Subsequent Entry Biologic Review Report€¦ · Inflectra (CT-P13; infliximab) is a subsequent...

November2017

Drug Inflectra(infliximab)

Indication• AdultswithmoderatelytoseverelyactiveCrohn’sdisease• AdultswithfistulizingCrohn’sdisease• Adultswithmoderatelytoseverelyactiveulcerativecolitis

ListingrequestForeachindication,listinasimilarmannertothepublicplanlistingcriteriaforRemicade

Dosageform(s) Intravenousinfusion(powderforsolution,100mg/vial)

NOCdate June10,2016

Manufacturer Hospira,aPfizerCompany

CommonDrugReviewSubsequentEntryBiologicReviewReport

ThisreviewreportwaspreparedbytheCanadianAgencyforDrugsandTechnologiesinHealth(CADTH).ThroughtheCADTHCommonDrugReview(CDR)process,CADTHundertakesreviewsofdrugsubmissions,resubmissions,andrequestsforadvice,andprovidesformularylistingrecommendationstoallCanadianpubliclyfundedfederal,provincial,andterritorialdrugplans,withtheexceptionofQuebec.Thereportcontainsanevidence-basedclinicaland/orpharmacoeconomicdrugreview,basedonpublishedandunpublishedmaterial,includingmanufacturersubmissions;studiesidentifiedthroughindependent,systematicliteraturesearches;andpatient-groupsubmissions.InaccordancewithCDRUpdate—Issue87,manufacturersmayrequestthatconfidentialinformationberedactedfromtheCDRClinicalandPharmacoeconomicReviewReports.TheinformationinthisreportisintendedtohelpCanadianhealthcaredecision-makers,healthcareprofessionals,healthsystemsleaders,andpolicy-makersmakewell-informeddecisionsandtherebyimprovethequalityofhealthcareservices.Theinformationinthisreportshouldnotbeusedasasubstitutefortheapplicationofclinicaljudgmentwithrespecttothecareofaparticularpatientorotherprofessionaljudgmentinanydecision-makingprocess,norisitintendedtoreplaceprofessionalmedicaladvice.WhileCADTHhastakencareinthepreparationofthisdocumenttoensurethatitscontentsareaccurate,complete,andup-to-dateasofthedateofpublication,CADTHdoesnotmakeanyguaranteetothateffect.CADTHisnotresponsibleforthequality,currency,propriety,accuracy,orreasonablenessofanystatements,information,orconclusionscontainedinthesourcedocumentation.CADTHisnotresponsibleforanyerrorsoromissionsorinjury,loss,ordamagearisingfromorrelatingtotheuse(ormisuse)ofanyinformation,statements,orconclusionscontainedinorimpliedbytheinformationinthisdocumentorinanyofthesourcedocumentation.ThisdocumentisintendedforuseinthecontextoftheCanadianhealthcaresystem.Otherhealthcaresystemsaredifferent;theissuesandinformationrelatedtothesubjectmatterofthisdocumentmaybedifferentinotherjurisdictionsand,ifusedoutsideofCanada,itisattheuser’srisk.Thisdisclaimerandanyquestionsormattersofanynaturearisingfromorrelatingtothecontentoruse(ormisuse)ofthisdocumentwillbegovernedbyandinterpretedinaccordancewiththelawsoftheProvinceofOntarioandthelawsofCanadaapplicabletherein,andallproceedingsshallbesubjecttotheexclusivejurisdictionofthecourtsoftheProvinceofOntario,Canada.CADTHtakessoleresponsibilityforthefinalformandcontentofthisdocument,subjecttothelimitationsnotedabove.ThestatementsandconclusionsinthisdocumentarethoseofCADTHandnotofitsadvisorycommitteesandreviewers.Thestatements,conclusions,andviewsexpressedhereindonotnecessarilyrepresenttheviewsofHealthCanadaoranyCanadianprovincialorterritorialgovernment.ProductionofthisdocumentismadepossiblebyfinancialcontributionsfromHealthCanadaandthegovernmentsofAlberta,BritishColumbia,Manitoba,NewBrunswick,NewfoundlandandLabrador,NorthwestTerritories,NovaScotia,Nunavut,Ontario,PrinceEdwardIsland,Saskatchewan,andYukon.Youarepermittedtomakecopiesofthisdocumentfornon-commercialpurposes,provideditisnotmodifiedwhenreproducedandappropriatecreditisgiventoCADTH.Youmaynototherwisecopy,modify,translate,postonawebsite,storeelectronically,republish,orredistributeanymaterialfromthisdocumentinanyformorbyanymeanswithoutthepriorwrittenpermissionofCADTH.PleasecontactCADTH’sVice-PresidentofCorporateServicesatcorporateservices@cadth.cawithanyinquiriesaboutthisnoticeorotherlegalmattersrelatingtoCADTH’sservices.

CDRSUBSEQUENTENTRYBIOLOGICREVIEWREPORTFORINFLECTRA

iCommonDrugReview November2017

TABLEOFCONTENTSABBREVIATIONS............................................................................................................................................iiEXECUTIVESUMMARY.................................................................................................................................iv1. PRODUCTINFORMATION....................................................................................................................1

1.1 OverviewoftheSEBProduct.....................................................................................................1 1.2 OverviewoftheReferenceProduct..........................................................................................4

2. INDICATIONS.......................................................................................................................................6

2.1 HealthCanada-ApprovedIndications........................................................................................63. MANUFACTURER’SREQUESTEDLISTINGCRITERIA.............................................................................7

3.1 RequestedListingCriteria..........................................................................................................7 3.2 RationaleforRequestedListingCriteria....................................................................................7

4. BIOSIMILARITY....................................................................................................................................8

4.1 QualityInformation...................................................................................................................8 4.2 KeyClinicalStudies....................................................................................................................9 4.3 Pharmacokinetics.....................................................................................................................24 4.4 Immunogenicity.......................................................................................................................25

5. CRITICALAPPRAISALOFCLINICALSTUDIES......................................................................................27

5.1 InternalValidity.......................................................................................................................27 5.2ExternalValidity..........................................................................................................................28

6. EXTRAPOLATIONOFINDICATIONS....................................................................................................30

6.1 Manufacturer’sRationaleforExtrapolation............................................................................30 6.2 HealthCanada’sConclusiononExtrapolation.........................................................................34 6.3 InternationalRegulatoryConclusionsonExtrapolation..........................................................35 6.4 CDRCommentsonExtrapolation............................................................................................36

7. COSTCOMPARISON..........................................................................................................................398. DISCUSSION.......................................................................................................................................429. CONCLUSION.....................................................................................................................................44APPENDIX1:ADDITIONALDATA................................................................................................................45APPENDIX2:DRUGPLANLISTINGSTATUSFORREFERENCEPRODUCT....................................................51APPENDIX3:SUMMARYOFPATIENTINPUT.............................................................................................67REFERENCES...............................................................................................................................................70

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ABBREVIATIONS5-ASA 5-aminosalicylicacidACPM AdvisoryCommitteeonPrescriptionMedicinesADA anti-drugantibodiesADCC antibody-dependentcell-mediatedcytotoxicityAE adverseeventAS ankylosingspondylitisATI anti-infliximabantibodiesCCC Crohn’sandColitisCanadaCD Crohn'sdiseaseCDAI Clinical/Crohn’sDiseaseActivityIndexCDC complement-dependentcytotoxicityCDEC CanadianDrugExpertCommitteeCDR CommonDrugReviewCSR ClinicalStudyReportCTD CommonTechnicalDocumentsDMARD disease-modifyingantirheumaticdrugEAP ExceptionalAccessProgramELISA enzyme-linkedimmunosorbentassayEMA EuropeanMedicineAgencyEU EuropeanUnionFCD FistulizingCrohn'sdiseaseFDA FoodandDrugAdministrationGI gastrointestinalHCP residualhostcellproteinHMW highmolecularweightIBD inflammatoryboweldiseaseIGF-1 recombinantinsulin-likegrowthfactor1IgG1 chimerichuman-murineimmunoglobulinG1IL interleukinIRR infusion-relatedreactionLD50 lethaldose50LOCF lastobservationcarriedforwardLPS lipopolysaccharideLRV log10reductionvalueMAH MarketingAuthorizationHolderMLR mixedlymphocytereactionMMP matrixmetalloproteinaseMSS MayoscoringsystemMTX methotrexateNDS NewDrugSubmissionNK naturalkillerNOC NoticeofCompliancePBMC peripheralbloodmononuclearcell

iiiCommonDrugReview November2017

PBRER periodicbenefit-riskevaluationreportPK pharmacokineticPsA psoriaticarthritisPsO plaquepsoriasisPSUR PeriodicSafetyUpdateReportRA rheumatoidarthritisRCT randomizedcontrolledtrialSAE seriousadverseeventSCCAI SimpleClinicalColitisActivityScoreSD standarddeviationSEB subsequententrybiologicSOC systemorganclassSNDS SupplementalNewDrugSubmissionsTNFalpha solubletumournecrosisfactoralphaTEAE treatment-emergentadverseeventTESAE treatment-emergentseriousadverseeventTGA TherapeuticGoodAdministrationtmTNFalpha transmembranetumournecrosisfactoralphaTNFalpha tumournecrosisfactoralphaTNFR TNFreceptorUC ulcerativecolitisUS UnitedStates

ivCommonDrugReview November2017

EXECUTIVESUMMARY

ApproachtotheReviewTheCADTHCommonDrugReview(CDR)approachtoreviewingInflectrafollowedtheCDRProcedureandSubmissionGuidelinesforSubsequentEntryBiologics(March,2014).TheCDRteamreviewedtheinformationprovidedbythemanufacturerregardingproductinformation,indicationsunderreview,themanufacturer’srequestedlistingcriteria,biosimilarity,extrapolation,andcost.ClinicalStudyReportsandpublishedarticleswerealsoappraised.Reviewersprovidedacriticalappraisaloftheclinicalevidence,adiscussionofextrapolationfromtheindicationsofrheumatoidarthritis(RA)andankylosingspondylitis(AS)toinflammatoryboweldisease(IBD),andanevaluationofcost.ProductInformationInflectra(CT-P13;infliximab)isasubsequententrybiologic(SEB)basedonthereferenceinfliximabproduct(Remicade).InflectrahasbeenapprovedinCanadaforthefollowingindications:• Useincombinationwithmethotrexate(MTX)forthereductioninsignsandsymptoms,inhibitionof

theprogressionofstructuraldamage,andimprovementinphysicalfunctioninadultpatientswithmoderatelytoseverelyactiveRA.

• ReductionofsignsandsymptomsandimprovementinphysicalfunctioninpatientswithactiveASwhohaverespondedinadequatelyto,orareintolerantto,conventionaltherapies.

• Reductionofsignsandsymptoms,inductionofmajorclinicalresponse,andinhibitionoftheprogressionofstructuraldamageofactivearthritis,andimprovementinphysicalfunctioninpatientswithpsoriaticarthritis(PsA).

• Treatmentofadultpatientswithchronic,moderatetosevereplaquepsoriasis(PsO)whoarecandidatesforsystemictherapy.Forpatientswithchronic,moderatePsO,Inflectrashouldbeusedafterphototherapyhasbeenshowntobeineffectiveorinappropriate.

• Reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealingandreductionofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveCrohn'sdisease(CD)whohavehadaninadequateresponsetoacorticosteroidand/oraminosalicylate.Inflectracanbeusedaloneorincombinationwithconventionaltherapy.

• TreatmentoffistulizingCD(FCD),inadultpatientswhohavenotrespondeddespiteafullandadequatecourseoftherapywithconventionaltreatment.

• Reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealing,andreductionoreliminationofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveulcerativecolitis(UC)whohavehadaninadequateresponsetoconventionaltherapy(i.e.,aminosalicylateand/orcorticosteroidand/oranimmunosuppressant).

ThemanufacturerisrequestingthatInflectrabereimbursedforadultswithCD,FCD,andUC.TheindicationsforRA,AS,PsO,andPsAwerepreviouslyreviewedbyCDRin2015.ClinicalEvidenceCT-P13PMS(post-marketingsurveillance)isanongoing(fouryear)phaseIV,open-label,singlearmstudyofCT-P13forallapprovedindicationsinSouthKorea.AninterimanalysiswasconductedinadultswithmoderatelytoseverelyactiveCD(N=83),FCD(N=12),andmoderatelytoseverelyactiveUC(N=78)across15studycentresinSouthKoreawithfollow-upof30weeks.CT-P13wasadministeredevery8weeks(±5days)afterinductiontherapyofthree5mg/kgdosesatweeks0,2,and6.Mostpatients(59.0%)receiveddosesof5mg/kg.Higherdosesof5mg/kgto10mg/kgwereadministeredto

