Transitioning from first- to second-generation biosimilars: An appraisal of regulatory and post-marketing challenges

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ContentslistsavailableatScienceDirect

Pharmacological

Research

jo u r n al hom e p ag e :w w w . e l s e v i e r . c o m / lo c a t e / y p h r s

Review

Article

Transitioning

from

ﬁrst-

to

second-generation

biosimilars:

An

appraisal

of

regulatory

and

post-marketing

challenges

Corrado

Blandizzi

a,∗

_,

_Mauro

_Galeazzi

b

_,

_Guido

_Valesini

c

a_Department_of_Clinical_and_Experimental_{Pharmacology,}_Unit_of_Pharmacology_and_{Pharmacovigilance,}_University_of_Pisa,_Pisa,_Italy b_Department_of_Medicine,_Surgery_and_{Neuroscience,}_Unit_of_{Rheumatology,}_University_of_Siena,_Siena,_Italy

c_Department_of_Internal_Medicine_and_Medical_Specialties,_Unit_of_{Rheumatology,}_Sapienza_University_of_Rome,_Rome,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received12September2017

Receivedinrevisedform31October2017 Accepted31October2017

Availableonline3November2017 Keywords: Biotherapeutics Bosimilars Monoclonalantibodies Clinicaldevelopment Pharmacovigilance Immunogenicity

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Second-generationbiosimilars(i.e.monoclonalantibodiesorproteinsgeneratedbyfusionofantibody andreceptormoieties)differinseveralrespectsascomparedtofirst-generationones(e.g.epoetins, bonemarrowstimulatingfactors,somatotropins).Inthisrespect,assecond-generationbiosimilarsare endowedwithmuchgreaterstructuralandmolecularcomplexity,whichmighttranslateintoanumber ofpharmacologicalandtherapeuticissues,theyraisenewchallengesformanufacturersandregulatory authoritiesaswellasnewconcernsforclinicians.Basedonthesearguments,thepresentarticlewas intendedtoreviewinformationonthemaindifferencesbetweenfirst-andsecond-generationbiosimilars fortreatmentofimmune-mediatedinflammatorydiseases,aswellastheirimpactonimmunogenicity, thedesignofclinicaltrialsandthecriticalissueofextrapolationoftherapeuticindications.Thepositions takenbyrelevantmedicalassociationsandthecrucialroleofpharmacovigilancearealsoreviewed. Accordingtocurrentknowledge,theinitialpost-marketingclinicalexperiencewithsecond-generation biosimilarsisprovidingencouragingresults,thoughtheirlong-termsafetyandefficacyaswellasthe scientificbasisunderlyingtheextrapolationoftherapeuticindicationsarestillmatterofdiscussion. Thereissomeconsensusthatmarketingapplicationsshouldrelyonstudiessupportingtheclinicaluse ofbiosimilarsintheirdifferenttargetdiseasesandpatientpopulations.Inparallel,clinicalsafetymust beensuredbyastrictcontrolofthemanufacturingprocessesandasolidpharmacovigilanceprogram. Itremainsthenaresponsibilityofthephysiciantodriveaproperuseofsecond-generationbiosimilars intoclinicalpractice,inaccordancewithguidelinesissuedbyscientificsocieties.

©2017TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction...307 2. First-generationbiosimilars...307 3. Second-generationbiosimilars...308 3.1. Immunogenicity...308

3.2. Designofclinicalstudies ... 309

3.3. Extrapolationoftherapeuticindications...310

3.4. Pharmacovigilance...310

3.5. Otherissues:naming,traceabilityandcosts...310

Abbreviations:ACR,AmericanCollegeofRheumatology;ADAb,anti-drugantibody;ADCC,antibody-dependentcell-mediatedcytotoxicity;AIFA,ItalianMedicinesAgency; CDC,complement-dependentcytotoxicity;CHMP,CommitteeforMedicinalProductsforHumanUse;DAS28,28-jointdiseaseactivityscore;ECCO,EuropeanCrohn’sand ColitisOrganization;EMA,EuropeanMedicinesAgency;FDA,FoodandDrugAdministration;IBD,inflammatoryboweldisease;IG-IBD,ItalianGroupofInflammatoryBowel Disease;IMID,immune-mediatedinflammatorydisease;mAb,monoclonalantibody;PASI,PsoriasisAreaandSeverityIndex;PRCA,pureredcellaplasia;RA,rheumatoid arthritis;SIDeMaST,ItalianSocietyofDermatology;SIR,ItalianSocietyofRheumatology;WHO,WorldHealthOrganization.

∗ Correspondingauthorat:DepartmentofClinicalandExperimentalPharmacology,UnitofPharmacologyandPharmacovigilance,UniversityofPisa,ViaRoma55,I-56126, Pisa,Italy.

E-mailaddress:corrado.blandizzi@med.unipi.it(C.Blandizzi). https://doi.org/10.1016/j.phrs.2017.10.015

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4. Positionstatementsofmedicalassociations...311 5. Conclusions...311 Disclosurestatement...312 Funding...312 References...312 1. Introduction

