Agency (AIFA) states that biosimilars cannot be consideredinterchangeable or simple substitutes of originators, except on case ofdocumented equality [17]. Moreover, it also states that in case of multi-ple indications (as it is the case for anti TNF-alpha) the biosimilarity hasto be demonstrated for each indication. Finally, the decision to prescribethe originator or the biosimilar is left to the clinician [18]. Whether theclinicians are aware of all the issues concerning biosimilarity is still to beinvestigated.

3. Traceability and interchangeability

Particular emphasis should be placed on the traceability, whichmeans to provide a reliable identification system, related to all produc-tion and distribution phases, either the originator or the biosimilar usedin clinical practice, so that the frequency and severity of adverse eventscan be certainly identified for each product. The interchangeability, thatmeans the possibility to switch among similarmolecules as they are thesame molecules, cannot be defined in the approval phase due to thepossible difference in rare adverse events and different susceptibilityto induce anti-drug antibodies. This topic has been discussed by theWorld Health Organization since 2006 [19]. They recognize that‘biosimilar’ is a regulatory and legal term distinct from the InternationalNon-proprietary Name (INN) assignment process. Although the policyfor the assignment of INNs should be applicable to biologicals in general,according to the EU position, the variability related to different glycosyl-ation is to be considered, and they recognize that significant variabilitycan be found between innovator biological products with the sameINN, or even for the same manufacturer [19]. Japan and South Koreaproposed to add every time the commercial name after the assignedINN, in order to better identify themolecule, rather than only the activeprinciple [19]. The needed post-marketing process to identify relevantsafety issues related to biosimilars cannot be performed precisely ifdifferentiation between molecules, beyond the INN, is not specified inthe safety reports.

Traceability will be possible only through large databases accumu-lated in post-marketing surveillance from safety studies or specificregistries. It should be possible to detect any significant difference inside effects or immunogenicity, if these data will be effectively andaccurately collected. In this way, the clinical community will be givenenough assurances about the safety of biosimilars with greater favor-able response. For the same concerns, interchangeability between theoriginator and its biosimilar is an important issue to discuss. If twomolecules are considered interchangeable, then it will be possible toswitch fromone to another. Currently, there are limiteddata on switchingto a biosimilar in terms of maintenance of response, immunogenicity orother safety issues [20,21]. Probably, in some cases, switching can bepossible, but the final decision should be tailored on the patient by theclinician; in the case of automatic replacement, a certain risk of loss ofresponse and loss of tolerance should be taken into account.

In the present paper, we report the current literature evidenceregarding biosimilars in chronic inflammatory rheumatic diseases, Pso,and inflammatory bowel diseases, and the perspective of the ItalianSociety of Rheumatology (SIR), Italian Society of Dermatology(SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD).

4. Biosimilars in rheumatology

Clinical trials on efficacy and safety comparisons between biosimilarsand originators are undertaken with a sample size usually smaller than

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normally required for the development of a biologic product. Theextrapolation of information related to clinical comparability withother previously licensed originators is easier if the same mechanismof action of the monoclonal antibody is involved. Nevertheless, forcertain indications, not only the reactions of Fab fragments with thetarget, but also the interaction of monoclonal antibody with someFcγR sub-types, may play a role in the mechanism of action and, inthis case, it is important to consider further experimental results [22].In particular, as far as the first biosimilar monoclonal antibody toinfliximab (CT-P13) is concerned, which was approved for marketingin South Korea for all the six indications of infliximab, the approvalwas based on a single equivalence trial conducted in patients with RA[23], and supplemented by a pharmacokinetic study in patients withAS [24]. They showed that infliximab and its biosimilar result are notdifferent in terms of clinical efficacy, safety and immunogenicity, bothat 30 and 104 weeks [20,21].