vCommonDrugReview November2017

41%ofpatients.TheefficacyanalysissetconsistedofpatientswhoreceivedatleastonedoseofCT-P13andhadatleastoneassessmentfollowingbaseline(N=145,83.8%).Allpatientswereincludedinthesafetyanalyses.Outcomesofclinicalresponse,remission,diseasecontrol,needforrescuemedication,andsafetywerereportedforpatientswithCD,FCD,andUCaswellasmucosalhealingforpatientswithUC.Basedonlastobservationcarriedforward(LOCF)imputation,amongCDinfliximab-naivepatients,31/39(79.5%)achievedclinicalresponseand23/39(59.0%)achievedclinicalremissionatweek30.AmongCDpatientswhowereswitchedfromRemicadetoCT-P13,25/31(80.6%)achievedremissionthroughoutvisitstwotosixand27/31(87.1%)patientsdidnotexperiencediseaseworsening.InFCDinfliximab-naivepatients,2/6(33.3%)achievedclinicalresponseand1/6(16.7%)achievedclinicalremission.InFCDpatientsswitchedfromRemicadetoCT-P13,clinicalremissionanddiseasecontrolwasachievedinonlyonepatientatvisitsix.InUCinfliximab-naivepatients,39/54(72.2%)achievedclinicalresponseand20/54(37.0%)achievedclinicalremissionatweek30.AmongUCpatientswhowereswitchedfromRemicadetoCT-P13,5/11(45.5%)achievedremissionthroughoutvisitstwotofiveandnopatientsexperienceddiseaseworsening.BasedoncompletecaseanalysisofUCinfliximab-naivepatients,9/13(69.2%)experiencedmucosalhealingatweek30while6/9(66.7%)patientswhowereswitchedfromRemicadetoCT-P13experiencedmucosalhealingthroughoutvisitstwotofive.ThemanufactureralsosubmitteddatatoHealthCanadasuggestingsimilarincidencesofclinicalresponseandremissionatweeks14and30forCDandUC,andmucosalhealingforUC,amongtreatment-naivepatientsintheCT-P13PMSstudyandpatientsfrompreviouslyconductedRemicadestudies.Atotalof51treatment-emergentadverseevents(TEAEs)in38patientsoccurredinCT-P13PMS.TherewerenonotabledifferencesinTEAEsbetweenpatientswhowereinfliximab-naive(23.9%)andthosewhoswitchedfromRemicade(18.3%).Nomalignancies,pneumonia,deaths,oranyothereventsofspecialinterestwereobservedduringthe30-weekinterimperiod.TheCT-P13PMSstudyislimitedbyitsuncontrolledobservationaldesign,smallsamplesize,absenceofimportantefficacyoutcomes,suchasextra-intestinalmanifestations,diseasebiomarkers,qualityoflife,andimmunogenicity,andshortdurationoffollow-up(30-weekinterimanalysis).ThegeneralizabilityoftheobservedoutcomesinpatientsfromSouthKoreatoCanadianpatientswithIBDisuncertain.OtherStudies:CT-P134.1isasmall(N=20)phaseIV,ongoing(fouryear),open-label,singlearmstudyconductedinadultpatientswithCDorUCinSouthKorea.Aninterimanalysisofefficacyandsafetyin10patients(vvvvvvvvvvvvvvv)fromvvvstudycentreswasavailableforreview.OtherobservationalstudiesofCT-P13inIBD,notsponsoredbythemanufacturer,havebeenconductedincohortsfromNorway,Hungary,theCzechRepublic,andKorea.Themanufacturerconductedasystematicliteraturesearchofrandomizedcontrolledtrials(RCTs)andobservationalstudiesofthereferenceproductRemicade,inpatientswithCDandUC.Ratesofinfusion-relatedreactions(IRRs),infections,pneumonia,tuberculosis,malignancies,andneedforsurgeryorhospitalizationwerecomparedwithratesfromobservationalstudiesofCT-P13(PMS+non-Celltrionsponsoredstudies).SafetydataweregenerallysimilarbetweenCT-P13andthereferenceproduct,Remicade,intreatment-naiveandswitchedpatientscombinedforIRRs,pneumonia,tuberculosis,andmalignancies.ThereweresomedifferencesbetweenRemicadeandCT-P13fortheratesofinfection,ratesofsurgery,anddisease-relatedhospitalization;however,theinterpretationofthedataislimitedduetothedifferencesinstudydesign,studypopulations,andoutcomedefinitions.Overall,datafromcumulativepost-marketingpatientexposuretoCT-P13fromOctober2013toDecember2015suggestthatnonewsafetysignalshaveemerged.

viCommonDrugReview November2017

ExtrapolationCT-P13(Inflectra)receivedmarketauthorizationinCanadainJanuary2014fortheindicationsofPsOandPsAbasedontheextrapolationofevidencefromstudiesconductedinpatientswithRAandAS.ExtrapolationwassupportedbysimilaritiesinthepathologyofRA,AS,PsA,andPsOandthemechanismofactionofalltumournecrosisfactoralpha(TNFalpha)blockersintheseindications.InJune2016,HealthCanadaapprovedCT-P13foradultCD,FCD,andUC.TheEuropeanMedicinesAgency(EMA),theFoodandDrugAdministration(FDA),andtheAustralianTherapeuticGoodsAdministrationhavealsoapprovedCT-P13forCDandUC.InHealthCanada’sinitialreviewofCT-P13forallindications,someconcernsaboutextrapolatingdatafromstudiesconductedinpatientswithRAandAStoIBDwerementioned.TheseincludeddifferencesindiseasemechanismsbetweenrheumaticandboweldiseasesandhigherriskofhepatosplenicT-celllymphomainpatientswithIBDtreatedwithinfliximab.ThepredominantformofTNFinRAandASissolubleTNFalpha(sTNFalpha);whereas,inCDandUC,transmembraneTNFalpha(tmTNFalpha)playsanadditionalandcentralrole.Also,unlikeRAandAS,inboweldiseasesantibody-dependentcell-mediatedcytotoxicity(ADCC)isanimportantmechanismofactionandismediatedbyafucosylationandFcγIIIareceptorbinding.MinordifferenceshavebeenobservedbetweenCT-P13andthereferenceproductinFcγIIIabindingandADCCactivityusinginvitroassayswithnaturalkiller(NK)cellsfrompatientswithCDandV/VorV/FFcγIIIagenotype(nodifferenceobservedwithF/Fgenotype).Inotherassaysusingperipheralbloodmononuclearcells(PBMCs)frompatientswithCDandV/ForF/FFcγIIIagenotype,nodifferenceinADCCactivitywasobserved.InJune2016,HealthCanadaauthorizedtheuseofCT-P13fortheIBDindicationsbasedonextrapolationfrompreviouslysubmittedclinicalstudiesinpatientswithRAandAS,comparablepharmacokinetics,andnewlysubmittedphysiochemicalandbiologicaldata.1OtherconsiderationsfortheextrapolationofdatabetweenRAandAS,andIBD,includedifferencesintreatmentstrategiesbetweentheindications,suchastheuseofconcomitantmedication,andthehigherdoses(>5mg/kg)ofCT-P13thatmaybeused.InCT-P13PMS,41%ofpatientsreceiveddoseshigherthan5mg/kgofCT-P13andnonotabledose-dependentdifferencesinthedistributionofTEAEswereobservedbetweenpatientswhoreceived5mg/kgorpatientswhoreceived>5mg/kg.However,theimmunogenicsimilarityofthehigherdosecomparedwitharegularorhigherdoseofRemicadeisuncertain.CostComparisonThemanufacturer’ssubmittedpriceforInflectra($525.00per100mgvial)is47%lowerthanthepriceofinfliximab($987.56per100mgvial),whenusingtheOntarioExceptionalAccessProgram(EAP)priceforinfliximab.ClinicalExpertComments1Theclinicalexpertconsultedforthisreviewnotedthatbothprivateandpublicdrugplanshaveguidelinesinplacethatstipulatewhichpatientsareeligiblefortreatmentwithanti-TNFdrugs,andCT-P13willfitwithinthatframework.Theexpertindicatedthatanimportantquestion,whichwillneedtobeaddressedifthedrugisintroduced,iswhetherpatientswhoarestableonthereferenceproduct,

1 ThisinformationisbasedoninformationprovidedindraftformbytheclinicalexpertconsultedbyCDRreviewersforthepurposeofthisreview.

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Remicade,willhavetheirtreatmentsubstitutedwithCT-P13orwhetheritwillonlybeusedintreatment-naivepatients.Endoscopicevaluationofdiseaseactivitymayberequiredinpatientswhoexperienceadiseaseflareafterswitching,andtherearesignificantbarrierstothatintermsofaccesstoendoscopy.Currently,limitedevidenceisavailabletoassessandpredictpatientresponsetoswitchingfromRemicadetoCT-P13.ConclusionCT-P13providescliniciansandpatientswithanotherpotentiallycost-effectivechoiceofabiologicaldrugforIBD.ThefocusofthisCDRreviewofCT-P13(Inflectra)isfortherecentlyapprovedindicationsofCD,FCD,andUCinadultpatients.TheNoticeofCompliance(NOC)fortheCD,FCD,andUCindicationswasgrantedsubsequenttoanearlierNOCforCT-P13fortheindicationsofRA,AS,PsO,andPsA.Ofnote,HealthCanadaapprovedtheindicationsofPsOandPsAbasedontheextrapolationofdatafromstudiesconductedwithpatientswithRAandAS.AllclinicalevidencecurrentlyavailableforCT-P13inpatientswithIBDisbasedonobservational,open-labelstudiesfromKoreaorEuropeinsmallnumbersofpatients.Thepivotalstudy,CT-P13PMS,isanobservational,open-labelstudyconductedinSouthKoreainpatientswithIBD,witha30-weekinterimanalysis.NaiveindirectcomparisonsofCT-P13withstudiesofRemicade(infliximab)suggestsimilarefficacyandsimilarsafetyforsomesafetyendpointsinpatientswithCDorUC.Nonetheless,intheabsenceofdatafromRCTs,theclinicalsimilarityofCT-P13andRemicadeforIBDintheCanadianpopulationremainsuncertain.GiventhattheresultsofCT-P13PMSarebasedonaninterimanalysis,theongoingmonitoringofCT-P13inpatientswithIBDwillbeimportantforevaluatinglong-termefficacyandsafety.Note:Referencesinsquarebrackets[]indicatethereferencescitedbythemanufacturer,whilethereferencescitedbyCDRareindicatedbysuperscripts.

1CommonDrugReview November2017

1. PRODUCTINFORMATION1.1 OverviewoftheSEBProductHospirahasaco-exclusivedistributionagreementinplacewithCelltrionHealthcareCorporationwherebyCelltrionHealthcareCorporationisthemanufactureroftheinfliximabbiosimilarCT-P13,whichismarketedundertheTradenameINFLECTRA®orREMSIMA®.CelltrionHealthcareCorporationistheMarketingAuthorizationHolder(MAH)forREMSIMA®(infliximab;CT-P13)inanumberofterritoriesandHospiraistheMAHforINFLECTRA®(infliximab;CT-P13)inanumberofterritories,someofwhichoverlapwithCelltrionHealthcareCorporation.Inthefollowingsectionsofthistemplate,CT-P13,INFLECTRA®andREMSIMA®allrefertothesamemolecule,theinfliximabbiosimilarmanufacturedbyCelltrion.InCanada,HospirahasacquiredtherighttomarketanddistributeINFLECTRA®(infliximab;CT-P13)fromCelltrionHealthcareCorporation.Characteristics Manufacturer-ProvidedDetails

INFLECTRA® REMICADE®Brandname: INFLECTRA® REMICADE®Non-proprietaryname: Infliximab InfliximabManufacturer: HospiraHealthcareCo. JanssenInc.Strength(s): 100mg/vial 100mg/vialDosageform: PowderforSolution,Sterile,

LyophilizedPowderforSolution,Sterile,Lyophilized

Routeofadministration: IntravenousInfusion IntravenousInfusionDrugIdentificationNumber(s): 02419475 02244016Therapeuticclassification: BiologicalResponseModifier BiologicalResponseModifierExcipients Sucrose,sodiumdihydrogen

phosphatemonohydrate,di-sodiumhydrogenphosphatedihydrate,polysorbate80.Nopreservativesarepresent.

Dibasicsodiumphosphatedihydrate,monobasicsodiumphosphatemonohydrate,polysorbateandsucrose.Nopreservativesarepresent.

Impuritiesa Product-relatedHighmolecularweightspecies:vvvvvvvvvvvOthers:seeTablebelowProcess-relatedResidualhostcellprotein:vvvvvvResidualhostcellDNA:vvvvv(max)ResidualProteinA:vvvvvvvvvvvvvvvOthers:seesectionbelow

Product-relatedHighmolecularweightspecies:vvvvvvvvvvvOthers:seeTablebelowProcess-relatedNotavailable,seeexplanationattheendofthissection

Source:INFLECTRA®andREMICADE®productmonographsaIncludebothproductandprocess-relatedimpurities.PleasenotethattherehavebeennochangestothemanufacturingofINFLECTRA®sincetheNewDrugSubmission(NDS)wasfiledtoHealthCanadain2012,andsubsequentNOCgrantedin2014fortheRA,AS,PsAandPsOindications.Thismeansthat,fortheconsiderationofthecurrentCDRsubmissionfortheindicationsofCDandUC,thepharmaceuticalform,composition,dosageform,strength,routeofadministration,purityandimpuritiesforINFLECTRA®remainthesameasdescribedinthefirstCDRINFLECTRA®submissionandpositiverecommendationin2014fortheRA,AS,PsAandPsOindications.

Therefore,fortheremainderofSection1.1ofthetemplate,thesameinformationthatwassubmittedintheoriginalINFLECTRA®CDRsubmissionisbeingincluded.Asfortheproduct-relatedimpurities,itwastestedinthe3-waysimilaritystudiesandtheresultsareinlinewithwhatwassubmittedintheoriginalCDRsubmission(CTDModule3.2.R).Ifmoredetailsarerequiredonthissection,theINFLECTRA®submissionfrom2014shouldbeconsulted.Pharmaceuticalform:chimerichuman-murineimmunoglobulinG1(IgG1)monoclonalantibody

Pharmaceuticalcomposition:astheformulationofINFLECTRA®wassetidenticaltothatofREMICADE®,thedosageformforbothproductscontain100mginfliximab,500mgsucrose,0.5mgpolysorbate80,2.2mgsodiumdihydrogenphosphatemonohydrateand6.1mgdi-sodiumhydrogenphosphatedihydrate.Nopreservativesarepresent.

Dosageform:bothINFLECTRA®andREMICADE®arethesamedosageform,namelyformulatedaswhitelyophilizedpowder.

Strength:bothINFLECTRA®andREMICADE®aresuppliedin100mgvialstobereconstitutedwith10mLsterilewaterresultinginafinalconcentrationof10mg/mL.Forbothproducts,thetotaldoseofthereconstitutedproductmustbefurtherdilutedto250mLwith0.9%SodiumChlorideInjectionUSP.

Routeofadministration:bothINFLECTRA®andREMICADE®areadministratedviaintravenousinfusion.(PleasebeadvisedthatintheREMICADE®productmonograph(p.3),routeofadministrationislistedasi.v.injection,however,infusioniscitedintheremainingofthedocument).

Purityandimpurities:Product-relatedimpuritiesProduct-relatedimpuritiesinclude:oxidizedvariants,deamidatedvariants,C-terminallysinevariants,glyco-variants,highmolecularweight(HMW)speciesaswellasmolecularfragments.Asummaryoftheresultsforproduct-relatedimpuritycomparisonbetweenINFLECTRA®drugproductandREMICADE®arepresentedinthetablebelow.Impurity TestMethod ResultsOxidizedvariants

PeptideMapping(liquidchromatography-mass-spectrometry;LC-MS)

• Basedontheavailabledata,itcanbeconcludedthatonlyverylowandcomparableamountsofoxidizedmolecularvariantsarepresentinIFTdrugproductandREMICADE®.