Overthelasttwodecades,biotechnologicaldrugs,commonly designatedasbiologics,haverevolutionizedthetherapeutic man-agementofpatients,notonlyinthefieldofhormonedeficiencies as wellas solid and hematologicmalignancies, but alsoin the area of immune-mediated inflammatory diseases (IMIDs), and havebecomeblockbustersforhealthcaresystemsworldwide.After dataprotectionorpatentscoveringbiopharmaceuticalagentshave beguntoexpire,severalbiosimilardrugshavebeendevelopedand approvedforuseindifferentclinicalconditions.Theterm ‘biosim-ilar’wasfirstintroducedbytheEuropeanMedicinesAgency(EMA) todescribebiologicmedicinesdevelopedas‘copies’ofinnovative biologics(commonlydesignatedasoriginators).However,unlike thegenericproductsofsmall-moleculedrugs,identicalcopiesof biologicscannotbeobtained.Thislimitationdependsmainlyon thecircumstancethat biologicsareproducedby livingcell sys-tems,whosebiosyntheticprocessesaresubjectedtointrinsicand unavoidablefactorsonbiological variability,andpartlyontheir highdegreeofcomplexityintermsofbothmolecularstructureand manufacturingprocedures.Therefore,thetermbiosimilarrefersto asortof‘copy’ofanauthorizedbrandedbiologicoriginatorthathas demonstratedsimilaritytotheoriginatorthroughoutthevarious stepsofarigorouscomparativeproceduredesignatedas ‘compara-bilityexercise’[1,2].Whileacknowledgingthepotentialfavorable impact of biosimilars on the pharmaceutical market, in terms ofboth costsavinganddrugaccessibility,theItalian Medicines Agency(AIFA)hastakenthepositionthatoriginatorsand biosim-ilarscannotbeconsideredasinterchangeablemedicinalproducts, thusexcludingthepracticeofautomaticsubstitutionand switch-ingand,inaccordancewiththeconceptofbiosimilarityissuedby theEMA,emphasizingtheprincipleofthedominantroleof clin-iciansinchoosingwhetherpatientsshouldbeprescribedwithan originatororitsbiosimilar[3].

Biosimilars,asallbiopharmaceuticals,areendowedwithhighly complexproteicstructuresandlargemolecularweight.Theyare produced through biosynthesis by genetically manipulated liv-ingcellsystems[e.g.EscherichiacoliandChinesehamsterovary cells],which,dependingongrowthconditionsandotherfactors, cangeneratemixtures ofrelated moleculesthat arequite diffi-culttoextract,purifyandcharacterize.Evenhavingaccesstothe exactDNAsequencecodingfortheoriginatorbiologic,itisvery difficulttoreplicateexactlyitsend-structure(i.e.tertiaryand qua-ternarystructures),includingpost-translationalchanges,suchas glycosylation,and toreproduceexactlythemanufacturing pro-cess.Accordingly,eachbiosimilar,eventhoughcloselysimilarto the referenceoriginator, will never reachthe level of identity. Inthisregard,particularattentionmustbepaid,ina regulatory perspective,tothepossibilitythatabiosimilarmightdisplay dif-ferentpatternsofimmunogenicactivity,withaconsequentriskof increasedpropensitytostimulatetheproductionofanti-drug anti-bodies(ADAbs),ascomparedwiththeoriginator[4–6].Thus,to copewiththeaboveissues,someregulatoryauthoritieshave devel-opedaspecificbiosimilarapprovalpathway,firstimplementedby EMAin2005,whichrequiresthedemonstrationofsimilaritywith therespectiveoriginatorintermsofphysico-chemicalproperties, pharmacology,efficacyandsafety,onthebasisofa comprehen-sivehead-to-headcomparabilityexercise.Ifcomparison failsat

anylevel,thebiologicproductisnolongereligibleasa biosimi-lar.Therefore,onlythebiologicproductsthatdisplaysubstantial similaritywiththeirrespective originatorsthroughoutall steps ofthecomparabilityexercisecanbedesignatedas‘biosimilar’by theregulatoryauthorityandapprovedforclinicaluse[7,8].Inthis context,animportantpointofnovelty,whichhasbeenmatterof muchdebate,pertainstothepossibilityforabiosimilarproduct ofgettingapprovalformultipleextrapolatedtherapeutic indica-tions(ideallyallthosepreviouslygrantedtotheoriginator),inthe faceofaclinicaldevelopmentbasedonasinglephaseIII compar-ativetrial,documentingitssimilaritywiththeoriginatorforonly onespecifictherapeuticindication.Thisisregardedasanissueof highclinicalrelevance,sinceitraisesthequestionofwhetherdata obtainedwithabiosimilarfrompatientsaffectedbyonespecific diseasearesufficienttoallowtheuseofsuchabiosimilarinpatients withotherdiseases,forwhichadirectdemonstrationof therapeu-ticequivalencehasnotbeenprovidedbyspecificclinicaltrials.In thisrespect,mostexpertsagreethatitispossiblethata biosimi-lar,demonstratedtobeeffectiveforonetherapeuticindication,is noteffectiveinotherindicationsforwhichtheoriginatorhadbeen previouslyapproved[9–11].

Notably,second-generationbiosimilars(i.e.monoclonal anti-bodies, mAbs, or proteins obtained by fusion of antibody and receptormoieties)differinseveralrespectsascomparedto ﬁrst-generationones(e.g.epoetins,bonemarrowstimulatingfactors, somatotropins),andthereforetheyraisenewchallengesfor man-ufacturersandregulatoryauthoritiesaswellasnewconcernsfor clinicians.Basedonthisbackground,thepresentarticlewas con-ceivedtoreviewcurrentinformationonmaindifferencesbetween ﬁrstandsecond-generationbiosimilarsfortreatmentofIMIDs,as wellastheirimpactonimmunogenicity,thedesignofclinical tri-alsandthecriticalissueofextrapolationoftherapeuticindications. Thepositionstakenbyrelevantmedicalassociationsandthecrucial roleofpharmacovigilancehavebeenreviewedaswell.

2. First-generationbiosimilars

ThefirstbiosimilarsapprovedbytheEMACommitteefor Medic-inal Products for Human Use (CHMP)were follow-on products oforiginatorbiologicsendowedwitha relativelylowmolecular weight,includingtwobiosimilarsofsomatropin,five erythropoi-etin biosimilars,andsevenbiosimilarsoffilgrastim.Since 2006, morethan20biosimilarproductshavebeenintroducedintothe Europeanmarket[12].Filgrastimandepoetin-alphawerethefirst biosimilarsproducedforuseinhematology-oncologythat over-camethestrictqualitycontrolsandregulatoryrequirementsfor approval bytheEuropeanagency,and havebeen usedfor sev-eralyearsassupportivetherapyofpatientsundergoinganticancer chemotherapy[13].