The FDA and the EMA require at least one clinical study in the mostsensitive patient population, measuring the most sensitive clinicalendpoint(s) to detect clinically meaningful difference both for efficacyand safety, including immunogenicity. Caution is recommended fordifferent safety risk profiles across indications due to different co-morbidities and concomitant medications. The large sample sizerequired for a comparative exercise trial [22] is the main reason togive a particular warning when considering the use of infliximabbiosimilars in the pediatric population, since the pharmacokinetics ofbiologics and biosimilars in children is still poorly defined and mustrepresent an aspect to be investigated before approving the freeadministration of biosimilars as equivalent to original products.Moreover, we should consider that the non-inferiority (or equivalence)evaluation margin of biosimilars is small based on the differencein efficacy between the reference product and the placebo (placebo-adjusted response) [25] and that RA was associated with the smallestplacebo-adjusted response to infliximab, compared to other indications.In other words, RA is likely to be the less sensitive clinical modelto detect a potential difference in efficacy between CT-P13 andinfliximab, particularly as studied in the equivalence trial of CT-P13patients [22].

Immunogenicity of monoclonal antibodies is the most importantgeneral safety concern on biosimilars. Anti-drug antibodies, in case ofbiological products, may cause adverse events and/or inhibit the actionof the drug. For example, a minor change in the manufacturing processof an erythropoietin product caused the production of autoantibodies toendogenous as well as exogenous erythropoietin, increasing theincidence of pure red cell aplasia (PRCA), a rare but fatal anemic condi-tion [26]. This means that the immunogenicity profile should be studiedin the patient population that carries the highest risk of an immuneresponse and immune-related adverse events [27]. However, RA isassociated with the fewest proportion of antibodies to infliximab(10%), mainly at a low titer [28], compared to other IMIDs, thus beingthe less appropriate population, from whom data on immunogenicitycan be extrapolated for the other indications to infliximab.

In conclusion, the Italian Society of Rheumatology states thatbiosimilars should be limited to the indications forwhom the “compara-bility test” was executed. Any claim must be validated with specificclinical trial, in particular for the extension of use of biosimilars inaxial spondyloarthritis, enteropathic or psoriatic arthritis, and, overall,pediatric patients. Validation should be conducted by direct comparisonof the results coming from well-designed clinical trials on the innova-tive product and the original treatment. This would result in a greatpotential for the appropriate use of biological therapies in pediatricrheumatic diseases and enteropathic arthritis, in terms of managementof the disease, and in terms of cost reduction.

However, as currently usual for the available biologics, the finalclinical decisions should always be made on an individual basis, takinginto account both the characteristics of the individual patient and theclinician's advice.

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5. Biosimilars in dermatology