Deamidatedvariants

Ion-exchangechromatography-highperformanceliquidchromatography(IEC-HPLC)

• vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv

C-lysineterminalvariants

IEC-HPLC • ItwasdemonstratedthatthedifferenceobservedbetweenINFLECTRA®andREMICADE®withrespecttotherelativeproportion(peakratio)ofthe6IEC-HPLCpeaksisattributabletoC-terminallysinevariability.

• However,ithasbeenshownthatC-terminallysinevariabilityholdsnobearingonbiologicalactivityinvitro,andthatC-terminallysineclippingoccursrapidlybothinvitroandinvivo,suggestingthatnearlyallinfliximabmoleculesarefullyclippedwithinseveralhoursfollowingdosing.

Impurity TestMethod ResultsGlyco-variants

SiteSpecificandN-LinkedGlycanAnalysisbyMeansofLC-MSPeptideMapping;OligosaccharideProfiling;MonosaccharideAnalysis;SialicAcidAnalysis

• Asparagine300wasshowntobetheonlysiteofN-glycosylationforbothINFLECTRA®andREMICADE®.NoO-linkedglycansweredetected,asonemightexpectforanIgG1monoclonalantibody,forINFLECTRA®ortheREMICADE®.

• BothINFLECTRA®drugproductandREMICADE®wereshowntocontainmostlyG0FandG1Fstructures.MinorspeciesincludingMan5,G2F,G0FminusN-acetylglucosamine,andG0weredetected.

• HPAEC-PADdatarevealthatthetypeandproportionoftheunchargedglycansisconservedbetweenINFLECTRA®andtheREMICADE®.

• Theidentifiedsugarswerevvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv;bothINFLECTRA®andREMICADE®hadsimilarmolarratiosforthe4sugars.

• ThemolarratioofneutralandaminosugarswasobservedtobehighlysimilarforINFLECTRA®drugproductandREMICADE®.

• INFLECTRA®samplescontainthesametypeaswellashighlysimilarlevelsofsialicacid(expressedasmolarratios)whencomparedtoREMICADE®.

Highmolecularweightspecies

Sizeexclusionchromatography(SEC)-HPLC

• INFLECTRA®drugproductandREMICADE®samplescontainprominentlymonomerdrugsubstancewithinacomparablerange(vvvvvvvvvvvvvvvvvvvvvvvvvvvvv,respectively).Theimpuritiesarehighmolecularweightspecies,whichareallvvvvacrossbothINFLECTRA®andREMICADE®products.

Molecularfragments

Capillaryelectrophoresissodiumdodecylsulfate(CE-SDS)(Reduced/Non-Reduced)

• INFLECTRA®andREMICADE®displaythesametypesofIgGfragments.

• INFLECTRA®drugproductandREMICADE®havesimilaramountofintactIgG(vvvvvvvvvvvvvvvvvvvvvvvvv,respectively)

Process-relatedimpuritiesProcess-relatedimpuritiesinclude:residualhostcellprotein(HCP),hostcellDNA,residualProteinA,recombinantInsulin-LikeGrowthFactor1(IGF-1),recombinanthumaninsulinandPluronicF-68.Abriefsummaryoftheseresultscanbefoundbelow.i. IntermsofHCP,thelevelthatwasdetectedacrossvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv

vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvisgenerallyconsideredasanacceptablelevelfortherapeuticproteins.

ii. ThelevelofresidualhostcellDNA,vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv,belowtheacceptancecriterionof≤4ppb(pg/mg)atrelease.

iii. TherangeofresidualProteinAvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv,belowthelimitof≤4ppm(ng/mg).

iv. TheabilityoftheINFLECTRA®purificationprocesstoclearIGF-1andrecombinantinsulinwasevaluatedaspartofaspikingstudy.Thestudydemonstratedthatthecapabilityofclearancebyspecificachromatographyvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv(Log10reductionvalue)forIGF-1andvvvvvvvvvvvvvvvvv.

v. vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv

vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.

ForREMICADE®,theprocess-relatedimpuritiesandtheirclearanceisspecifictoeachmanufacturingprocess,therefore,Celltrion(manufacturerofINFLECTRA®)doesnothaveinformationonthemanufacturingprocessofREMICADE®andthetestsusedtodemonstrateclearanceoftheimpuritiesinthatprocess.ItisalsotechnicallyinappropriatetoapplyaCelltrionimpuritiestesttoREMICADE®togeneratethisdata.Theapproachisthereforeforthebiosimilarcompanytodevelopthemanufacturingprocessandcontrolstrategytoremoveprocess-relatedimpuritiesandtomaintaintheimpuritiesatthelowestpossibleleveltomeettheregulatoryrequirement.Process-relatedimpuritiessuchasresidualhostcellprotein,residualDNA,andendotoxinallfitthisapproach.Duetothesereasons,therearenoregulatoryagenciesrequestingthiscomparativeanalysis.1.2 OverviewoftheReferenceProductThereferenceproductdescribedinthissubmissionisREMICADE®(Infliximab;PowderforSolution,Sterile,Lyophilized,100mg/vial).REMICADE®iscurrentlyauthorizedforsaleandmarketinginCanada(DIN:02244016).TheinfliximabdrugsubstanceisachimericIgG1κantibody1328aminoacidsinlengththatiscomposedofhumanconstantandmurinevariableregions.InfliximabneutralizesthebiologicalactivityofhumanTNFαbybindingwithhighaffinitytothesolubleandtransmembraneformsofTNFα(sTNFα,andtmTNFα)andinhibitstheirbindingtoTNFreceptors(TNFRs).InCanada,REMICADE®(infliximab)isindicatedfor:1. useincombinationwithMTXforthereductioninsignsandsymptoms,inhibitionoftheprogression

ofstructuraldamageandimprovementinphysicalfunctioninadultpatientswithmoderatelytoseverelyactiveRA.

2. thereductionofsignsandsymptomsandimprovementinphysicalfunctioninpatientswithactiveASwhohaverespondedinadequately,orareintolerantto,conventionaltherapies.

3. reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealingandreductionofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveCDwhohavehadaninadequateresponsetoacorticosteroidand/oraminosalicylate.REMICADE®canbeusedaloneorincombinationwithconventionaltherapy.

4. reductionofsignsandsymptomsandinductionandmaintenanceofclinicalremissioninpediatricpatientswithmoderatelytoseverelyactiveCDwhohavehadaninadequateresponsetoconventionaltherapy(corticosteroidand/oraminosalicylateand/oranimmunosuppressant).ThesafetyandefficacyofREMICADE®isnotestablishedinpatientslessthan9yearsofage.

5. treatmentofFCD,inadultpatientswhohavenotrespondeddespiteafullandadequatecourseoftherapywithconventionaltreatment.

6. reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealing,andreductionoreliminationofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveUCwhohavehadaninadequateresponsetoconventionaltherapy(i.e.,aminosalicylateand/orcorticosteroidand/oranimmunosuppressant).

7. reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremission,andinductionofmucosalhealinginpediatricpatientswithmoderatelytoseverelyactiveUCwhohavehadaninadequateresponsetoconventionaltherapy(i.e.,aminosalicylateand/orcorticosteroidand/oranimmunosuppressant).ThesafetyandefficacyofREMICADE®havenotbeenestablishedinpatientslessthan6yearsofage.

8. reductionofsignsandsymptoms,inductionofmajorclinicalresponse,andinhibitionoftheprogressionofstructuraldamageofactivearthritis,andimprovementinphysicalfunctioninpatientswithPsA.

9. treatmentofadultpatientswithchronicmoderatetoseverePsOwhoarecandidatesforsystemictherapy.ForpatientswithchronicmoderatePsO,REMICADE®shouldbeusedafterphototherapyhasbeenshowntobeineffectiveorinappropriate.Whenassessingtheseverityofpsoriasis,thephysicianshouldconsidertheextentofinvolvement,locationoflesions,responsetoprevioustreatments,andimpactofdiseaseonthepatient’squalityoflife.

2. INDICATIONS

2.1 HealthCanada-ApprovedIndicationsIndication(s) Extrapolation• useincombinationwithmethotrexateforthereductioninsignsand

symptoms,inhibitionoftheprogressionofstructuraldamageandimprovementinphysicalfunctioninadultpatientswithmoderatelytoseverelyactiverheumatoidarthritis.

• thereductionofsignsandsymptomsandimprovementinphysicalfunctioninpatientswithactiveankylosingspondylitiswhohaverespondedinadequately,orareintolerantto,conventionaltherapies.

• reductionofsignsandsymptoms,inductionofmajorclinicalresponse,andinhibitionoftheprogressionofstructuraldamageofactivearthritis,andimprovementinphysicalfunctioninpatientswithpsoriaticarthritis.

• treatmentofadultpatientswithchronicmoderatetosevereplaquepsoriasiswhoarecandidatesforsystemictherapy.Forpatientswithchronicmoderateplaquepsoriasis,INFLECTRA®shouldbeusedafterphototherapyhasbeenshowntobeineffectiveorinappropriate.Whenassessingtheseverityofpsoriasis,thephysicianshouldconsidertheextentofinvolvement,locationoflesions,responsetoprevioustreatments,andimpactofdiseaseonthepatient’squalityoflife.

• reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealingandreductionofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveCrohn’sdiseasewhohavehadaninadequateresponsetoacorticosteroidand/oraminosalicylate.INFLECTRA®canbeusedaloneorincombinationwithconventionaltherapy

• treatmentoffistulizingCrohn’sdisease,inadultpatientswhohavenotrespondeddespiteafullandadequatecourseoftherapywithconventionaltreatment.

• reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealing,andreductionoreliminationofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveulcerativecolitiswhohavehadaninadequateresponsetoconventionaltherapy(i.e.,aminosalicylateand/orcorticosteroidand/oranimmunosuppressant).

3. MANUFACTURER’SREQUESTEDLISTINGCRITERIA

3.1 RequestedListingCriteriaRequestedListingCriteria• ListinasimilarmannertothepublicplanlistingcriteriaforREMICADE®.• Alternatively:reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremission

andmucosalhealingandreductionofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveCrohn’sdiseasewhohavehadaninadequateresponsetoacorticosteroidand/oraminosalicylate.INFLECTRA®canbeusedaloneorincombinationwithconventionaltherapy.

• ListinasimilarmannertothepublicplanlistingcriteriaforREMICADE®.• Alternatively:treatmentoffistulisingCrohn’sdisease,inadultpatientswhohavenotresponded

despiteafullandadequatecourseoftherapywithconventionaltreatment.• ListinasimilarmannertothepublicplanlistingscriteriaforREMICADE®.• Alternatively:reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremission

andmucosalhealing,andreductionoreliminationofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveulcerativecolitiswhohavehadaninadequateresponsetoconventionaltherapy(i.e.,aminosalicylateand/orcorticosteroidand/oranimmunosuppressant).

3.2 RationaleforRequestedListingCriteriaTheover-archingrationalefortherequestedlistingcriteriaforallindicationslistedbelowisbasedontheprincipleofdemonstratedbiosimilaritybetweenINFLECTRA®andthecurrentlyreimbursedreferencemedicinalproduct,REMICADE®.First,theformulationofINFLECTRA®hasbeendesignedtoreplicatethatofREMICADE®andbothdrugproductsareidenticalwithrespecttostrength,pharmaceuticalform,routeofadministration,andcompositioninexcipients(seeSection1.1above).Second,theactivesubstanceofINFLECTRA®,infliximab,hasbeendevelopedasasimilarbiologicalmedicinalproducttothatoftheactivesubstanceofREMICADE®(infliximab).Specifically,anextensiveseriesoforthogonalmethodsweredesignedtocomparethephysiochemicalpropertiesaswellasthebiologicalactivitiesofINFLECTRA®andREMICADE®,andresultsclearlydemonstratedthattheactivesubstanceishighlysimilarbetweenthesetwoproducts(seeSection4.1fordetailedinformation).In2014,theCanadianDrugExpertCommittee(CDEC)issuedapositiverecommendationforINFLECTRA®forthePsAandPsOindicationsviaextrapolation.Similarly,thedatatosupporttheCDandUCindicationsforINFLECTRA®viaextrapolationisbasedonthetotalityoftheevidencecollectedfromthequality,non-clinical,andclinicalcomparabilityexercise.PleaseseebelowinSection6forManufacturer’srationale,aswellasInternationalRegulatoryConclusionstosupporttheCDandUCindicationsviaextrapolation.Currently,infliximab(REMICADE®)isreimbursedbyallCDR-participatingdrugplansacrossthecountryforthetreatmentofCD(seeAppendix2).Consequently,weanticipatethatINFLECTRA®willalsobereimbursedunderthesameclinicalcriteriaasREMICADE®fromtheseCDR-participatingdrugplans,assumingthattheCDECissuesapositiverecommendationforINFLECTRA®forCD.Currently,5oftheCDRparticipatingdrugplansreimburseinfliximab(REMICADE®)fortheUCindication.Inthese5provinces,weanticipateINFLECTRA®willalsobereimbursedunderthesameclinicalcriteriaasREMICADE®,assumingthattheCDECissuesapositiverecommendationforINFLECTRA®forUC.

TheCDR-participatingdrugplansthatdonotcurrentlyreimburseREMICADE®forUCmayfindthatsignificantcostsavingsassociatedwithusingINFLECTRA®maytakethisopportunitytoexpandtreatmentoptionstothepatientswhorequiretreatmentforthisindication.AssumingapositiveHealthCanadaandCDECrecommendationfortheseindications,therequestedlistingcriteriaarereasonableandjustified.