The regulatory pathway for biosimilars introduced into the Europeanmarketonedecadeago hasbeentakenasareference byotherregulatoryauthorities,includingtheUS FoodandDrug Administration(FDA).Accordingtosucha pathway,aftera bio-logicproductisgeneratedandintendedtobehighlysimilartoan originator,similarityhastobedemonstratedinbothnon-clinical (i.e.invitroandanimaltesting)andclinicalstudies.Thedesignof thesestudiesbytheproprietaryofthebiosimilarproductisoften subjectedtopreliminarydiscussionandagreementwiththe

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reg-ulatoryauthorities,suchastheEMAorFDA.Inallinstances,the generalbackgroundprincipleunderlyingtheoverallapproval pro-cedureofbiosimilarsisthatthehigherthelevelofsimilarity,in termsofstructuralandinvitrobiological/pharmacological prop-erties,thelessclinicalevidenceisneededtodemonstrateclinical similarity[14–16].Moreover,inordertogainlong-termevidence ontheefficacyand safety of biosimilarproducts, rigorous pro-gramsofpost-marketingpharmacovigilance,aimedatconfirming theinitialpatternsofefficacyandsafetyaswellastominimize andproperlymanageanyriskofunexpectedsafetyissues,arethen requiredbytheregulatoryauthorities[17,18].

Thehighstrictnessimposedbyregulatoryagencieson post-marketingpharmacovigilanceprogramsiswidelyjustiﬁedalsoin thelight of somelessons learned fromthe occurrence of seri-ous adverse events caused by immunogenic reactions against ﬁrst-generationbiologics.Themostrepresentativeepisodeinthe Europeanarea dates backto 2002, when a report described a seriesofpatientsaffectedbychronicrenalfailure,whohad devel-opedsevereanemiaassociatedwithpureredcellaplasia(PRCA) upontreatmentwithhumanrecombinantepoetinalpha.Allthese patientstestedpositiveforneutralizinganti-erythropoietin anti-bodies, theinduction of which was ascribed tochanges in the biologicproductresulting fromvariationsofthemanufacturing process[19].Subsequently,additionalcasesofPRCAwerereported inpatientstreatedwithepoetinbetaanddarbopoetinalpha[20].Of interest,casesofPRCAoccurredalsointhesettingofaregistration clinicaltrialonbiosimilarepoetinalpha. Asa consequence,this studywasdiscontinuedandthemanufacturerofbiosimilar epo-etinundertookaninvestigationalprogramaimedatunravelling theunderlyingcausesofthisissue[21].

Despite the strictness of regulatory procedures underlying biosimilardevelopmentandapproval,intheEuropeanUnionthe useofepoetinandfilgrastimbiosimilarsintheclinicalpracticehas beenratherslow,possiblyduetoaninitiallackoftrustbypatients andphysiciansintheefficacyand/orsafetyofbiosimilars,andin theirinterchangeabilitywiththeoriginatorproduct[18].However, thereisnowmorethanadecadeofclinicalexperience accumu-latedwiththese‘first-generationbiosimilars’,andtheoutcomes, intermsofbotheffectivenessandsafetyintheclinicalpractice, includingthoseconcerningtheextrapolatedtherapeutic indica-tions,havebeenwellreassuring.Accordingly,itcanbereasonably statedthatforthesefirstbiologicproductsthebiosimilarapproach drawnbytheEMA,atbothpre-andpost-marketinglevel,hasbeen proventobesuccessful.

3. Second-generationbiosimilars

Asecondwaveofbiosimilarmedicinalproductshasstartedto entertheclinicalusesince2013followingthepatentexpirationof originatorbiologicswithhighlycomplexmolecularstructures,such asmAbsorproteinsgeneratedbyfusionofantibodyand recep-tormoieties,approvedfortreatmentofcancerorIMIDs.Itisquite clearthatthese‘second-generation’biosimilarsrepresentadistinct therapeuticclassinseveralrespectsascomparedtoepoetins,bone marrowstimulatingfactorsandsomatropins.Indeed,thestructure andmolecularcomplexityofanimmunoglobulinfarexceedsthatof aﬁrst-generationbiosimilar.Toappreciatethesigniﬁcanceofsuch adifference,itisjustenoughtoconsiderthatthemolecularweight ofhematopoieticgrowthfactorsfallsintherangeof15–20kDa, whilethatofmAbsisabout150kDa.

TheentryofmAbs and fusion proteinsamong biosimilars is goingtohaveasignificantclinicalimpact,sincethemajorityoftheir respectiveoriginatorsarecurrentlyregardedassafeandeffective drugsavailableforlargenumbersofpatientsasdisease modify-ingtherapiesinthefieldsofinflammationandoncology[22–24].

However,second-generationbiosimilarsraisesignificantnew chal-lengeswhencomparedwiththeirfirst-generationcounterparts, whichareemployedasreplacementtherapiesortreatmentsfor supportive care. A central issue is that mAbs and fusion pro-teinsareapprovedforverydifferenttherapeuticindications,thus makingtheextrapolationoftheirefficacyandsafetytoother ther-apeutic indications particularlydifficult.In this respect, several expertshave claimedthat similaritytesting betweenoriginator andbiosimilarmAbsorfusionproteinsismoredifficultthanthat requiredforfirst-generationbiosimilars[25,26].Inkeepingwith thesepositions,theEMAandFDAhaverecognizedthedifficultyof assessingsimilaritybetweenmAbproducts,andEMA,in particu-lar,issueddistinctguidelinesforbiosimilarmAbsin2012.While theregulatorypathforcomparabilityexercisehasremained sim-ilartotheoverarchingguidelines,theupdatedguidelinesonmAb biosimilarsrequiremorestringentclinicaltestingand immuno-genicassessment[1].Indeed,theremightberelevantdifferences betweenasecond-generationbiosimilaranditsrespective origi-natorthatcannotbedetecteduntilextendedclinicalstudieshave beencarriedout.Nevertheless,despitesuchacautiousapproach, furtherscrutinyanddiscussionarenecessarytounderstandfully thepotentialimpactofsecond-generationbiosimilarsonclinical outcomesinthepost-marketingsetting.