The introduction of biological therapeutics for the treatment ofchronic plaque Pso has significantly improved several important patientoutcomes including quality of life, and allowing an effective long-termcontrol of the skin disease. Indeed, the proportion of patients whomaintain the therapy is significantly higher for those receiving TNF-αblockers than conventional treatments, most likely because the formersaremuch better tolerated. Conventional drugsmore easily induce organtoxicity and negatively affect cardiometabolic comorbidities which arevery common in patients with Pso. In particular, cyclosporine inducesnephrotoxicity and hypertension, methotrexate liver damage, andacitretin can result in skin andmucosal toxicity [29]. Currently approvedbiologics for the treatment of chronic plaque Pso include the TNF-alphainhibitors adalimumab, etanercept and infliximab, and ustekinumab, ananti-IL-12/23 monoclonal antibody. Although biosimilars may improveaccess to expensive biological agents, concerns have been raisedregarding their clinical use. In particular, due to the complexities ofmanufacturing copies of biological therapeutics, SIDeMaST hasquestionedwhether biosimilarswill confer identical biological function,efficacy and toxicity to reference products, both in the short and longterms. Thus, the key question for biosimilars is not whether differencesexist comparedwith the reference, butwhether differences are clinicallyrelevant. The acceptance of biosimilars among dermatologists requiresunderstanding the regulatory processes governing their approval. ForEMA and FDA, a biosimilar clinical development programmust demon-strate equivalence to a reference product already licensed (andmanufactured) for use in Europe or in the USA, respectively. Thedemonstration of biosimilarity is significantly different from genericdrug approval, where only pharmacokinetics equivalence must beshown. Extensive, non-clinical physiochemical and biological charac-terization is required to address structural, functional and immunoge-nicity concerns, prior to efficacy and safety trials. Thus, the chemistry,manufacturing and portion controls of a biosimilar application are likelylarger and more detailed than that of the reference product. A clinicaldata requirement that must be demonstrated is equivalent to referenceproduct, as opposed to superior safety and efficacy. Both EMA and FDArequire randomized controlled trials (RCT) to be of sufficient size toestablish clinical equivalence; however, rare adverse events and long-term efficacy and safety will be assessed only through post marketingsurveillance. Thus, as for reference agents, stringent post-approvalpharmacovigilance is paramount. Extrapolation of clinical data permitsthe approval of a biosimilar for a therapeutic indication in which it hasnot been clinically evaluated, but for which the reference agent isapproved. However, extrapolation may be less appropriate when thetwo therapeutic indications involve distinctly different practices anddisease biology, and will therefore be considered by EMA/FDA ‘case-by-case’ [30]. We believe that consideration of separate clinical trialsfor biosimilars in different therapeutic indications would be thereforevery important. Automatic substitution would enable pharmacists todispense a biosimilar, instead of the reference agent, without priorconsent of the prescribing physician. EMA has recently designated abiosimilar as automatically substitutable, although each country willfollow its own national guidelines [17,31]. Finally, nomenclature mustallow physicians to identify biosimilar products and communicateprescriptions accurately with pharmacists. It is important that physi-cians distinguish between biological ‘intended copies’ and biosimilars.To attain the biosimilar status, an agent must undergo the requiredcomparability qualification in accordance with scientific principlesendorsed by authorities, such as EMA or FDA. Despite these stringentapproval processes, significant savings in costs are expected. Once avail-able, physicians who prescribe biological therapies must be aware ofany developments concerning biosimilars, and be vigilant in their use.Currently, there are no biosimilar monoclonal antibodies and solublereceptor constructs that have been approved by EMA or FDA for treat-ment of chronic plaque Pso with specifically designed RCTs, and all

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these aspects should be considered at the time of the introduction ofbiosimilars for the management of skin diseases.

6. Biosimilars in inflammatory bowel disease

Infliximab and adalimumab are the only biologics currentlyapproved for the treatment of Crohn's disease (CD), and, togetherwith golimumab [32], for ulcerative colitis (UC) in the European Union(EU) [33]. In the Western countries outside EU, also certolizumabpegol and natalizumab are approved for Crohn's disease. At present,two infliximab biosimilars have been filed for the EMA, Inflectra®, andRemsima® [34,35], although there are currently no studies comparinginfliximab and biosimilars in IBD. In this particular case, EMA hasaccepted the regulatory filing of the biosimilar companies by extrapo-lating data from chronic inflammatory rheumatic diseases, in particularfrom the PLANETRA trial [23], which investigated combination therapywith biosimilar infliximab and methotrexate in RA. However, there areseveral data which show that evidence on rheumatic diseases cannotbe directly translated on inflammatory bowel diseases, starting fromdifferent mechanisms on pathogenesis [36]. Etanercept and abataceptwork well in rheumatic diseases, but are completely ineffective in IBD[37,38]. The dosage of anti TNFs used in rheumatology is sometimesdifferent from those used in IBD, and also the dose optimization is differ-ent [39]. It is thus needed to conduct well-designed non-inferiority orequivalence trials to compare biosimilars and infliximab.

The ItalianGroup for the study of Inflammatory Bowel Disease statesthat adequate studies and surveillance are urgently required, beforeapproving the use of biosimilars in IBD, in line with the position of theEuropean Crohn's and Colitis Organization [40].