4. BIOSIMILARITY4.1 QualityInformationAproductcharacterizationexercisewasconductedpreviouslyusingarangeofstate-of-the-artmethodologiestodemonstratecomparabilitybetweenCT-P13andEuropeanUnion(EU)approvedREMICADE®.Theresultsofthese2-waysimilaritystudiescomparingCT-P13withEU-approvedREMICADE®werepresentedinthepreviousCDRsubmissionin(CTDModule3.2.R.5)oftheinitialSubmission.Subsequently,awiderangeoforthogonaltestmethodswereperformedtodeterminecomparabilityofCT-P13andREMICADE®ina3-waystudy(CTDModule3.2.R-reg-infodocument)usingEUandUnitedStates(US)approvedREMICADE®.Thesestudiesincludedanextensivecomparativeanalysisofprimary,secondaryandtertiarystructure,glycanprofilesandofpost-translationalmodificationsaswellascomparativestabilitystudies.Inaddition,manybiologicalassayshavebeenincludedtoevaluatesimilarityinallbiologicalactivitiesassociatedwithknownandputativefunctionsandtherapeuticeffects.Theanalyticalmethodsandbiologicalassaysusedinsimilaritystudieshavebeensuitablyvalidatedorqualifiedtoprovideahighlevelofassurancethatthemethodscoulddetectanyslightdifferencesandarescientificallysound,fitforpurpose,reliableandreproducible.Similaritywaspreviouslydemonstratedintermsofprimarystructure,secondaryandhigherorderstructureaswellassimilardisulfidebonding.ThisinformationwasincludedintheoriginalCDRSubmissionforINFLECTRA®aspartoftheCommonTechnicalDocuments(CTD).Foreaseofreference,thesameCTDdocumentsareincludedinthissection,andtheinformationcanbefoundintheCTD3.2.R-regdocument(Modules3.2.R.2.2,3.2.R.2.3.1,3.2.R.2.3.2,3.2.R.2.3.3,3.2.R.2.3.4,3.2.R.2.3.5and3.2.R.2.3.6).BelowisasummaryofkeyfindingsrelatedtoqualityattributesaswellasbiologicalactivitiesinrelationtoCDandUC:Qualityattributes:Asimilarglycosylationprofilewithminordifferencesinafucosylatedglycans(G0+Man5),whichresultsinalowerbindingaffinitytoFcγRIIIaandaloweractivityinthemostsensitiveADCCassayusingNKcellsaseffectorcellsandtmTNFαJurkattargetcellswasobservedforCT-P13.TheimpactofthelowerlevelofafucosylatedglycansinCT-P13hasbeencomprehensivelyinvestigated:1. The3-waystudyconfirmedthattherewasnodifferenceinbindingtoFcγRI,FcγRIIa,FcγRIIband

FcRn,C1qbinding(enzyme-linkedimmunosorbentassay-ELISA)andcomplement-dependentcytotoxicity(CDC)activityduetodifferencesincoreafucosylationlevels.

2. TheimpactonFcfunctionalityislimitedtoaslightreductioninrelativebindingaffinityofCT-P13torecombinantFcγRIIIa(VandFhemizygote).

3. TheslightdifferenceinafucosylatedglycansCT-P13doesnothavediscernibleimpactonimmunogenicityfollowingrepeatedadministrationusingthesensitiveassayappliedintheclinicalstudyprogram.

Biologicactivity:Inaddition,approximately20differentorthogonalbiologicaltestsdirectlyrelatedtothemechanismsofactionordownstreamtherapeuticeffectswereperformedwhichcomparedCT-P13tobothEUandUSapprovedREMICADE®anddemonstrated:• HighlysimilarbindingaffinitytosTNFα,neutralizationofsTNFα,suppressionofcytokineinduction

bysTNFαandsuppressionofapoptosisbysTNFα• SimilarbindingaffinitytotmTNFα,andresultingcytokinesuppressionthroughreversesignaling

followingbindingtotmTNFαhavebeenobservedforCT-P13versusEUandUSapprovedREMICADE®.Theinductionofapoptosisthroughreversesignalinghasbeenshowntobesimilar.

• Highlysimilarininductionofregulatorymacrophages,suppressionofT-cellproliferationandinmediatingwoundhealing

• HighlysimilarFcγRIa,FcγRIIa,FcγRnandC1qbindingaffinityandCDCactivity• SlightdifferencesinbindingaffinitytotheFcγRIIIaandFcγRIIIbreceptorobservedforCT-P13in

comparisonwithREMICADE®wereobserved.Therelevanceofthisfindingwaspreviouslyinvestigatedusingfurthermodelsanditwasdemonstratedthatthedifferencewasnotclinicallymeaningful.Thefindingsarealsosupportedbydatafromtheliterature.

• MarginaldifferencesinADCCactivityusingoneartificialcellsystemwereshowntohavenoclinicallymeaningfuleffect,sinceusingmoreclinicallyrelevantmodelsandasimilarassaysystemwithcellsderivedfromdonors,highsimilaritywasdemonstrated.Incommonwithotheranti-TNFmonoclonals,infliximabdoesnotinducediscernibleADCCactivityagainstnaturallyderivedtargetcells.Thus,ADCCdoesnotappeartoplayaroleinmediatingtherapeuticeffect.

Inconclusion,thesecomprehensiveanalyseshaveshownthatCT-P13issimilartoEUandUSapprovedREMICADE®inprimarystructure,higherorderstructure,aggregateandmonomericpurity,andpost-translationalmodifications.ThedifferencesdetectedbythesehighlysensitivemethodshavebeenshowntobeofnoclinicalrelevanceinASandRAstudiesandhighlyunlikelytohaveaclinicallymeaningfulimpactonefficacyorsafetyinIBDindications.TheextensiverangesofinvitroandexvivobiologicalassayshavedemonstratedcomparablebiologicalactivitiesforCT-P13andEUandUSapprovedREMICADE®inassaysmimickingtheputativemechanismsofactionofinfliximabinCDandUC.AbriefoverviewofthetestsandconclusionsfortheoligosaccharideprofilingandbiologicactivitycomparisonbetweenCT-P13andREMICADE®arepresentedinTable1ofAppendix1.4.2 KeyClinicalStudiesPleasenotethattheapprovalofINFLECTRA®fortheIBDindicationsfrombothHealthCanadaandtheCDRrelyontheconceptofextrapolation(seeSection6forfurtherexplanation).Therefore,basedonthealreadyestablishedhighdegreeofsimilaritybetweenINFLECTRA®andREMICADE®,postmarketingstudies(studyreports)willbeusedtoevaluatetheclinicalsafetyandefficacyofINFLECTRA®inCDandUCpatients.

4.2.1 Post-MarketingSurveillanceofCT-P13100mg(Infliximab)(monoclonalantibody,recombinant)toEvaluateitsSafetyandEfficacyinKorea

StudyName Design Objectives PopulationPost-MarketingSurveillanceofCT-P13100mg(Infliximab)(monoclonalantibody,recombinant)toEvaluateitsSafetyandEfficacyinKorea.ReferredtoinremainderofdocumentasstudyCT-P13PMS

Phase4open-labelsafetysurveillancestudy

TheobjectivesofthisPMSwastoevaluatethesafetyandefficacyofCT-P13inKoreaunderroutinecare.

• AdultpatientswithmoderatetosevereactiveCDwhohadnotrespondeddespiteafullandadequatecourseoftherapywithcorticosteroidand/orandimmunosuppressant;orwhowereintoleranttoorhadmedicalcontraindicationsforsuchtherapies.

• AdultpatientswithFCDwhodidnotshowanyresponsetogeneraltreatments(includingantibiotics,drainageandimmunosuppressivetherapy).

• AdultpatientswithmoderatetosevereactiveUCwhohadaninadequateresponsetoconventionaltherapyincludingcorticosteroidsand6-mercaptopurineorazathioprine,orwhowereintoleranttoorhadmedicalcontraindicationsforsuchtherapies.

a) StudyCharacteristicsBriefdescriptionofthestudyThisPMSisanongoing,open-label,single-arm,phase4studythatisdesignedtoevaluatethesafetyandefficacyofCT-P13inallapprovedindicationsinSouthKorea.Thissurveillanceisplannedtobecarriedoutinapproximately60studycentersinSouthKoreawithanapproximatesamplesizeof1,600patients.AninterimanalysiswasperformedtoevaluatesafetyandefficacyofCT-P13inthespecificIBDpatientpopulation.Thisinterimanalysisincluded173patientswithIBDthathavebeentreatedwithCT-P13across15participatingIBDclinicalstudycenters.IBDpatientsenrolledinthisstudywereeithernaïvetoinfliximab(N=113)orwerepreviouslytreatedwithREMICADE®(N=60).Patientdisposition,demographicandbaselinecharacteristicsaredetailedbelow.IBDpatientsenrolledinthisstudycouldhavebeeneithernaïvetoinfliximaborwerepreviouslytreatedwithREMICADE®.Thereisnospecifieddosingwindow,asPMSisanobservationalstudy.Patientswillbetreatedaccordingtotheproductlabelandwillbefollowed-upuptoandincludingWeek30.Efficacyevaluationswereperformedaccordingtoplannedvisitsandcriteriasetforeachindividualindication:FCD,UCandCD.AllAdverseEvents(AEs)andSeriousAdverseEvents(SAEs)whichoccurredduringorafterCT-P13exposurewerecollectedthroughoutthestudy.

Characteristics Detailsfor(providestudyname)ST

UDYDESIGN

Objective ToevaluatethesafetyandefficacyofCT-P13inKoreaunderroutinecare.Studyperiod InitiationDate:23January2013

CompletionDate:on-goingCut-offdateforthisreport:14November2014

Studycentres Thisstudywasconductedat15clinicalcentersinKorea.Design ObservationalPhase4study,openlabel,singlearmInclusioncriteria AdultspatientswithmoderatetosevereCD,FCDandUCExclusioncriteria N/A

GS Intervention N/A

Comparator(s) N/A

Run-in N/ATreatment N/Aasthisisanon-goingPostMarketingSurveillanceStudyFollow-up ForFCDandmoderatetosevereactiveUC,theefficacyevaluationwas

performedatbaseline,Week14andWeek30.TheevaluationofefficacyincaseswithmoderatetosevereactiveCDwasperformedatbaseline,Week2andWeek30.AllAEsandSAEswhichoccurredduringandafterCT-P13exposurewerecollectedthroughoutthestudy.

PrimaryEndPoint(s) N/A

OtherEndPoints • ClinicalresponseforCDandUC• ClinicalremissionforCDandUC• DiseasecontrolforCDandUC• RescuemedicationforCDandUC• MucosalhealingforUC

Publications • ParkSH,KimYH,LeeJHetal.ExpertRevGastroenterolHepatol.2015:9:sup1,35-44[1].

• clinicaltrials.govidentificationcode(e.g.,NCTXXXXXXXX):N/Ab) InterventionandComparatorsDosingandAdministrationDoseandregimenincludingdoseescalationwerecompliedwiththeapprovedposologybyKoreanMinistryofFoodandDrugSafetyandtimeintervalsbetweendoseswerecontrolledflexiblyupontheinvestigator’sdecisionunderroutinecare.PleaserefertotheCT-P13Koreanlabelfordosingandadministration[2].PatientswillbetreatedwithCT-P13every8weeks(±5days)followinginductiontherapy.ForFCDandmoderatetosevereactiveUC,theefficacyevaluationwasperformedatbaseline,Week14andWeek30.TheevaluationofefficacyincaseswithmoderatetosevereactiveCDwasperformedatbaseline,Week2andWeek30.AllAEsandSAEswhichoccurredduringandafterCT-P13exposurewerecollectedthroughoutthestudy.

ReferenceProductusedintheTrial:N/APlacebosandControls(ifapplicable):N/AConcomitantMedicationsAnynewtreatments(i.e.,treatmentsnotongoingatstudyentry)anddoseincreaseforexistingmedicationswereconsideredasrescuetreatments.Concomitantmedicationsforothermedicalconditionswerepermittedasclinicallyindicatedsubjecttospecificprotocolrequirementsoutlinedbelow.Permittedmedicationsincludedthefollowing:• Paracetamol• Oral5-AminosalicylicAcid(5-ASA)treatment• Inhaledortopicaldermatological(notperrectum)corticosteroids• Systemiccorticosteroids(e.g.,prednisone,budesonide,cortisoneacetate)• Oral5-ASAtreatmentinpatientsnotreceivingthismedicationatstudyentry.Forpatientsreceiving

5-ASAatstudyentry,noincreaseindosagewasallowed.• Corticosteroidsor5-ASAsperrectum• OthertreatmentsforUC,eithersystemicortopical,initiatedduringthetreatmentorobservation

period• AntibioticsusedfortreatmentofIBD.Theseincluded,butwerenotexclusiveto,agentsinthe

quinoloneclassandmetronidazole.c) Outcomes(KeyEfficacyandSafetyOutcomes)Efficacyevaluationsaretobeperformedaccordingtoplannedvisitsandcriteriasetforeachindividualindication.Allefficacyevaluationsaredescribedbelowbyindication:PatientswithFCD:• Proportionofpatientsachievingclinicalresponsedefinedasareductionofatleast50%from

baselineinthenumberofdrainingfistulas[3].• Proportionofpatientsachievingclinicalremissiondefinedastheabsenceofdrainingfistulas[3].• Proportionofpatientswithdiseasecontroldefinedbytheexclusionoflossofresponsecasesfrom

diseasecontrol.Lossofresponseisdefinedbytherecrudescenceofdrainingfistulas,theneedforachangeinmedicationforCDortheneedforadditionaltherapyforpersistentorworseningluminaldiseaseactivity,theneedforasurgicalprocedureforCD,orthediscontinuationofthestudymedicationowingtoaperceivedlackofefficacy[3].

PatientswithModeratetoSevereActiveCD:• Proportionofpatientsachievingclinicalresponsedefinedbya≥25%and≥70pointsdecreasein

ClinicalDiseaseActivityIndex(CDAI)scorefrombaselinescores[4].• ProportionofpatentsachievingclinicalremissiondefinedbyCDAIscoreof<150[4].• Proportionofpatientswithdiseasecontroldefinedbytheexclusionofdiseaseworseningcases

fromdiseasecontrol.DiseaseworseningisdefinedbyanincreaseinCDAIofatleast70pointsfromthequalifyingscorewithatotalscoreofatleast175andanincreaseinCDAIof35%ormorefromthebaselinevalue,ortheintroductionofanewtreatmentforactiveCD[4].