IthasbeenestimatedthateighttherapeuticmAbswillundergo patentexpirationintheEuropeanUnionandUSbefore2020, mean-ingthatthepharmaceuticalmarketwillbeopenedtotheentryof awidearrayofsecond-generationbiosimilarproducts.Thefirst biosimilarmAb,CT-P13(havinginfliximabasthereference origi-nator)wasauthorisedforclinicalusewithintheEuropeanUnion inSeptember2013[27],anditisnowavailableinmorethan70 countriesworldwide[28].Asubstantialpipelineofbiosimilarsis currentlyunderdevelopment,includingseveralmAbsand some fusionproteins,withover700productsreportedtobeinthe pre-clinicalorclinicalphase[28,29].Inparticular,thenumberofmAbs orfusionproteinscurrentlyunderdevelopmentasbiosimilarsfor treatmentofIMIDsisbeinggreatlygrowing.Consequently,asa relativelynewphenomenon inrheumatology,over80%of com-parativestudies(phaseIII)forbiosimilarshavebeenplannedto bestartedfrom2013onward[30,31].Atpresent,inthesettingof IMIDs,biosimilarsofadalimumab,etanercept,infliximaband rit-uximabhavereachedthestageofclinicaldevelopment,andthe availabledatahavebeenpublishedorpresentedatinternational scientificmeetings[32].Whilethepotentialpharmacoeconomic benefitsand cost-effectivenessof second-generationbiosimilars seemquiteclear,severalpointsofconcernsstillremainpending, anddeservecarefulconsideration.

3.1. Immunogenicity

Unwanted immunogenicity of biologics is a major safety concernduringthedrugdevelopmentphase.Thisissueis acknowl-edgedbyhealthagenciesandthereforetheystronglyrecommend assessingtheimmunogenicityofbiologicsinclinicaltrialsaswell astomonitorpatientsafterdrugapproval[33].TheEMA recog-nizesthat“immunogenicityofmAbsiscomplexandtherearea numberofoftenpoorlyunderstoodfactors,whichmakeitdifﬁcult topredictwithanycertaintywhetheratherapeuticordiagnostic mAbislikelytoprovideaclinicallyrelevantimmuneresponse”[1]. Currentevidencesupportstheviewthattheincidence, characteris-tics,andclinicalconsequencesofimmunogenicity,varygreatlyand thatsuchheterogeneitydependsonmanydifferentfactors[34–37]. Indeed, several product quality attributes have been shown to beofimportanceasdeterminantsofmAbimmunogenicactivity [38,39],suchastheprimaryaminoacidicsequence,thepropensity togeneratemacromolecularaggregates,thepresenceofhost-cell impuritiesintheﬁnalproduct,andtheglycosylationprocess.

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Fur-thermore,smallfluctuationsinthemanufacturingprocess,suchas minorchangesincellculturepH,temperatureandmedia ingredi-ents,mayimpactsignificantlyonthemolecularpropertiesofthe finalproduct,throughtheintroductionofmicro-heterogeneities [40–42].Eventhesmallestchangesinthemolecularshapeofa ther-apeuticproteincanmodifyitssolubilityoritsbiologicalfunctions, orcanevenincreaseitsimmunogenicitybyuncoveringantigenic domainsoveritsmolecule[43–45].Owingtoallthesereasons,the immunogenicityofbiologicsand,consequently,the immunogenic-ityofmAbbiosimilars,incomparisontotheiroriginators,isactually unpredictableand,assuch,itmustbealwayssubjectedtocareful investigationbeforeapprovalaswellastoadequatefollow-upover thepost-marketingphase[6].However,itmustbeacknowledged alsothattheassessmentofimmunogenicityinclinicalstudiesis hamperedbya numberofissues,withparticularregardforthe typesofassaysemployedandtheclinicalmeaningoftheresults intermsofsafetyand/ortherapeuticefficacyofthebiologicdrug [46].Therefore,greatcautionmustbeexercisedwhencomparing theimmunogenicitypatternsofdifferentmAbsonthebasisof dif-ferentassaymethodologies,sincethiscomparisoncouldleadto misleadingconclusions.

3.2. Designofclinicalstudies

PhaseIIIclinicaltrialscomparingbiosimilarswiththeir respec-tivereferenceoriginatorsareclinicalstudiesdesignedtoassess therapeuticequivalence,atvariancewithconventional random-izedcontrolledtrialsthataredesignedtodemonstratesuperiority ofonetreatmentcomparedtoanother.Inthesettingofbiosimilar development,theappropriatedesign oftherapeuticequivalence studies is faced with a number of methodological challenges. When implementing an equivalence study, the classical rigor-ous ‘intention-to-treat’ approach – relying onthe concept that morepatientsleavinganinterventionarmduetotheoccurrence of adverse eventswould representa biasin favor of theother treatment,iftheanalyseswerelimitedonlytothepatientsthat completedtheprotocol–wouldonthecontrarybiastowardthe conclusionthatthebiosimilarisequivalent.Forthisreason,itis rec-ommendedthatequivalencestudiesforbiosimilarsshouldperform ‘perprotocol’analysesandpresenttheirdatawith95%conﬁdence intervalsforadifference,ratherthanwithasinglepvalue.In par-ticular,equivalencecouldbedeclared,accordingtothegenerally acceptedstandard, iftheconﬁdenceintervalsofthecomparator compound(thebiosimilarproduct)liewithin±15%ofthose esti-matedforthereferencecompound(theoriginatorproduct)[47].