7. Discussion

The development of biosimilars for the treatment of immune-mediated disease may be important to decrease the costs of biologicaltherapy. However, it is required to demonstrate their equality in termsof efficacy and safety. Studies on erythropoietin demonstrated that asimple change in the formulation of the molecule can lead to relevantunexpected adverse events, especially concerning immunogenicity [9,16,41]. Given the complexity of anti TNFs and their relevant immunoge-nicity, this point should be carefully considered. Moreover, cliniciansoften do not know that also original molecules can undergo modifica-tions in manufacturing after the approval from Regulatory Agencies,which can somehow impact on the effects of the agent itself [42]. Thisshould be also taken into account for biosimilars, which come alreadyfrom a modification in the manufacturing process compared to theoriginator. Post-translational modifications, such as glycosylation, mayoccur from changes in cell lines and/or manufacturing processes,resulting in products that are highly similar, but not identical toapproved ‘reference’ agents, hence the term is ‘biosimilar’, rather than‘bioidentical’. The potential for protein modification to alter biologicalfunction is especially true for complex therapeutic proteins, such asmonoclonal antibodies and soluble receptor constructs. Subtle changesin protein conformation may result in altered function, insolubility orincreased immunogenicity that is a major determinant to loss of clinicalefficacy in patients who undergo biological treatments [43]. Activity ofmonoclonal antibodies and soluble receptor constructs depends notonly upon interactions with target antigen, but also upon Fc receptor(FcγR) function [44]. Mutations of one amino acid are sufficient toimpair Fc interactions, thereby altering complement activation and/orantibody-dependent cytotoxicity, and reducing the efficacyof therapeu-tic monoclonal antibodies.

The methodological issues in comparing biosimilars and originatorare a key point. A non-inferiority comparison is the most correctapproach, but it is limited by the large sample size required. Moreover,phase III are usually underpowered for safety, thus a well-designedcomparative trial for biosimilars should start with α = 0.25 and

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β = 0.90, which results in a higher sample size required than the com-mon placebo-controlled trials for efficacy [45]. The absence of placeboand the lower response due to immunogenicity should be also takeninto account in the sample size calculation. Li et al. [45] have proposedan asymmetrical biosimilarity margin with different non-inferiorityand non-superiority margin, which can improve the feasibility of thetrial. Probably, such trial needs an interim analysis to adjust the samplesize during the investigation phase, and get statistically significantresults [45]. The trial design should also consider the different out-comes, and get an adequate sample size for all of them.

Finally, clinicians and patients should be aware of all mattersconcerning biosimilarity. The similarity, but not equality, should beclear, and the current lack of data for biosimilars in certain diseasesshould be also underlined. The interchangeability and substitutionbetweenmolecules should be left to the expert and informed clinicians.The point of view of patients' associations should also be carefullyconsidered. A consensus between clinicians, patients, payers, and/orpublic health organizations needs to be reached, especially to carefullyconsider advantages and issues related to the use of biosimilars, fromdifferent points of views [46].

In conclusion, we can clearly state that:

- Biosimilars cannot be considered interchangeable or simple substi-tutes of originator, until recent and preliminary data will beconfirmed. The complexity of the molecule, dosing, and immunoge-nicity issues needs careful investigation on these aspects.

- Biosimilars should be demonstrated to be effective and safe inimmunemediated-diseases in RCTs of sufficient dimension. Efficacyassessmentmerely based on clinical response is not always compre-hensive, as specific endpoints should be also investigated.

- The use of biosimilars in children affected by chronic immune-mediated diseases, such as RA, AS, PsA, Pso and IBD needs to becarefully investigated, especially in terms of safety.

- Biosimilars need to be tested by well-designed trials with anadequate sample size calculation.

- Post-marketing surveillance for safety and immunogenicity has toclearly differ the biosimilars from the originator. The name“infliximab” should not be used in the reports, but rather thecommercial name, in order to monitor particular effects which candifferentiate between the agents. In this context, we did not findanything correct to identify an originator monoclonal antibodiesand its biosimilar with the same INN.