PatientswithModeratetoSevereActiveUC:• ProportionofpatientsachievingclinicalresponsedefinedbyadecreaseinpartialMayoscoresfrom

baselineofatleast2pointsandatleast30%,withanaccompanyingdecreaseinthesubscoreforrectalbleedingofatleast1point,oranabsolutesubscoreforrectalbleedingof0or1[5].

• Proportionofpatientsachievingclinicalremission,whichisdefinedasatotalpartialMayoscoreof2pointsorlower,withnoindividualsubscoreexceeding1point[6].

• ProportionofpatientsachievingmucosalhealingdefinedbyMayoendoscopicsubscoreof≤1point.

• Proportionofpatientswithdiseasecontroldefinedthatdiseaseworseningcaseisexcludedfromdiseasecontrol.DiseaseworseningisdefinedbyanincreaseinpartialMayoscoreof≥3pointsfrombaseline(=beforeswitching)valueandapartialMayoscore≥5points.

PatientswithModeratetoSevereActiveCDandUC:• ForallIBDpatients,proportionofpatientsreceivingrescuemedicationwasassessed.Rescue

medicationisdefinedasanyconcomitantmedicationthatwerecommencedafterthefirstinfusiondatetotreatneworunresolvedsymptomsofCDorUC[7][8].

Thesafetyendpointswere:• Seriousadverseevents(SAEs).SAEwasconsideredassuchifit:

o resultedindeathorlife-threatening;o requiredinpatienthospitalizationorprolongationofexistinghospitalization;o causedapersistentorsignificantdisability/incapacity;o resultedinacongenitalanomaly/birthdefect;oro associatedwithanyothermedicallyimportantcondition.

• Adverseevents(AEs)• OtherinformationaboutsafetyAdverseeventswerecodedusingtheMedicalDictionaryforRegulatoryActivitiesVersion16.0.d) StatisticalAnalyses• AllstatisticalanalyseswereconductedusingSASVersion9.3(SASInstitute,Inc.).Continuousdata

weresummarizedusingdescriptivestatistics:n,mean,standarddeviation,median,minimumandmaximum,unlessotherwiseindicated.Categoricaldataweresummarizedusingcountsandpercentages.Datapresentedinlistingsweresortedbyindicationandthenbypatientnumberandvisit,whereapplicable.Allanalyseswereperformedbysubgroup(Naïve,Switch):NaïvegroupconsistsofpatientswhohadnotreceivedatleastonedoseofREMICADE®beforefirstinfusionofCT-P13.

• SwitchgroupconsistsofpatientswhohadeverreceivedatleastonedoseofREMICADE®beforefirstinfusionofCT-P13.

PremedicationThepremedicationwassummarizedbyindication,drugclassandpreferredtermforthesafetypopulation.Thepremedicationwasqualifiedwhencorticosteroids,antihistaminesoranalgesicswerecommencedatCT-P13infusiondateforthepurposeofprophylaxis.Afrequencytableforthemaximumamountofdosereceived(mg/kg)ispresentedbyindicationforpatientsinthesafetyanalysisset.PleaserefertoPMSstudyreport,Table9-4[9,Table9-4]showingthenumberandpercentageofpatientswithineachcategoryofamountofdosereceivedateachvisit

EfficacyanalysisTheefficacyanalysissetconsistedofallpatientswhoreceivedatleastonedoseofCT-P13andhadatleastoneassessmentfollowingbaseline.Efficacyanalyseswereperformedontheefficacyanalysissetbyapplyingdifferentcriteriaforeachindication.Theproportionofpatientsachievingclinicalresponse,remissionanddiseasecontrolwereanalyzedbyindication.DescriptivestatisticsforactualvalueandchangefromBaselinewerepresentedbyindicationandvisitfornumberoffistulas,CDAIandMayoscore.LOCFmethodwasconsideredformissingdataimputationforclinicalresponseandremissionfornaïveCDandUCpatients.TheproportionofpatientsachievingmucosalhealingwasanalyzedinUCpatients.Therescuetherapywillbesummarizedbyindication,drugclassandpreferredtermforthesafetypopulation.TherescuetherapywasqualifiedwhenanyconcomitantmedicationwerecommencedafterthefirstinfusiondatetotreatneworunresolvedsymptomsofCDorUC.Discontinuedpatientswerenotincludedinthesummarytablesforefficacyanalysisateachvisit.SafetyanalysisThesafetyanalysissetconsistedofallpatientswhoreceiveatleastonedose(fullorpartial)ofthestudytreatmentduringanydosingperiod.Allanalysesofsafetywereconductedusingthesafetyanalysisset.SafetyanalyseswereperformedbypresentingdataonTreatment-EmergentAdverseEvents(TEAEs),anddurationofREMICADE®andCT-P13administration.TEAEsweresummarizedbyrelationship,intensity,systemorganclass,andpreferredtermdisplayingthenumberandpercentageofpatientswithatleastoneAEusingonlytheworstintensityrecordedateachlevelofsummarization.ThetotalnumberofeventsandnumberofpatientswithatleastoneAEoverallsystemorganclasseswasalsodisplayed.AdverseeventswerecodedusingtheMedicalDictionaryforRegulatoryActivitiesVersion16.0.RescuetherapyandpremedicationwerecodedusingtheWHODrugDictionaryVersion01September2013.AnalysisSetsTABLE1:NUMBEROFIBDPATIENTSINEACHPOPULATION-CT-P13PMSSTUDY

Analysisset ModeratetosevereactiveCD

FistulisingactiveCD ModeratetosevereactiveUC

Total Total

Naïve Switched Naïve Switched Naïve Switched Naïve Switched

Safetyanalysisset1 43 40 8 4 62 16 113 60 173

Efficacyanalysisset2 39 31 6 4 54 11 99 46 145

Source:[10,Table1]1Patientsadministeredatleast1doseofCT-P132Patientsadministeredatleast1doseofCT-P13andhadatleastoneofassessmentaftertreatmentForthedescriptionofthestatisticsprotocol,pleaserefertotheClinicalTrialStudyReport[9,page8].

e) ResultsBaselineCharacteristicsTABLE2:SUMMARYOFDEMOGRAPHICANDBASELINECHARACTERISTICSFOR(CT-P13PMSSTUDYSAFETYANALYSISSETINTREATMENT-NAÏVEPATIENTS)Parameter Moderatetosevere

activeCD(N=43)FistulisingactiveCD(N=8)

ModeratetosevereactiveUC(N=62)

Total(N=113)

Age(years) 31.8(10.88) 27.9(10.13) 45.2(14.57) 38.9(14.71)

Mean(SD)

Median(range) 30.0(18-67) 25.5(18-48) 46.5(19-74) 39.0(18-74)

Sex,no(%) 34(79.1) 6(75.0) 40(64.5) 80(70.8)

Female 9(20.9) 2(25.0) 22(35.5) 33(29.2)

Bodyweight(kg) 57.1(12.13) 71.2(11.77) 58.5(9.67) 58.8(11.26)

Mean(SD)

Median(range) 54.8(35-80) 67.9(57-93) 58.2(40-81) 58.0(35-93)

Baselinediseaseactivity1

340.0(90.35) 1.6(0.92) 6.8(1.13) n/a

Mean(SD)Median(range) 340.6(181-564) 1.0(1-3) 7.0(3-9)

Source:[10,Table2]1CDAIformoderatetosevereactiveCD,No.offistulaforfistulisingactiveCDandpartialMayoscoringsystem(MSS)inmoderatetosevereactiveUCpatientswereusedtoassessdiseaseactivity.

TABLE3:SUMMARYOFDEMOGRAPHICANDBASELINECHARACTERISTICSFOR(CT-P13PMSSTUDYSAFETYANALYSISSETINSWITCHEDPATIENTS)Parameter Moderatetosevere

activeCD(N=40)FistulisingactiveCD(N=4)

ModeratetosevereactiveUC(N=16)

Total(N=60)

Age(years) 31.1(10.41) 33.0(13.34) 42.9(13.54) 34.3(12.43)

Mean(SD)

Median(range) 28.5(19-60) 33.5(20-45) 41.0(21-64) 30.0(19-64)

Sex,no(%) 24(60.0) 3(75.0) 9(56.3) 36(60.0)

Female 16(40.0) 1(25.0) 7(43.8) 24(40.0)

Bodyweight(kg) 58.9(13.45) 64.4(12.36) 58.0(9.46) 59.0(12.34)

Mean(SD)

Median(range) 60.0(37-97) 64.3(50-79) 56.9(40-73) 59.0(37-97)

Baselinediseaseactivity1

168.9(112.65) 0.5(0.58) 4.8(2.81) n/a

Mean(SD)

Median(range) 134.0(24-412) 0.5(0-1) 4.5(0-9)

Source:[10,Table3]1DAIformoderatetosevereactiveCD,No.offistularforfistulisingactiveCDandpartialMSSinmoderatetosevereactiveUCpatientsusedtoassessdiseaseactivity.

ThedemographicandbaselinecharacteristicsofpatientswereinlinewithtargetpatientpopulationinCT-P13andREMICADE®label.Overall,therewerenoimportantdifferencesbetweenCDandUCpatientsexceptthatUCpatientswereslightlyolderthanCDpatients.TherewasgreaterproportionofmalescomparedtofemalesinCDandUCsubgroups.Baselinediseasecharacteristicsinallsubgroupswereinlinewithmoderate-to-severeactivestatusofthedisease.Themajorityofinfliximab-naïvepatientswereexposedtoatleast3dosesoftreatmentwhichspanned6weekinductionperiodwith52.2%ofpatientsreachingdose6(30weeks).Likewise,themajorityofswitchedpatientswereexposedtoatleast3dosesoftreatmentand65.0%ofpatientsreacheddose5.ConcomitantConditionsandMedicationsAtotalof48of173(27.7%)patientsrequiredrescuemedicationtocontrolIBDsymptoms.However,lessthan15%ofCDandUCpatientsrequiredrescueanti-inflammatory,corticosteroidsorimmunosuppressionagents.Overall,theproportionofuseofrescuemedicationwashigherininfliximab-naïvegroupscomparedtoswitchedgroups[9,page10].EfficacyResultsThestudywasnotpoweredforefficacybuthadapositiveoutcomefortheefficacyendpointofinductionandmaintenanceofresponseinCD,FCDandUCpatientsregardlessoftreatment-naïveorswitchstatus.Pleaseseebelowkeyefficacyresults.2,3(A)Thefollowingresultsarebasedoncompletecaseanalysis:(i)AmongCDinfliximab-naïvepatients,vvvvvvvvvvvvandvvvvvvvvvvvvachievedclinicalresponseandvvvvvvvvvvvvandvvvvvvvvvvvvachievedclinicalremissionatweek14and30,respectively.(ii)AmongFCDinfliximab-naïvepatients,vvvvvvvvvandvvvvvvvvvachievedclinicalresponseatweek14and30,respectively.vvvvvvvvvvandvvvvvvvvvvachievedclinicalremissionatweek14and30,respectively.vvvvvvvvvvvvvvvvvvvvvvvvvvv.(iii)AmongFCDpatientsswitchedfromREMICADE®toCT-P13,clinicalremissionanddiseasecontrolwasvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv(iv)AmongUCinfliximab-naïvepatients,vvvvvvvvvvvvandvvvvvvvvvvvvachievedclinicalresponseandvvvvvvvvvvvvandvvvvvvvvvvvachievedclinicalremissionatweek14and30,respectively.(v)vvvvvvvvvvvvandvvvvvvvvvvvUCinfliximab-naïvepatientsexperiencedmucosalhealingatweek14and30whilevvvvvvvvvvpatientswhowereswitchedfromREMICADE®toCT-P13experiencedmucosalhealingthroughoutvisits2-5.(B)ThefollowingresultsarebasedonimputationofmissingdatawithLOCFandincludeallpatientsintheefficacyanalysisset.Theneedforrescuemedicationincludesallpatientsinsafetyanalysisset:(i)AmongCDinfliximab-naïvepatients,34/39(87.2%)and31/39(79.5%)achievedclinicalresponseatweek14and30,respectively.27/39(69.2%)and23/39(59.0%)achievedclinicalremissionatweek14and30,respectively.Rescuemedicationwasneededby7/43(16.3).

(ii)AmongCDpatientswhowereswitchedfromREMICADE®toCT-P13,25/31(80.6%)achievedremissionthroughoutvisits2-6and27/31(87.1%)patientsdidnotexperiencediseaseworsening.Rescuemedicationwasneededby9/40(22.5%).(iii)AmongUCinfliximab-naïvepatients,40/53(75.5%)and39/54(72.2%)achievedclinicalresponseatweek14and30,respectively.26/53(49.1%)and20/54(37.0%)achievedclinicalremissionatweek14and30,respectively.Rescuemedicationwasneededby30/62(48.4%).(iv)AmongUCpatientswhowereswitchedfromREMICADE®toCT-P13,5/11(45.5%)achievedremissionthroughoutvisits2-5andnopatientsexperienceddiseaseworsening.Rescuemedicationwasneededby2/16(12.5%).SafetyResultsSafetyassessmentswerecarriedoutduringandafterCT-P13exposureandeventswererecordediftheyoccurredatanytimeduringthestudyperiod.2,3

Overall,CT-P13waswell-toleratedinalltreatedpatients.51TEAEwerereportedin38patients(22.0%).InpatientswithCD,19eventsoccurredin15/83patients(18.1%),inFCD2eventsoccurredin2/12patients(16.7%),andinUC30eventsoccurredin21/78patients(26.9%).22eventswereconsideredtoberelatedtotreatmentin18patients.Mosteventswereofmildseverityin25patients.FiveTESAEswerereportedin5(2.9%)patients:moderatetreatment-relatedtuberculosis(improved),moderatetreatment-relatedlungabscess(resolved),moderatetreatment-relatedanaphylacticreaction(resolved),severetreatment-relatedIRR(resolved),andseveretreatment-unrelatedabdominalpain(resolved).Amongthese5TESAEs,atotalof4caseswereconsideredtoberelatedtotreatmentand3casesledtodiscontinuationfromthestudy(IRR,lungabscess,andanaphylacticreaction).Infectionandseriousinfectionwerereportedin9patients(5.2%,vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv)and2patients(1.2%),respectively.Onlyonepatient(0.6%)hadactivetuberculosisafterCT-P13exposure.Infusion-relatedreactionincludinghypersensitivityandanaphylaxiswasreportedin9patients(5.2%).Therewerenopatientswithmalignancy,pneumonia,deathoranyothereventsofspecialinterestreportedinthestudy.Doseescalationresults• Themajorityofpatients(59.0%)receiveddosesof5mg/kgofCT-P13.41.0%patientsweretreated

withdoses>5-≤10mg/kg.Therewerenonotabledifferencesindose-escalationbetweeninfliximab-naïveandswitchedpatients.