Theprimarytherapeuticindicationselectedforthecomparative evaluationof biosimilarsis usuallytheone consideredas sufﬁ-cientlysensitive,oreventhemostsensitiveforsuchevaluation. Commonly,thisisthetherapeuticindicationthat,inthecaseofthe originatorproduct,demonstratedthegreatesteffectsize.However, ithasbeenappreciatedthatusingthemostsensitive therapeu-ticindicationisnotnecessarilytheoptimalchoiceifinvestigators arenotwillingtousetheoriginatorproducttotreatthat indica-tion[7,12,14].Moreover,inhisownguidelines,theWorldHealth Organization(WHO)suggeststhat,ifextrapolationtoother ther-apeuticindicationsisbeingconsideredforabiosimilar[48],the patientpopulationselectedforthecomparativestudyof equiva-lenceshouldbetheonethatcarriesthehighestriskofdeveloping immunogenicresponses,whichmaynotbenecessarilythemost sensitivepopulationintermsofeffectsize.

Anotherissuethatdeservescareful considerationin compar-ative studies for theapproval of biosimilars is the appropriate selectionofendpoints,sincesomeregulatoryauthorities recom-mendtheuseofsufﬁcientlysensitiveendpoints[7,12,14].Avery importantpointofinterestisthat,inequivalencetrialsfor biosim-ilars,primaryendpointsdonothavetobenecessarilyidenticalto

thoseusedfortheregistrativeclinicaltrialsoftheoriginator prod-uct.Indeed,basedonrecommendationsbyregulatoryauthorities, differentadhocprimaryendpointscanbeimplementedtofacilitate thedetectionofrelevantdifferencesbetweentheoriginatorandthe proposedbiosimilar.Inparticular,tobetterassessthetherapeutic equivalenceofbiosimilars,primaryendpointsbasedon continu-ousversusdichotomousmeasureshavebeensuggestedtobemore sensitive.Forinstance,inthesettingofrheumatoidarthritis(RA), theuseof28-joint diseaseactivityscore(DAS28)appearstobe preferabletoresponseratesbasedon20%improvementin Ameri-canCollegeofRheumatology(ACR)criteria(ACR20),andlikewise, inpatientswithpsoriasis, themeanPsoriasisAreaand Severity Index(PASI)is regardedasmore convenientthan the75%PASI responserate[49,50].However,itisnoteworthythat,while com-parisonsandtherapeuticuseofﬁrst-generationbiosimilarsaswell assecond-generationbiosimilarsforIMIDscanrelyonthe assess-mentofrelativelyfastand objectiveclinicalresponses,in other ﬁelds,andparticularlyinoncology,theevaluationofclinical out-comestosecond-generationbiosimilarsisamajorpointofconcern. Indeed,inthesettingofanticancertherapy,includingneoadjuvant treatments,clinicalresponsesmaytakemonthsbeforeallowing objectiveevaluations,andtheydonotalwayscorrelatewithactual improvementsinprogressionfreeoroverallsurvival[51].

Anadditionalpointdeservingconsiderationisthemagnitudeof marginssetouttodeterminetheequivalenceofefﬁcacybetween theproposedbiosimilarandthereferenceoriginatorproduct.Of note,theFDAhasissuedaguidanceforadvisingonthestatistical calculationofequivalence margins,whichappearstobe accept-ablealsototheEMA[52].Accordingly,thestatisticallyestimated marginsshouldbebasedonavailabledatafortheoriginatorin com-parisonwithplaceboorstandardofcaretherapyratherthanan activecontrol.

Withregardfortheassessmentofimmunogenicity,itis note-worthy that several patient- and treatment-related factorscan affectimmunogenicresponsesagainsttherapeuticproteins dur-ingtheimplementationofclinicalstudies[34].Therefore,when startingaclinicalcomparativetrialaimedatmeasuring immuno-genicity,amongsttheotherendpoints,theoptimalstudydesign should beselected depending onthe biosimilarproduct under investigation.First,validatedassaystodetectADAbsareneeded, and,whenADAbsaredetected,theirneutralizingcapacityshould betested,aswell.TheEMAguidelineonimmunogenicity assess-ment ofmAbs intended for in vivoclinical usesuggestsassays basedoncompetitiveligandbindingasthebestchoiceforADAb detectioninpatients’sera[34].Second,thebestpatient popula-tionfor assessingimmunogenicityshouldpossiblybethesame enrolledinapharmacokineticstudyor,forsomemAbs,itcould consistofhealthyvolunteers,whoareknowntodevelopalively immune response following a single dose of biologic within a fewdays [34,39].Third,itis crucialtochoosetheoptimaldose oftheoriginatorandbiosimilarmAbemployedforclinical stud-ies, in orderto maximise theprobability todetect ADAbs.The EMAguidelineonmAbbiosimilarsstatesthat“somemAbsinhibit ADAbformationwhenadministeredathighdoses,andin these cases studies conductedwith low doses canbe more sensitive tocompareimmunogenicityofthemAbbiosimilarandoriginal product”[34].Theguidelinestressesalsotheconceptthatclinical studiesonimmunogenicityareparticularlyimportantwhenthe biosimilarmAbisproducedusingadifferentexpressioncell sys-temascomparedtotheoriginatorproduct,recommendingthat“in someinstances,IgEtestingpriortoclinicaladministrationneeds to be considered for patients if the mAb contains non-human carbohydrate structures(e.g.␣-Gal), in ordertopreventsevere anaphylaxis”[34].