- Interchangeability cannot be automatic, unless its effectiveness andsafety will be exhaustively demonstrated. It should be currentlyleft to the clinician's responsibility to choose whether to switchfrom an originator to a biosimilar, based on patients' characteristics.Neither other paramedical characters nor Healthcare payers shouldbe allowed to change the prescription or impose the use ofbiosimilars instead of their originator.

Conflict of interest

G.F. served as a consultant and a member of Advisory Boards forMSD, Takeda Pharmaceuticals, and Janssen Pharmaceuticals; G.G. hasreceived advisory/speaker honoraria and/or research funding fromAbbVie, Almirall, Boehringer Ingelheim, Celgene, Dompè, Eli-Lilly,Galderma, GSK, Janssen, Leo Pharma, Otsuka, Merck-Serono, Maruho,MSD, Novartis and Pfizer. G.L. served as a consultant and a member ofAdvisory Boards for MSD, Pfizer, AbbVie, BMS, UCB and ROCHE, andhas received advisory/speaker honoraria and/or research funding fromMSD, Pfizer, AbbVie, BMS, UCB and ROCHE; A.O. served as an advisoryboard member for AbbVie and MSD, and received lecture grants forAbbVie, Sofar, Chiesi, and Takeda Pharmaceuticals; S.D. Silvio Danesehas served as a speaker, consultant and advisory board member forSchering-Plough, Abbott Laboratories, Merck & Co., UCB Pharma,Ferring, Cellerix, Millennium Takeda, Nycomed, Pharmacosmos,

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Actelion, Alpha Wasserman, Genentech, Grunenthal, Pfizer, AstraZeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson &Johnson; I.O. has received advisory/speaker honoraria from AbbVie,Roche, MSD, Novartis, and Pfizer.

Take-home messages

• Biosimilar agents are monoclonal antibodies similar to previouslyapproved biologics.

• Biosimilarity for monoclonal antibodies has been investigated only inrheumatoid arthritis and ankylosing spondylitis.

• EMA approved the use of biosimilars for all indications, includingpsoriasis and inflammatory bowel disease.

• Biosimilars still need to be tested for efficacy and safety by well-designed trials with an adequate sample size calculation, especiallyfor psoriasis and inflammatory bowel diseases.

• Caution is recommended for extrapolation of data across indication,interchangeability and traceability.

• Post-marketing surveillance for safety and immunogenicity is stronglyrequired.

Acknowledgments

We thank the IG-IBD members Fernando Rizzello, Vito Annese,Alessandro Armuzzi, Livia Biancone, Fabrizio Bossa, Emma Calabrese,Fabiana Castiglione, Michele Comberlato, Salvatore Cucchiara, MarcoDaperno, Walter Fries, Paolo Gionchetti, Giovanni Latella, Anna Kohn,Gianmichele Meucci, Claudio Papi, Maria Beatrice Principi, AntonioRispo, Simone Saibeni, and Maurizio Vecchi for their suggestions andcritical revision of the final version of the manuscript.

References

[1] Wiens A, Venson R, Correr CJ, Otuki MF, Pontarolo R. Meta-analysis of theefficacy and safety of adalimumab, etanercept, and infliximab for the treatment ofrheumatoid arthritis. Pharmacotherapy 2010;30:339–53.

[2] Bansback N, Sizto S, Sun H, Feldman S, Willian MK, Anis A. Efficacy of systemictreatments for moderate to severe plaque psoriasis: systematic review and meta-analysis. Dermatology 2009;219:209–18.

[3] Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF.Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol 2008;6:644–53.

[4] Bodger K, Kikuchi T, Hughes D. Cost-effectiveness of biological therapy for Crohn'sdisease: Markov cohort analyses incorporating United Kingdom patient-level costdata. Aliment Pharmacol Ther 2009;30:265–74.

[5] Liu Y, Wu EQ, Bensimon AG, Fan CP, Bao Y, Ganguli A, et al. Cost per responderassociated with biologic therapies for Crohn's disease, psoriasis, and rheumatoidarthritis. Adv Ther 2012;29:620–34.