TherewerenonotabledifferencesinincidenceofTEAEsbetweeninfliximab-naïveandswitchedpatientswith23.9%and18.3%ofpatients,respectively,reportedTEAEs.Furthermore,therewerenonotabledose-dependentdifferencesindistributionofTEAEsbetweenpatientswhoreceived5mg/kgor>5mg/kgdosesofCT-P13[9,page10].4.2.2 OtherLinesofEvidenceforUseofCT-P13inIBDa) OtherOngoingStudiesSponsoredbyCelltrion

(i)CT-P133.4:ThisisaphaseIIIefficacyandsafetystudytodemonstratenon-inferiorityofCT-P13withRemicadeinadultswithactiveCDover54weeks.Thedesignisrandomized,double-blind,parallelgroup.Anenrollmentof214patientsisplanned.Inaninterimanalysis(week14),formationofADAwas

foundtobesimilarbetweenCT-P13andUS-licensedRemicadeinpatientsreceiving5mg/kg[75,page65].(ii)CT-P134.3:ThisisaphaseIV,observationalregistrystudyintheEuropeanUnionandSouthKoreatoevaluatetheefficacyandsafetyofCT-P13inpatientswithCDorUCovera5yearperiod.Anenrollmentof500patientsisplanned.Noresultsareavailabletodate.b) Non-CelltrionSponsoredStudiesThemanufacturerconductedasystematicsearchtoidentifynon-CelltrionsponsoredstudiesthatevaluatedtheuseofCT-P13inIBD.Sixobservationalstudiesinadultpatientswereidentified.ThesestudieswereconductedinNorway4,Hungary5,6,theCzechRepublic7,andKorea.8,9Eachstudyissummarizedbrieflyandselectedresultsprovided.Norway4:Aprospective,observationalstudywasconductedinasinglecenterin46patientswithCDand32patientswithUC.PatientsreceivedthreeinductiondosesofCT-P13atweeks0,2,and6,withthemajorityreceiving5mg/kg.Efficacyandsafetywereassesseduptoweek14.OfthepatientswithCD,79%achievedremission(Harvey-BradshawIndexscore≤4)andofthepatientswithUC,56%achievedremission(partialMayoscore≤2).StatisticallysignificantreductionsinC-reactiveproteinandcalprotectinfrombaselinetoweek14wereobserved.AdverseeffectsincludedIRRs(1patientwithCDand1withUC),colectomy(1patientwithUC),muscleandjointpainduetoantibodyformation(1patientwithCD),andinfections(patientswithCD:infectiousenterocolitis,herpeszoster,herpessimplex,recurrentupperairwayinfection;patientswithUC:pneumoniaanderysipelas).Hungary5,6:Gecseetal.conductedanationwide,multicentreprospectiveobservationalstudytoassesstheefficacy,safety,andimmunogenicityofCT-P13inpatientswithCD(N=126)orUC(N=84).PatientsreceivedCT-P135mg/kginductionatweeks0,2,and6andthenevery8weeksthereafter.Clinicalresponsewasachievedby81.4%ofpatientswithCD(decreaseinCDAI>70oratleast50%reductioninthenumberofdrainingfistulas)and77.6%ofpatientswithUC(decreaseinpartialMayoscore>3)atweek14.Clinicalremissionwasachievedby53.6%ofpatientswithCD(CDAI<150ornofistuladrainage)and58.6%ofpatientswithUC(partialMayoscore<3).Significantlymorepatientswhowereinfliximab-naïveachievedclinicalremissionatweek14comparedwithpatientswhohadpreviouslyreceivedtheinnovatorproduct.Infusion-relatedreactionswereexperiencedin14(6.6%)patientsandinfectionsin12(5.7%).Infusion-relatedreactionsoccurredatahigherincidenceinpatientswhowereswitchedfrominnovatorproduct(27%vs.2.5%).Molnaretal.examinedmucosalhealingsubsequenttoCT-P13administrationin12patientswithUC.Atweek6,clinicalresponsewasobtainedby2patients,clinicalremissionby5patients,andmucosalhealingwasobservedin7patients.TheCzechRepublic7:Apost-marketsurveillancestudyof140patientswithIBD(107CDand33UC)wasconductedwithaninterimanalysisofefficacyandsafetyatweek10(completefollow-upwillbetoweek30).Ofthe140patients,36weretreatment-naïveand104wereswitchedtoCT-P13fromotherbiologicalagents.Efficacydatawereavailablefortreatment-naïvepatientsonly(23CDand13UC).StatisticallysignificantreductionsinHarvey-BradshawIndexforCDandSimpleClinicalColitisActivityScore(SCCAI)forUCfrombaselinetoweek10wereobserved.Clinicalresponsewasobtainedby5patients(21.7%)withCD(decreaseinHarvey-BradshawIndex≥3)and6(46.2%)patientswithUC(decreaseinSCCAI≤2).Clinicalremissionwasobtainedby17(73.9%)patientswithCD(Harvey-BradshawIndex≤4)and2(15.4%)patientswithUC(SCCAI≤2).Comparedwithbaseline,therewerestatisticallysignificantreductionsinC-reactiveproteinandfecalcalprotectininbothCDandUC.Six

TEAEs(IRRs,pneumonia,C.difficileinfection,tonsillitis,anddermatitispsoriasiform)wereexperiencedby6(4.3%)patients(3CDand3UC).Korea8,9:Kangetal.evaluated17patientswithIBD(8CDand9UC)whoreceivedCT-P13atasinglestudycenter.Amongtreatment-naïvepatients(N=8),clinicalresponse(CD:decreaseCDAI>60;UC:decrease>30%intheactivityindex+decreaseinrectalbleedingandendoscopysubscores)andremission(CD:CDAI<150;UC:Mayoscore≤2andnosubscores>1)wereachievedin7(2CDand5UC)atweek8.AmongpatientswhoswitchedtoCT-P13frominnovatorproduct(N=9),8hadsimilarclinicaloutcomes.OnepatientwithCDhadlossofresponse.Jungetal.conductedaretrospectivemulticenterstudyinpatientswithCD(N=59)andUC(N=51)withfollow-upto54weeks.Atweek8,clinicalresponseandremissionintreatment-naïvepatientswithCD(N=32)were90.6%and84.4%respectively.Atweek54,clinicalresponseoccurredin7/8(87.5%)andremissionin6/8(75.0%).Intreatment-naïvepatientswithUC(N=42),clinicalresponseandremissionatweek8were81.0%and38.1%respectively.Atweek54,clinicalresponseoccurredin12/12(100%)andremissionin6/12(50%).MucosalhealinginUCwasachievedin14/24(58.3%)atweek8andin2/3(66.7%)atweek54.Amongpatientswhoswitchedfromthereferenceproduct(27CDand9UC),efficacywasmaintainedin25(92.6%)withCDand6(66.7%)withUC.TherewerestatisticallysignificantdeclinesinC-reactiveproteinanderythrocytesedimentationrateinCDandUC.Six(11.8%)patientswithUCexperiencedanAE.4.2.3 SummaryofSafetySectiona) SafetyEvaluationPlanTheobjectiveoftheclinicaldevelopmentprogramforCT-P13wastodemonstratethatCT-P13iscomparabletothereferencemedicinalproduct,REMICADE®,intermsofitsclinicalpharmacology,efficacyandsafety.DatafromclinicaltrialsinRAandASpatientsshowedthatthesafetyprofilesofCT-P13andREMICADE®weresimilar.Inviewofthesedataandthestructural,biological,toxicologicalandpharmacokinetic(PK)comparabilitytothereferencedrugproductREMICADE®(CTDModules3.2Rand2.4),CT-P13isalsoexpectedtodisplayacomparablesafetyprofileinCDandUCpatients.Therefore,thesafetyevaluationinCDandUCpatientswasbasedonthesafetyprofileofREMICADE®aspresentedintheproductinformationfromREMICADE®productmonograph[11]andtheSummaryofProductcharacteristics[12].TocomparethesafetydataofCT-P13andthatofREMICADE®,literaturesearcheshavebeenperformedtoidentifyarticlesreportingREMICADE®studies.Thedatafromthesehistoricalstudieswereincludedinthemeta-analyseswithregardtotheincidenceofAdverseEventofSpecialInterest(AESI),inparticulartotheincidenceof(seeCTDModule2.7.4.2.1.5):• Infectionsincludingseriousinfections,pneumonia,activetuberculosis• Infusion-relatedreactionsincludinganaphylacticreactions• MalignanciesincludinglymphomaTheliteraturesearchesfocusedonRCTsandalsoconsideredobservationalstudies.PublicationswereselectedwhentheyreportedthemethodologyofcollectingsafetydataandspecificallyAEsandwhentheincidenceofAEswasclearlycapturedandreportedusingreliabledenominators.Forfurtherdetails,refertoaSystematicLiteratureReviewontheSafetyofinfliximabinthetreatmentofpatientswithCDandUC[13]andaSystematicliteraturereviewreportonREMICADE®observationalstudies[14].Belowarecomparisonsofoverallrates(per100patient-yearswith95%confidenceintervals)fromRCTsofRemicade(ACCENTI,ACCENTII,andSONIC,+others),observationalstudiesofRemicade,andobservationalstudiesofCT-P13.10

1.Infusion-relatedreactions:CD:Remicade(RCTs)–vvvvvvvvvvvvvvvper100patient-yearsRemicade(observational)-vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patient-yearsUC:Remicade(RCTs)–vvvvvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patientyears2.Infections:CD:Remicade(RCTs)–vvvvvvvvvvvvvvvper100patient-yearsRemicade(observational)-vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patient-yearsUC:Remicade(RCTs)–vvvvvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patientyears

3.Pneumonia:CD:Remicade(RCTs)–vvvvvvvvvvvvper100patient-years*Remicade(observational)–vper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patient-yearsUC:Remicade(RCTs)–vvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvper100patient-years*PneumoniawasnotreportedinACCENTI,ACCENTII,orSONIC

4.Tuberculosis:CD:Remicade(RCTs)–vvvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patient-yearsUC:Remicade(RCTs)–vvvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvvvper100patientyearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vper100patient-years5.Malignancies:CD:Remicade(RCTs)–vvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vper100patient-yearsUC:Remicade(RCTs)–vvvvvvvvvvvvper100patient-years

Remicade(observational)–vper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vper100-patient-years

6.Surgery:CD:Remicade(RCTs)–vvvvvvvvvvvvper100patient-years*Remicade(observational)–vvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patient-yearsUC:Remicade(RCTs)–vvvvvvvvvvvvvvvper100patient-years*

Remicade(observational)–vvvvvvvvvvvvvper100patient-yearsCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvper100-patient-years*DatafromthemajorRCTsofRemicade+otherRCTs

7.Disease-RelatedHospitalization:CD:Remicade(RCT)–vvvvvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvvCT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvvper100patient-yearsUC:Remicade(RCT)–vvvvvvvvvvvvvvvper100patient-yearsRemicade(observational)–vvvvvvvvvvv

CT-P13(PMS+non-Celltrionsponsoredstudies)–vvvvvvvvvvvvper100-patient-yearsInaddition,safetydatawascollectedfromseveralpost-marketingobservationalstudies.Thesafetypopulationandoutcomesarefurtherdescribedinthesectionsbelow.ForadditionalinformationonthespecificstudiespleaserefertotheClinicalStudyReports(CSRs)includedinthelistedreferences.b) SafetyPopulationsEvaluatedThesafetydatabaseofCT-P13consistsofdatafromthe2ongoingclinicaltrialsconductedwithCT-P13forCDandUC:thePhase4trialCT-P134.1inIBDpatients[15],andtheobservationalPhase4trialCT-P13PMS[9].ThelatterstudyisdescribedindetailinSection4.2.CT-P134.1isasmall(N=20)phaseIV,ongoing(fouryear),open-label,singlearmstudyconductedinadultpatientswithCDorUCinSouthKorea.11Aninterimanalysisofefficacyandsafetyin10patients(vvvvvvvvv)fromvstudycentershasbeenpresented.vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.AnalysesofthesafetyofCT-P13atdoses>5mg/kgincludeddatafromStudyCT-P13PMSandStudyB2P13111,whichisanExtensionStudyofthePhaseI/IIClinicalStudyofCT-P13inTreatmentofPatientswithRheumatoidArthritis[16].ForStudyCT-P13PMSvvvvvvvvvvvvvvvvv,thesafetyanalysissetconsistedofallpatientswhoreceivedatleastonedose(fullorpartial)ofthestudytreatmentduringanydosingperiod.Atotalof173IBDpatientshavebeentreatedwithCT-P13inStudyCT-P13PMSand75patientsweretreatedwithdoses>5mg/kg.InStudyB2P13111,vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.Atotalof71RApatientsweretreatedwithCT-P13.vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.c) OverviewofSafetyThesafetydatabaseofCT-P13inIBDpatientshasbeenspeciallyevaluatedwithregardtotheidentifiedandpotentialrisksofREMICADE®i.e.,IRRs,infections,inparticularpneumoniaandtuberculosis,andmalignancies.Inaddition,analysesoneventsofsurgeryordisease-relatedhospitalizationhavebeenperformed.Theresultsoftheseanalysesarepresentedinthefollowingsections.Inaddition,thefindingsonIRRs,infections,pneumonia,tuberculosisandmalignanciesfromRCTsconductedwithREMICADE®aswellasfromobservationalstudiesaresummarizedandcomparedwiththesafetydatafromStudyCT-P13PMS,StudyCT-P134.1,andnon-CELLTRIONsponsoredstudies.d) TreatmentEmergentAdverseEvents(TEAS)StudyCT-P13PMS(InterimCSR)Atotalof51TEAEswerereportedin38patients(22.0%).Ofthese,22eventswereconsideredtoberelatedtotreatmentin18patients.TherewasnonotabledifferenceinincidenceofTEAEsbetweeninfliximab-naïveandswitchedpatientswith23.9%and18.3%ofpatientsreportingTEAEs,respectively.MoreTEAEswerereportedbyUCpatientscomparedtoCDpatients;30TEAEsbyUCpatientsand19TEAEsbyCDpatients.PatientswithFCDreported2TEAEs.Themostfrequently(≥5patients)reportedsystemorganclasses(SOCs)includedinfectionsandinfestations(9patients),skinandsubcutaneous