Finally,seekingengagementwithregulatoryauthoritiesearly andoftenisessentialtostreamlineabiosimilardevelopment

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path-way,anditisrecommendedinboththeEMAandFDAguidance documents[7,12,14].

3.3. Extrapolationoftherapeuticindications

TheintrinsiccomplexityofmAbandfusionproteinstructures, theheterogeneityintroducedbysmallchangesin the manufac-turingprocess and thecomplicationsthat might arisewiththe introductionofsecond-generationbiosimilarsintothe pharmaceu-ticalmarketarematterofintensivedebateamongtheexperts,with particularregardfortheissueofextrapolatedtherapeutic indica-tions.Itiswellknownthatmonomericgrowthfactors/hormones orcytokines,endowedwitharelativelysimplepolypeptidic struc-ture,aretypicallyequippedwithasingleactivesitethatbindsthe samereceptororfamilyofreceptorsforeachtherapeutic indica-tion(inthemajorityofcasesthesamereceptor,andtherebythe samemechanismofaction,isinvolvedacrossalltherapeutic indi-cations).Ontheotherhand,mAbs,besidestheirprimarybinding sitesthatinteractwithspecific‘antigenic’moleculartargets,are endowedalsowithadditionalbindingsites,locatedintheir differ-entmoleculardomains(mainlytheFcregion),knowntointeract withdifferentreceptors(e.g.FcRnandFc_␥R)andtoelicitavariety ofdifferent‘ancillary’effects[53–55].Ofnote,thenetcontribution ofeachmodeofactioninhumans,includingantibody-dependent cell-mediatedcytotoxicity(ADCC),complement-dependent cyto-toxicity(CDC) andapoptosis,remains presentlyunknown,even thoughthereisconvincingevidencethatsuchancillaryeffects con-tributeatdifferentextentstotheefficacy(ortolerability)ofmAbs acrosstheirdifferenttherapeuticindications[56,57].Furthermore, itmustbeconsideredthat,particularlyinthefieldofIMIDs, treat-mentregimensofthesamemAborfusionproteincanvaryacross thedifferenttherapeuticindicationsintermsofdosestrength, dos-ingtimeandpossiblecombinationwithtraditionalsmall-molecule drugs(particularlyimmunosuppressants)[6,58].

Whenaddressingtheissueofextrapolationoftherapeutic indi-cation, the 2012 EMA guideline on similar biologic medicinal productscontainingmAbssuggeststhat,ifdifferentmechanisms ofactionareconsideredorsuspectedtoberelevant,“applicants shouldproviderelevantdatatosupportextrapolationtoallclaimed clinicalindications”,includingdiscussionofpublisheddataon anti-genreceptorsandmechanismsofaction,potencyassays,invitro assaysdemonstratingthefunctionalityofthemolecule,andany relevantclinical data[1]. Notably,it hasbeencommented that extrapolationshouldbeconsiderednotasa“bonus”forthe man-ufacturerofthebiosimilar,butratherasacommitmenttoprovide rigorousscientificevidence[59].Inarecentreview,itappearsthat themajorityofbiosimilarsdevelopedfordifferentIMIDsare evalu-atedcomparativelyforefficacy,safetyandimmunogenicityagainst theoriginatorinonlyonetherapeuticindication,withRAbeing themostcommoncondition,followedbypsoriasis[30].Several expertshaveraisedconcernsabouttheoversimplificationof clin-icalbiosimilardevelopment.Inparticular,theyclaimthat,given thatmAbshavecomplexmechanismsofactionthatinmostcases arepoorlyoronlypartlyunderstood,andthattreatmentregimens, studyendpointsandstudypopulationsoftenvaryamong therapeu-ticindications,grantingofextrapolationoftherapeuticindication byregulatoryauthoritiesshouldnotbestraightforward[58–60].It isthereforenotsurprisingthat,inthecaseoftheinfliximab biosim-ilarCT-P13,subjectedtoclinicalevaluationinARandankylosing spondylitis,grantingofmarketingauthorizationforinflammatory boweldiseases(IBDs)bytheEMAandotherregulatoryagencies throughamereextrapolationoftherapeuticindicationhasledto livelydiscussionsquestioningthescientificbasissupportingsucha decision[10,11,61–63].Reassuringly,theNOR-SWITCHtrial,aimed atexaminingefficacy,safety andimmunogenicityfollowingthe switchfromoriginatortobiosimilarinfliximab in patientswith

differentIMIDs,includingCrohndisease,hasshownalackof signif-icantchangesintheparametersoftherapeuticeffectivenessalong withasimilarincidenceofADAbsdetectedduringthestudy:(17 [7.1%]withtheoriginatorand19[7.9%]withthebiosimilar)[64]. 3.4. Pharmacovigilance

Thelimitedexperiencewithsecond-generationbiosimilarsin termsofefficacy,safetyandimmunogenicityatthetimeof reg-ulatoryapproval makesrigorouspharmacovigilanceprogramsa publichealthconcernthatneedstobeaddressedandwell imple-mented,inordertoacquireinformationaboutlong-termpatient safety andoutcomes, aswellas toreassure physicians in their clinicalpractice.Forinstance,ifsubtle,butofpotentialclinical rele-vance,differencesinthepatternsofimmunogenicityareunlikelyto bedetectedduringthedevelopmentofbiosimilarmAbs,the reg-ulatoryauthoritymayrequireadditionalpost-marketingstudies, specificallydesignedtodetectsmalldifferencesin immunogenic-ity. Accordingly,a program ofactive pharmacovigilanceshould beensuredbymeansofpatientregistriessupportedbysponsors and/or interested scientific societies. Additionalpost-marketing safetyassessmenttoolsmightincludealsotargetedquestionnaires, phaseIVstudies,andlong-termfollow-upprograms[65–67].The importanceofarobustpharmacovigilanceplanisemphasizedalso bythelackofaguidanceonwhetherandhowproductdivergence over time shouldberegulated.Indeed, post-marketingchanges introducedbymanufacturersintoanoriginatorand/orits biosim-ilarmayleadtoalong-termlossofsimilarity(divergence)intheir qualityattributes aswellaspharmacologicaland immunogenic properties[68],whichinturnmayresultinalossofequivalence [69,70].