[6] Lapadula G, Ferraccioli GF. Biosimilars in rheumatology: pharmacological andpharmacoeconomic issues. Clin Exp Rheumatol 2012;30:S102–6.

[7] Cuadrado MJ, Sciascia S, Bosch X, Khamashta MA, Ramos-Casals M. Is it time forbiosimilars in autoimmune diseases? Autoimmun Rev 2013;12:954–7.

[8] EuropeanMedicine Agency. Procedural advice for users of the centralised procedurefor similar biological medicinal products applications; 2011.

[9] Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, et al. Biosimilars:what clinicians should know. Blood 2012;120:5111–7.

[10] EbbersHC, Pieters T, LeufkensHG, Schellekens H. Effective pharmaceutical regulationneeds alignment with doctors. Drug Discov Today 2012;17:100–3.

[11] Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Narayanan G, et al.Biosimilars—why terminology matters. Nat Biotechnol 2011;29:690–3.

[12] Comparability of biotechnological/biological products: note for guidance onbiotechnological/biological products subject to changes in their manufacturingprocess. ICH Topic Q5E; 2003.

[13] European Medicine Agency. Similar biological medicinal products containingbiotechnology-derived proteins as active substance: quality issues; 2005 [EMA/CHMP/BWP/49348/2005].

[14] European Medicine Agency. Similar biological medicinal products containingbiotechnology-derived proteins as active substance: non-clinical and clinical issues;2005 [EMA/CHMP/BWP/42832/2005].

[15] EuropeanMedicine Agency. Procedural advice for users of the centralised procedurefor similar bio-logical medicinal products applications; 2013 [EMA/940451/2011].

[16] Ebbers HC, Crow SA, Vulto AG, Schellekens H. Interchangeability, immunogenicityand biosimilars. Nat Biotechnol 2012;30:1186–90.

[17] Agenzia Italiana del Farmaco. Position Paper sui farmaci biosimilari. http://www.agenziafarmaco.gov.it/it/content/position-paper. [Accessed on Feb, 2, 2014].

Please cite this article as: Fiorino G, et al, The use of biosimilars in immune-Society of Dermatology (..., Autoimmun Rev (2014), http://dx.doi.org/10.1

ED P

RO

OF

[18] Agenzia Italiana del Farmaco. Position paper sui farmaci biosimilari. http://www.agenziafarmaco.gov.it/it/content/position-paper. [Accessed on Sept. 29, 2013].

[19] World Health Organization.WHO informal consultation on International Nonpropri-etary Names (INN) policy for biosimilar products. http://www.who.int/medicines/services/inn/inn_bio/en/index.html. [Accessed on Dec, 2, 2013].

[20] Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre EB, Lanzon A, et al. Efficacyand safety of CT-P13 (infliximab biosimilar) over two years in patients withrheumatoid arthritis: comparison between continued CT-P13 and switching frominfliximab to CT. http://ww2.rheumatology.org/apps/MyAnnualMeeting/Abstracts?SearchString=biosimilar&Day=-1. [Accessed on Feb, 2, 2014].

[21] Park W, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, Lee YA, et al. Efficacyand safety of CT-P13 (infliximab biosimilar) over two years in patients withankylosing spondylitis: comparison between continuing with CT-P13 and switchingfrom infliximab to CT-P13. http://ww2.rheumatology.org/apps/MyAnnualMeeting/Abstract/39201. [Accessed on Feb, 02, 2014].

[22] Lee H. Is extrapolation of the safety and efficacy data in one indication to anotherappropriate for biosimilars? AAPS J 2013.

[23] Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk S, et al. Arandomised, double-blind, parallel-group study to demonstrate equivalence inefficacy and safety of CT-P13 compared with innovator infliximab whencoadministered with methotrexate in patients with active rheumatoid arthritis:the PLANETRA study. Ann Rheum Dis 2013;72:1613–20.