tissuedisorders(8patients),gastrointestinal(GI)disorders(5patients),generaldisordersandadministrationsiteconditions(5patients).MostTEAEswereofmildseverity(10patientsreportedmildTEAEsconsideredrelatedtotreatmentand15patientsreportedmildTEAEsconsideredtobeunrelatedtotreatment);7patientsreportedrelatedmoderateTEAEsandalso7patientsreportedunrelatedmoderateTEAEs.TwoTEAEswereassessedtobeofsevereseverity.InfectionsandGIdisorderswerethemostfrequentlyreportedTEAEs,whichisnotinconsistentwiththesafetyprofileofREMICADE®inIBDpatients.StudyCT-P134.1(InterimCSR)vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvve) DeathsNodeathswerereportedintheinterimCSRsofStudiesCT-P13PMS,vvvvvvvvvvvvvvvvvvv.f) TreatmentEmergentSeriousAdverseEvents(TESAEs)StudyCT-P13PMS(InterimCSR)FiveTESAEswerereportedby5(2.9%)patientsinthestudy(CTDModule2.5-12);ofthese,4wereconsideredtoberelatedand1tobeunrelatedtotreatment.TheTESAEswerereportedby4patientsreceiving5mg/kgasmaximumdoseand1patientinthe>5mg/kg-≤7mg/kggroup.TheTESAEsreportedinthestudyareconsistentwiththesafetyprofileofREMICADE®asdescribedintheREMICADE®ProductMonograph[11].NounexpectedTESAEoccurredduringthestudy.StudyCT-P134.1(InterimCSR)vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvg) ReactionsDuetoInfusionoftheStudyDrugsvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.InStudyCT-P13PMS,atotalof10IRRswerereportedby9IBD(9of173;5.2%)patients,vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.IntheCDgroup,2patientsreportedIRRs(bothswitchedtoCT-P13)andintheUCgroup8patients(6infliximab-naïve,2switch).NoneofthepatientswithFCDreportedIRRs.FourIRRsledtopermanentdiscontinuationoftreatment.TheincidenceofIRRswasnothigherinthegroupofpatientsreceivingdosesof>5mg/kg(3of71,4.2%)comparedtopatientsreceiving5mg/kgasmaximumdose(6of102,5.9%).InStudyCT-P134.1,2(20%)patientsexperiencedIRRs;1patientexperiencingvomiting(possiblerelated,moderate)andnausea(possiblerelated,moderate)intheCDgroup,1patientreportingskinexfoliation(possible,mild)andrash(probable/likely,mild)intheUCgroup.NoneoftheseIRRsledtodiscontinuationoftreatment.

h) InfectionsInStudyCT-P13PMS,atotalof10TEAEsofinfectionswerereportedby9IBDpatients;ofthese,3wereconsideredtoberelatedand6tobeunrelatedtotreatment.The3TEAEsconsideredtoberelatedincluded:1TEAEoftuberculosis(moderate)experiencedbyaFCDpatient,1TEAEofrhinitis(mild)reportedbyatreatment-naïveUCpatient,and1TEAEoflungabscess(moderate)reportedbyatreatment-switchUCpatient.Theeventofrhinitis,however,wasconfirmedtobeanIRRbythesiteinvestigator.TEAEsunrelatedtotreatmentincludedfolliculitis(mild),upperrespiratoryinfections(3mild,2moderate),andurinarytractinfection(moderate).Theincidenceofinfectionswasnothigherinthegroupofpatientsreceivingdosesof>5mg/kg(2of71,2.8%)comparedtopatientsreceiving5mg/kgasmaximumdose(7of102,6.9%).vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvOverall,1caseoftuberculosis(StudyCT-P13PMS)wasreportedinIBDpatients.Forfurtherdetails,refertoCTDModule2.7.4.i) SurgeryNocasesofsurgerywerereportedintheperiodcoveredbythePMSinterimCSR.j) Hospitalization(disease-related)InStudyCT-P13PMS,1treatment-naïvepatientwithCDwashospitalized.NoothercasesofhospitalizationwerereportedintheperiodcoveredbytheinterimCSR[17,Table24].k) Post-marketingDataAspreviouslymentioned,REMSIMA®andINFLECTRA®arethesamemolecule,theinfliximabbiosimilar(CT-P13)manufacturedbyCelltrionHealthcareCorporation,justmarketedanddistributedunderdifferentcommercialnamesindifferentcountries.Assuch,thepostmarketingdataforCT-P13isbasedonboththeperiodicbenefit-riskevaluationreport(PBRER)[18],dated23Mar2015fortheREMSIMA®brandaswellastheperiodicsafetyupdatereport(PSUR)dated29Mar2016fortheINFLECTRA®brand[19]REMSIMA®(infliximab;CT-P13)Thisreportcontainssafetydatafromindividualcasereportsderivedfrompost-marketingspontaneousreporting,publishedliteratureandclinicaltrials,coveringtheperiodfrom20Jul2014to20Jan2015(forfurtherdetails,seeCTDModule2.7.4).vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.Duringthereportingperiod,nonew,ongoing,orclosedsignalswereidentifiedforinfliximab.Nonewinformationwasreceivedforthepreviouslyidentifiedorpotentialrisksandtherewasnoupdateonmissinginformationduringthisreportingperiod.Therewerenoactionstakenorriskminimizationactivitiesproposedforanysafetyreason.Overall,nosignificantnewsafetyinformationwasidentifiedfromthereviewofworldwidesafetydataduringthereportingperiodthatwouldwarrantchangestotheReferenceSafetyInformationofinfliximab.Thebenefit-riskratioofinfliximabremainsfavorable.ThisreportsummarizesthesafetyinformationreceivedbytheProductSafetyDepartmentofHospira,forINFLECTRA®(infliximab),duringtheperiod21Jul2015to20Jan2016(forfurtherdetails,seethePSURdocumentincludedinthelistedreferences).SourcesofadversereportingdatawithinthisPSURincludespontaneousreports(medicallyconfirmedandnon-medicallyconfirmed),reportsfromregulatory

authorities,reportsfromnon-Hospirasponsoredstudiesornamedpatient/compassionateuseprograms,andtheliterature.vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.DuringthereportingperiodcoveredbythisPSUR,therewerenoactionstakenwithINFLECTRA®(infliximab)forsafetyreasons,byeithertheRegulatoryAuthoritiesor,byHospiraastheMAHandnochangesintheefficacyofINFLECTRA®(infliximab)werereportedeither.Followingareviewoftheadverseeventinformationreceivedduringthe6monthperiodcoveredbythisreport,therisk-benefitbalanceofINFLECTRA®(infliximab)isconsideredfavorable4.3 PharmacokineticsThePKsimilarityofREMICADE®andCT-P13wasdemonstratedbyaphaseI(CT-P131.1)studyinASpatientswith5mg/kgandaphaseIII(CT-133.1)studyinRApatientswith3mg/kg.ThesestudieswerepresentedanddescribedwithinthepreviousCDRsubmissionforINFLECTRA®.DoseproportionalityofCT−P13intherangeof3−10mg/kgwasanalyzedinaPKmodelingstudytosupportIBDindicationdosingregimen.TheprimaryobjectiveofthisanalysiswastoevaluatethedoseproportionalityofCT−P13basedonthefollowing:pharmacokineticdatafromthephaseIstudy,externalvalidationwithphaseIIIdataandreviewofpreviouspharmacokineticstudiesonREMICADE®.RefertotheCT-P13PKModellingReportforfurtherdetails[20].ThisstudyhasshownthattherearenodifferencesinpharmacokineticparametersbetweenREMICADE®andCT−P13.BothREMICADE®andCT−P13appeartobedoseproportionalinthedoserangeof3−5mg/kgbasedontheexternalvalidation.ThepharmacokineticparametersofREMICADE®areknowntobeproportionaltothedosesgiven(5and10mg/kginpatientswithCD,5,10,and20mg/kginpatientswithRA)inpreviouspharmacokineticsreportsofREMICADE®andCT-P13werelinear(doseproportionalexposure)inourstudiesasobservedinpreviousreports.ForfurtherdiscussiononREMICADE®PKlinearity,pleaserefertoAppendixI.Inaddition,severalnon-sponsoredstudieshaveinvestigatedCT-P13PKinIBDpopulation.Anoverviewofthedataisprovidedbelow.TheObservationalHungarianNationwideIBDStudy[21,22],thatenrolled90CDpatientsand51UCpatientsasofFebruary,15,2015,showedthatforbothCDandUCpatients,troughlevelsincreasedfrompre-dosestatusatweek0toweek2andsubsequentlystabilizedbetweenweeks6and14.Preliminaryresultsthroughinductiontherapymeasuredbyweek14showedtherapeuticallymeaningfulconcentrationsofdrugpresentinpatients.AsimilarstudywasdonebythesamegroupusingREMICADE®[23].TheresultsinthecurrentstudyforCT-P13arecomparabletothosereportedpreviouslyforREMICADE®[22].AcohortstudythatiscurrentlyunderwayinNorway[24,25]hasenrolled44CDpatientsand30UCpatientsasofJanuary,31,2015,including56patientswhowerenaïvetoinfliximabtherapyand18patientswhowereswitchedfromREMICADE®toCT-P13.Themeantroughlevelsatweek14inCDpatientswas7.0mg/L(range:0.0-21.8mg/L),andforUCpatientsitwas6.1mg/L(range:0.0–16.7mg/L)[25].AnotherobservationalstudyfromPraguein140IBDpatientsshowedamediantroughlevelofCT-P13inalltreatment-naïvepatientsof14.8µg/mL(0.9-45.0µg/mL)and8.7µg/mL(0.2-45.0µg/mL)atWeeks2and6,respectively.ThemediantroughlevelofCT-P13inallswitchedpatientswere2.4(0-22.0µg/mL)atbaselineand3.2(0-19.0µg/mL)atweek8afterthefirstinfusion[26].Inconclusion,CT-P13hasdemonstratedalinearandpredictablepharmacokineticprofilethatwashighlysimilartoREMICADE®inmodeling,sponsoredandnon-sponsoredobservationalstudies.

4.4 ImmunogenicityImmunogenicitydatawasthoroughlyassessedinthekeypivotalstudiespresentedinthepreviousCDRsubmission(PLANETASandPLANETRAStudies).ThefollowingsectionsummarizesdatarelevanttoCDandUCandbrieflydiscussesimmunogenicitysimilarity.AseriesofstudieswereundertakentoinvestigateifimmunereactivityagainstREMICADE®iscross-reactivewithCT-P13.SerafromIBDpatientswhodevelopedanti-infliximab(ATI)antibodiesfollowingtreatmentwithREMICADE®wereexaminedforcross-reactivitytoCT-P13bycomparisonofantibodytitersusinganELISAassay[27,28].52seraobtainedfrom46IBDpatientsandhealthyindividualsweretested.NoneofthepatientswaseverexposedtoCT-P13.Testingwasperformedbyasensitiveandvalidatedanti-Lambdachainsemi-quantitativeELISA.ATIdetectionforthisassayis2.7µg/ml.WhentestingREMICADE®-sensitizedIBDsera,therewasstrongcorrelationbetweentitersofATIreactivetoEU-approvedREMICADE®andtitersofATIcross-reactivewithUSapprovedREMICADE®andCT-P13inpatientsneverexposedtoUSapprovedREMICADE®ortoCT-P13.Thesesimilarcross-reactivityresultspointtosharedimmuno-dominantepitopesonREMICADE®andCT-P13.Whilstthesereassuringdataweregeneratedinvitro,theysupportthenotionthattheimmunogenicpotentialofREMICADE®andCT-P13andthecharacteristicsofcross-reactivitywithclinicallyrelevantanti-drugantibodies(ADA)inIBDpatientsaresimilarandwilltranslateintosimilarimmunogenicityfeaturesinclinicalsettings.AnothercohortexperiencefundedbytheNorwegianGovernmentisbeingconductedtoaccumulateexperiencewithCT-P13inNorwayfollowingproductlaunchinJanuary2014.ThisNor-Switchstudyisanongoingrandomized,double-blind,parallelgroupstudywith500patientsacrossallindications[24].vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvInHungary,aprospective,multicenter,observationalcohortwasdesignedtoexaminethesafetyandefficacyofCT-P13inclinicalresponseandtheinductionandmaintenanceofremissioninCDandUC[29],[21].vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.TABLE4:VVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVV

TheimmunogenicityintermsofADApositivityresultsobtainedbyCELLTRION from Studies CT-P131.1and CT-P133.1(whichpreviouslypresentedanddescribedinthepreviousCDRSubmissionforINFLECTRA®) are in line with those reported in theliteratureindicatingthatthestateofthearttestmethodologyappliedinCT-P13studiesprovidesresultsinlinewiththoseoftheassaysemployedinthemorerecentlyreportedstudies.TheuseofconcomitantMTXandotherimmunomodulatorytherapiesisknowntodifferbetweenapprovedconditions.Nevertheless, it isevidentthattheASandRApatientpopulationsrepresentsensitivepopulationsinwhichtocompareimmunogenicityofCT-P13andREMICADE®.Theimmunogenicityinotherpopulations(PsO,PsA,CDandUC)isnotlikelytodifferfromthelevelsobservedinASandRApatientssincetheuseofMTXiseitherlesscommon(PsO,CDandUC)

vvvvvvvv vvvvv vvvvv vvvvvv

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oroptionallyindicated(PsA)andthereforeapproximatetoconditionstestedintheCT-P13clinicalprogram.Overall,theresultsoftheimmunogenicityassessmentofthestudiesconductedwithCT-P13showthattheproportionofpatientsdevelopingADAswhiletreatedwithCT-P13issimilartothatforthosetreatedwithREMICADE®.