Overall,pharmacovigilanceisofcriticalimportancewhileusing biosimilarsinclinicalpracticeanditisnecessarytocollectsafety dataacrossthedifferentcountriestodetectallsafetysignals. How-ever,atpresent thereisasubstantiallackofconsensusonhow toimplementandmaintainanadequateandeffectivesystemof pharmacovigilanceonbiosimilars[71].

3.5. Otherissues:naming,traceabilityandcosts

Animportantchallengetohealthcareprofessionalsistoavoid confusionamong originatorsand biosimilars, aswellas among differentbiosimilars ofthesameoriginator,toensure appropri-ateprescribingand accuratereporting ofadverse eventsinthe post-marketingphase.Inthisrespect,expertsandcliniciansare increasinglyclaimingthat,inordertoachieveanadequateuseof biologicsintheclinicalpractice,theinternationalnon-proprietary name(INN)shouldnotbeemployedastheonlymeanfortheir identification.Indeed,relyingonacommonnamingsystemof origi-natorsandbiosimilarsmakesitdifficulttoimputeadverseeventsto aspecificmedicinalproduct,withanunavoidablenegativeimpact onadequateregulatoryactionsandsafemanagementofpatients [72].Thisissueisfosteringmuchdiscussion,andseveralsolutions arebeingproposed,includingtheuseofthebrandname,theINN incombinationwiththebrandname,ortheuseofcodes,basedon lettersand/ornumbersasaprefixorsuffixtotheINN,allowinga uniqueidentificationoftheproduct.In2012,theEuropean Com-missionreleasedtheDirective2012/52/EU,which,forallbiologics, includingbiosimilars,establishestheuseofbrandnamestoensure anunambiguousidentificationofbiologicmedicinalproducts[73]. Despiteacknowledgingthatbiosimilarsaresimilar,butnot iden-tical,totheiroriginators,in2013EMAconfirmedthatbiosimilars mustsharethesameINNwiththeiroriginators,while differenti-ations,withparticularregardforpharmacovigilance,shouldrely solelyontheuseofbrandnames[74].Sincethispositionisnot sharedunanimouslybyotherCountries,possiblealternativestothe

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soleuseofINNarebeingconsideredbyacommitteeoftheWorld HealthOrganization,andoneproposalhasbeenthata4-digitcode mightbeadoptedtodifferentiatebiosimilarsfromtheirrespective originators[72].

With specific regard for post-marketing surveillance, what-everbethesolutiontakenforbiologicnaming,itisimportantto considerthat appropriate reportingofadverse eventsfor origi-natorsand biosimilarscannotrelysolely ontheirbrandnames. Indeed,adverseeventsmightstemfrominadvertentchangesin themanufacturingprocessesorstoringconditions,andtherefore itisstronglyrecommendedthat,whenreportingtotheregulatory authority,thebatchnumbershouldbealwaysprovidedin addi-tiontothebrandname[75].However,currentevidencesuggests thatthemajorityofphysiciansmaynotcomplyfullywiththese recommendations.Forinstance,inasurveyonEuropeanandUS pharmacovigilancedatabases,Vermeeretal.[76],whenassessing thereportsofadverseeventstobiologics,observedthat,whilethe largemajorityofphysicianshadprovidedappropriateinformation onbrandnames,veryfewofthemhadtakencareofindicatingbatch numbers,thushamperingthepossibilityofgoingbacktospecific dataonproductionandstoringofthosespecificmedicinalproducts. Anotherimportantissueonthedevelopmentandclinicaluse of biosimilars pertains totheir economic impacton healthcare systems.Currently,worldexpenditureformedicineshasbeen esti-matedtoreach1.4trillionUSdollarsby2020,withupto60%of thispaymentburdeningongovernments.Anumberofcost-saving measureshavebeenthenimplementedworldwidetorestraindrug costs,includingincentivestogenericdruguse.However,sincea substantialportionofglobaldrugexpenditureresultsfrom ther-apieswithbiologics,biosimilarsofferthepromiseofhelpingto achieve substantial cost savings, which might bereinvested to expandtheaccessofpatientstotreatmentswithinnovative biolog-icsortoimprovethequalityofotherhealthcarefacilities.Indeed, consistentlywiththis expectation,intheEuropeanareasavings from2.3to11.7billionEuroshavebeenestimatedforUnited King-dom,GermanyandFranceovertheperiodfrom2007to2020asa consequenceoffirst-generationbiosimilarmarketing[77,78].

Basedoncurrentknowledge,it isexpectedthat evenhigher savings could be achieved with second-generation biologics in theareaofIMIDtherapies.Atpresent,one-yeartreatmentofRA withbiologicsisquitemoreexpensivethanmethotrexate(inUSA: 10,000–30,000USdollarsforbiologicssagainstabout3000US dol-larsforconventionaldiseasemodifyinganti-rheumaticdrugs).In thisrespect,itisnoteworthythat,followingapprovalofthefirst infliximabbiosimilar,somebudget-impactevaluationshave esti-matedthat,in theUnitedKingdom,Germany,Franceand Italy, accordingtothreescenariosof10%,20%and30%discounts,cost savingsofabout96,233and433Eurosmightbeachieved, respec-tively, after switching RA patients to the infliximab biosimilar [77,79].