[24] Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, et al. A randomised,double-blind, multicentre, parallel-group, prospective study comparing the pharma-cokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients withankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013;72:1605–12.

[25] Food and Drug Administration, Center for Drug Evaluation, Research (CDER), Centerfor Biologics Evaluation, Research (CBER). Guidance for industry. Non-inferiorityclinical trials. http://www.fda.gov/downloads/Drugs//Guidances/UCM202140.pdf.[Accessed on Dec 2, 2013].

[26] Schellekens H. Immunologic mechanisms of EPO-associated pure red cell aplasia.Best Pract Res Clin Haematol 2005;18:473–80.

[27] World Health Organization. Guidelines on evaluation of similar biotherapeuticproducts (SBPs). http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. [Accessed on Dec 2, 2013].

[28] Flood J. Tumor necrosis factor inhibitors in the treatment of chronic inflammatorydiseases. A review of immunogenicity and potential implications. Manag Care2009;18:1–5.

[29] Gisondi P, Cazzaniga S, Chimenti S, Giannetti A, Maccarone M, Picardo M, et al.Metabolic abnormalities associatedwith initiation of systemic treatment for psoriasis:evidence from the Italian Psocare Registry. J Eur Acad Dermatol Venereol 2013;27:e30–41.

[30] Lee H, Yim DS, Zhou H, Peck CC. Evidence of effectiveness: how much can weextrapolate from existing studies? AAPS J 2005;7:E467–74.

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

[32] European Medicine Agency. Simponi: EPAR—summary for the public. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000992/human_med_001053.jsp&mid=WC0b01ac058001d124. [Accessed on Feb, 2, 2014].

[33] Peyrin-Biroulet L, Fiorino G, Buisson A, Danese S. First-line therapy in adult Crohn'sdisease: who should receive anti-TNF agents? Nat Rev Gastroenterol Hepatol2013;10:345–51.

[34] European Medicines Agency. Inflectra. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002778/smops/Positive/human_smop_000531.jsp&mid=WC0b01ac058001d127. [Accessed on Sept. 29, 2013].

[35] European Medicines Agency. Remsima. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002576/smops/Positive/human_smop_000532.jsp&mid=WC0b01ac058001d127. [Accessed on Sept. 29, 2013].

[36] Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonistmechanisms of action: a comprehensive review. Pharmacol Ther 2008;117:244–79.

[37] Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, et al. Etanercept foractive Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastro-enterology 2001;121:1088–94.

[38] Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR, Panaccione R, et al.Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 2012;143:62–9[e4].

[39] Gecse KB, Khanna R, van den Brink GR, Ponsioen CY, Lowenberg M, Jairath V, et al.Biosimilars in IBD: hope or expectation? Gut 2013;62:803–7.

[40] Danese S, Gomollon F. ECCO position statement: The use of biosimilar medicines inthe treatment of inflammatory bowel disease (IBD). J Crohns Colitis 2013;7:586–9.

[41] Mikhail A, Farouk M. Epoetin biosimilars in Europe: five years on. Adv Ther2013;30:28–40.

[42] Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis2013;72:315–8.

[43] Baert F, NomanM, Vermeire S, Van Assche G, D' Haens G, Carbonez A, et al. Influenceof immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N EnglJ Med 2003;348:601–8.

[44] Isaacs JD, Greenwood J, Waldmann H. Therapy with monoclonal antibodies. Thecontribution of Fc gamma receptor binding and the influence of C(H)1 and C(H)3domains on in vivo effector function. J Immunol 1998;161:3862–9.

[45] Li Y, Liu Q, Wood P, Johri A. Statistical considerations in biosimilar clinical efficacytrials with asymmetrical margins. Stat Med 2013;32:393–405.

[46] Mendes de Abreu M, Strand V, Levy RA, Araujo DV. Putting the value into biosimilardecision making: the judgment value criteria. Autoimmun Rev 2014.

mediated disease: A joint Italian Society of Rheumatology (SIR), Italian016/j.autrev.2014.02.004