4. Positionstatementsofmedicalassociations

Severalmedicalsocietiesandotherorganizationshaveissued positionstatementsonbiosimilars.TheItalianSocietyof Rheuma-tology (SIR) has publishedtwo position papers [11,80], one of whichwasissuedjointlywiththeItalianSocietyofDermatology (SIDeMaST)andtheItalianGroupofInflammatoryBowelDisease (IG-IBD).Inbothpapers,theSIRhaspointedoutanumberof criti-cismspertainingtotheapprovalofsecond-generationbiosimilars: 1)clinicaldataarecurrentlyavailableonlyfor RAand ankylos-ingspondylitis,referringtoarelativelysmallnumberofpatients, andthusprovidinginsufficientinformationconcerninglong-term efficacyaswellassafetyandfrequencyofrareadverseevents;2) conversely,directevidenceonefficacy,safetyand

immunogenic-ityofbiosimilarsisstilllackinginpsoriasis,psoriaticarthritisand IBDsas wellas pediatricpatients;3) withregard for immuno-genicity,longerobservationperiodsarerequired,sinceADAbsmay developafterseveraladministrationsandsometimesevenafterone yearoftreatment;4)whenconsideringtheextrapolationof ther-apeuticindications,thereisalackofsufficientscientificevidence supportingautomatictranslationofindicationsfromanoriginator toitsbiosimilar,particularlybecauseofthecomplexanddifferent pharmacologicalmechanism(s)ofactioninthedifferentapproved clinicalindications.Overall,theSIRconcludedthat,giventhe lim-itedknowledgeonefficacyandsafetyofsecond-generationmAbs, itismandatorytosetrules,performadhocclinicaltrialsand imple-mentappropriatedrugsurveillanceprograms.

TheACR, in itspositionstatement,recommended that long-termpost-marketingregistry-baseddatacollectionbeestablished tomonitorforless common,but potentiallyimportant,adverse events,andthatthedecisionofsubstitutingasecond-generation biosimilarproductshouldnot betakenwithoutsupportby the knowledgeofprescribingphysicians[12].

In2013,theEuropeanCrohn’sandColitisOrganization(ECCO) releasedapositionstatementontheuseofbiosimilarsinthe treat-mentofIBD,statingthat“abiosimilarproveneffectiveandsafefor oneindicationmaynotnecessarilybeeffectiveandsafeforasecond indicationforwhichthereferencebiologichasbeenshowntobe safeandeffective”.Furthermore,theorganizationrequested spe-cificstudiesinpatientswithIBD,inordertoestablishefficacyand safetyforthisindication,statingthattheexperiencewith biolog-icshasshownthatefficacyinIBDdoesnotnecessarilycorrelateto efficacyinotherindications,suchasRA[10].However,itisworth mentioningalsothat,basedonearlypost-marketingexperience, theopinionofsomescientificsocieties,suchastheECCO,has grad-uallychanged towardsa moreconfident positionontheuseof second-generationbiosimilars[81].

5. Conclusions

Second-generation biosimilars, namely mAbs and antibody-receptor fusion proteins, differin severalrespects ascompared tofirst-generationones,suchasepoetins,bonemarrow stimulat-ingfactorsandsomatotropins,havingmuchgreaterstructuraland molecularcomplexity,thusraisingnewchallengesfor manufac-turersandregulatoryauthorities,andnewconcernsforclinicians. Despitesomeissuesremainmatterofdiscussion,withparticular regard forlong-termsafety andefficacyandthescientific basis underlyingtheextrapolationoftherapeuticindication,theinitial post-marketingclinicalexperiencewithinfliximabbiosimilarsis showingencouragingresults[82–87].ThewayforbiosimilarmAbs andantibody-receptorfusionproteinsisnowopenandpaved,and wehavetocomplywiththisnewcontext.Whatreallymattersto cliniciansistobeassuredthattheirpatients’treatmentisbased onsolidscientific evidence,obtainedbythemostsensitiveand advancedmethodologies.Robustprogramsofclinicaldevelopment mustberequiredforeachnewagentintendedtobeapprovedas abiosimilarproduct.Eachmarketingapplicationshouldinclude studiessupportingtheuseofthebiosimilardruginthedifferent targetdiseasesandpatientpopulations.Safetymustbeensured alsobyastrictcontrolofthemanufacturingprocessandasolid pharmacovigilanceprogram,withfulltraceabilityandavoidance ofsubstitutionwithoutmedicaldecision.Alltheaboveactionswill helpsettlingallcontroversiesandincreasingtheconfidenceofboth physiciansandpatientsinbiosimilars.

We believethat it remains aresponsibility of thephysician, accordingtoscientiﬁcsocietyguidelines,todrivethe implementa-tionofnewbiosimilarsintoclinicalpractice,whileconcomitantly continuingtosearch forbettertherapeutic approaches.

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Biosim-ilarshave certainlythepotentialofimpactingpositivelyonthe overalltreatmentscenario,allowingsigniﬁcantcostsavings and greateraccessibility tovaluable, effectivetreatments. However, greatresponsibilityandcautionisrequiredbythehealthcare com-munitytoensuretheappropriatedevelopmentandclinicaluseof biosimilars.Likewise,fromaregulatorystandpoint,lessemphasis shouldbe given tosimilarity at detrimentof safety, and over-relianceoncomparativeclinicaldatashould beavoided.In the meantime,additionalclinicalstudiesandtheimplementationof activepost-marketingsurveillancewillhopefullyincrease physi-cians’conﬁdenceinsecond-generationbiosimilars.

Disclosurestatement

CorradoBlandizzi,MauroGaleazziandGuidoValesinireceived anhonorariumfromPﬁzerinconnectionwiththedevelopmentof thismanuscript.

Funding

MedicalwritingandeditorialsupportwasprovidedbyCDMand MariellaD’AndreaM.D.(MedicalDepartment,PﬁzerItalia),andwas fundedbyPﬁzer.

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