5. CRITICALAPPRAISALOFCLINICALSTUDIES

5.1 InternalValidityMostclinicalevidencecurrentlyavailabletoevaluatetheefficacyandsafetyofCT-P13forCDorUCcomesfromobservationalstudies(Celltrion-sponsoredstudies,non–Celltrion-sponsoredstudies,andpost-marketingdata).OneRCT(CT-P133.4)comparedCT-P13withthereferenceproduct,Remicade,inadultswithCD.TheobservationalstudiesofCT-P13inCDorUCareallsinglearmwithoutdirectcomparisonswithRemicade.OnlynaiveindirectcomparisonsofsafetyendpointsandsomeefficacyendpointswithRemicadeareavailablefromthemanufacturer’ssystematicreview10andmanufacturer-submitteddatatoHealthCanada.{20}TheabsenceofrandomizedtrialsintheclinicalbodyofevidenceforCT-P13inboweldiseasesmakesitdifficulttoascribeanyobservedimprovementsinefficacy,oranyapparentmaintenanceoftreatmenteffect,totheintervention.Inaddition,thedegreeofsimilarityinefficacy,safety,andimmunogenicitybetweenCT-P13andRemicadehaveyettobeclearlydelineatedwithexperimentaltrials.Inthediscussionbelow,specificcriticalappraisalpointsareprovidedforthestudyCT-P13PMS,asthiswasthekeyclinicalstudypresentedinthemanufacturer’ssubmission.CT-P13PMSisanongoing(fouryear)phaseIV,open-label,singlearmstudyofCT-P13forallapprovedindicationsinSouthKorea.AninterimanalysiswasconductedinadultswithmoderatelytoseverelyactiveCD(N=83),FCD(N=12),andUC(N=78)across15studycentresinSouthKoreawithfollow-upof30weeks.Ofthe173patients,113weretreatment-naivetoinfliximaband60wereswitchedtoCT-P13fromthereferenceproduct,Remicade.CT-P13wasadministeredevery8weeks(±5days)afterinductiontherapyofthree5mg/kgdosesatweeks0,2,and6.Mostpatients(59.0%)receiveddosesof5mg/kg.Higherdosesof5mg/kgto10mg/kgwereadministeredto41%ofpatientswithaflexibletitrationschedule.Themajorityofpatientsreceivedatleastthreedosesoftreatmentduringasixweekinductionperiod(90.3%oftreatment-naiveand86.7%oftreatment-switch).Amongtreatment-naiveandtreatment-switchpatients,52.2%and11.7%respectivelyreacheddose6atweek30.TheefficacyanalysissetconsistedofpatientswhoreceivedatleastonedoseofCT-P13andhadatleastoneassessmentfollowingbaseline(N=145,83.8%).MissingdatawereimputedusingLOCF.Allpatientswereincludedinsafetyanalyses.ThemanufacturersubmitteddatatoHealthCanadasuggestingsimilarefficacyforclinicalresponseandremissioninCDandUCandmucosalhealinginUCatweeks14and30betweenCT-P13PMSandhistoricalRemicadedata.{20}TheinternalvalidityofCT-P13PMSislimitedbecauseofitsnon-comparative,open-labelstudydesign.ThemagnitudeofimprovementinefficacyoutcomesduetoCT-P13administrationincomparisonwithRemicadeisunknownwithoutacomparatorgroup.Also,confounders,suchasvariationsinsymptomsovertimeandtheeffectofconcomitanttreatments,couldnotbeadjustedforwithanon-comparativestudydesign.Theabsenceofblindingmayhaveinfluencedtheassessmentofsubjectivecomponentsofthescoringtools,suchasseverityofabdominalpainandgeneralwell-beingoftheCDAIandphysician’sglobalassessmentoftheMayoscore.Thesamplesizeisrelativelysmall,withatotalof83patientswithCD,12withFCD,and78withUC.Whenanalyseswerestratifiedaccordingtotreatment-naiveorswitchstatus,samplesizesbecameevensmallermakingitdifficulttodrawconclusions(e.g.,inFCD,only8patientsweretreatment-naiveand4patientstreatment-switch).PatientswhoreceivedatleastonedoseofCT-P13butwhodidnothaveatleastonepost-baselineefficacyassessment(n=28,16.2%)wereexcludedfromefficacyanalyses.Ofthe

28patientsexcludedfromefficacyanalyses,8discontinuedtreatmentforthefollowingreasons:lackofefficacyandswitchtoanothertreatment(n=2),experienceofanAE(n=4),losstofollow-up(n=1),andpregnancy(n=1).13Thecompletecaseanalysesshowedthataconsiderablenumberofpatientswerenotevaluatedatfollow-upvisits(e.g.,only14/39and20/39patientswhowereinfliximab-naivewithCDwereevaluatedatweeks14and30respectively;only44/54and23/43patientswhowereinfliximab-naivewithUCwereevaluatedatweeks14and30respectively).Missingdata(excludingthe16.2%ofpatientswhowereexcludedfromtheefficacyset)wereimputedusingLOCFandthemanufacturerpresentedanalysesshowingsimilarresultsforclinicalresponseandremissioninCDandUCusingcompletecaseandLOCFmethods.2ThemethodofimputingdatausingLOCF,however,mayoverestimatetreatmentbenefitifpatientswithdrewfromthestudybecausetheyexperiencedworseningofoutcomes.TheLOCFimputationwillassumethatpatientswhowithdrewremainedconstantinoutcomemeasuresfromthepointofwithdrawalandworseninginoutcomes,ifpresent,wouldnotbecaptured.WhiletheefficacyoutcomesassessedbythestudywereappropriatebasedontypicaloutcomesevaluatedintrialsofCDandUC(i.e.,clinicalresponsedefinedbyCDAI,numberofdrainingfistulas,Mayoscore,clinicalremission,endoscopicmucosalhealingforUC,diseasecontrolforpatientswhoswitchedfromreferenceproduct,andneedforrescuemedication)andthethresholdsusedtodefineclinicalresponseandremissionwereappropriate,14dataareabsentforotherimportantoutcomesofIBD.Theseotheroutcomesincludeextra-intestinalmanifestations,diseasebiomarkers(e.g.,C-reactiveprotein,fecalcalprotectin),qualityoflife,andimmunogenicity.Certainnon-Celltrionsponsoredstudiesprovideddataondiseasebiomarkers,butaresimilarlylimitedbyobservational,singlearmdesigns.Thefollow-upperiodof30weeksisalsotooshorttoadequatelyevaluatesomeoutcomes,suchastheneedforsurgeryandmortality.CT-P13PMSpresentspreliminary,interimresultsand,therefore,longer-termfollow-upisneededtoassessifefficacyandsafetyoutcomesremainstable.Qualityoflife,concernaboutdiseaseflare-ups,anxietyandstress,andcaregiverburdenhavebeenidentifiedbypatientsasimportantconcernsandtheimpactofCT-P13ontheseaspectsofdiseasearecurrentlyunknown(Appendix3).5.2ExternalValidity TheprimarylimitationwithrespecttotheexternalvalidityofCT-P13PMSisthedifficultyindirectlyapplyingtheresultsobservedinpatientswithIBDfromKoreatotheCanadianpopulation,duetodifferencesindietandmicrobiotabetweenthecountries.ThesamplepopulationofCT-P13PMSwerefromstudycentresinSouthKorea.Ofthetreatment-naivepatients,themeanage(standarddeviation[SD])was38.9(14.7)years(CD:31.8years,FCD:27.9years,UC:45.2years).Oftreatment-switchpatients,themeanage(SD)was34.3(12.4)years(CD:31.1years,FCD:33.0years,UC:42.9years).Mostpatientshadmoderatelytoseverelyactivedisease,althoughtherewerealsopatientswithCDAIscores<220orpartialMayoscore<6,whichindicatelowerdiseaseseverity.3Femalesappearedtobeunderrepresentedinthestudy(29.2%amongtreatment-naiveand40%amongtreatment-switchpatients).EstimatesofprevalenceofIBDbysexvaryamongstudiesandbyregion.InEuropeanandNorthAmericanpopulations,female-maledistributionhasbeenfoundtorangefromequalto2.5:1.15TherearespecialdiseaseandmanagementconsiderationsofIBDrelevantparticularlytofemales,suchasahigherincidenceofextra-intestinalmanifestationsobservedinwomen,whichwerenotaddressedbythisstudy.16

TheadministereddoseofCT-P13wasinaccordancewiththedosingrecommendationsofinfliximabforCDandUC.CT-P13wasgivenintravenouslystartingwiththreedosesofinductionof5mg/kgatweeks0,2,and6,andthen5mg/kgevery8weeksthereafter.Forpatientswithincompleteresponse,thedosewasincreasedupto10mg/kg.Themajority(89.0%)completedthe3dosesofinductiontherapy.However,only66(38.2%)completed6dosesoftreatmentbyweek30.Morepatientsinthetreatment-naivegroup(59/113,52.2%)received6dosescomparedwiththetreatment-switchgroup(7/60,11.7%).Themanufacturerexplainedthatthelargediscrepancyinreaching6dosesamongtreatment-naiveandtreatment-switchgroupswasduetodifferencesinintervalsbetweendosesratherthananysafetyconcerns.Treatment-naivepatientsweregiventhreedosesofinductionwithin6weeks;whereas,switchpatientsreceivedeachdoseatapproximately8-weekintervalsand,therefore,theswitchgroupgenerallytookbeyond30weeks(mean:34.5±8.1weeks)toreachdose6.{20}The5mg/kgdosewasreceivedbythemajorityofpatients(59%)and41%receiveddosesof5mg/kgto10mg/kg.Thestudypopulationincludedthosewhoweretreatment-naive(113/173,65.3%)andtreatment-switchfromthereferenceproduct(60/173,34.7%).Patientswereallowedtoreceivepremedicationsofanalgesics(acetaminophen),antihistamines(chlorpheniramine,piprinhydrinate),orcorticosteroids(hydrocortisone,dexamethasone,methylprednisolone)beforeorduringCT-P13infusion.Atleast1premedicationwasadministeredto49/173(28.3%)patients.Thefollowingconcomitantmedicationswerepermitted:acetaminophen,5-ASAwithnoincreaseindoseallowed,corticosteroids,othertopicalorsystemictreatmentsforUC,andantibioticsforIBD.RescuemedicationsweredefinedasinitiationofconcomitantmedicationafterthefirstinfusiondatetotreatneworunresolvedsymptomsofCDorUCandwereadministeredifneeded.Drugsadministeredwereantidiarrheals,intestinalanti-inflammatory/anti-infectives(e.g.,sulfasalazine),systemiccorticosteroids,andimmunosuppressants(azathioprine).Rescuemedicationwasadministeredto48/173(27.7%)ofpatients.Theinclusionoftreatment-naiveandtreatment-switchpatientsandtheadministrationofpremedicationsand/orrescuemedicationsalongwithCT-P13arereflectiveofclinicalpractice.

6. EXTRAPOLATIONOFINDICATIONS

6.1 Manufacturer’sRationaleforExtrapolationThedatatosupporttheIBDindicationisbasedonthetotalityofevidencecollectedfromthequality,non-clinical,andclinicalcomparabilityexercise.ApositionpaperpreparedbyCELLTRIONtosupportextrapolationinIBDissummarizedinthefollowingsections.RefertoCT-P13ExtrapolationPositionPaperwhichwassubmittedtoHealthCanada[30]forcompletedetails.a) Pathophysiology–Crohn’sDisease/UlcerativeColitisTNFαisapleiotropiccytokinewithnumerousbiologicalfunctions[31][30]andhasbeenshowntobecriticalinthepathogenesisofIBD[30,page26].BothCDandUCarechronicinflammatorydisordersthatarecharacterizedbyadysregulatedmucosalimmuneresponse.InCD,inflammationistypicallyseenthroughouttheintestinalwall;whereasinUC,inflammationistypicallyrestrictedtosuperficialtissuese.g.thelaminapropria.InIBDpatients,immunecellspresentattheinflammationsitewillleadtoanoverproductionofTNFα[32,33].MucosalinflammationinthesmallandlargeintestineduetoIBDisaccompaniedbybarrierdysfunctionwhichleadstotwomainconsequences.First,smallsolutesandwatercanflowintothelumenandcauseleakfluxdiarrhea.Secondly,largermoleculesandevenmicroflora,whichundernormalconditionseitherdonotorcrosstheepithelialbarriertoonlyasmalldegree,allowingforimmunetoleranceinduction.TNFαsignalingisalsoimplicatedinmucosaldamage,aswellasinthedevelopmentofulcersandfistulasviathestimulationofmyofibroblasts[34].MyofibroblastsareknowntocausedamagetostructuresoftheGItractbysecretingmatrixmetalloproteinases(MMPs).TheexpressionofMMPsisincreasedintheinflamedgutandhighlevelsofMMPshavebeenassociatedwithmucosaldegradation,ulcerationandfistulas[34].AsincreasedlevelsofTNFαarealsopresentintheinflamedgut,andmyofibroblastsareknowntobesensitivetopro-inflammatorycytokines,TNFαhasbeenproposedtobetheinitiatingfactorthatdrivestheincreaseinMMPs.Thissequenceofeventshasrecentlybeenconfirmedby[35]whohaveshownthatTNFαisabletoincreasetheexpressionofMMP-3inhumancolonicmyofibroblasts.TheroleofTNFαisalsorelatedtotheinductionoflocallyandsystemicallyproducedpro-inflammatorycytokines,increasingepithelialapoptosisandalteringT-cellregulationviareversesignalingpathways[36],[37].DamagetoepithelialcellsbydirecteffectofcytokinessuchasTNFαvianecrosisorapoptosiscancontributetothelossofepithelialbarrier.Indeed,therearesignificantchangesinepithelialtightjunctionstructureandfunction,notonlyinCDbutalsoinUC.Inaddition,therateofapoptosiswasalsofoundtobeupregulatedinUC,therebycontributingtothebarrierdefect.Interestingly,innon-IBDformsofcolitis,suchascollagenouscolitis,therateofmucosalapoptosisisnotaltered[38].Additionally,inhibitoryimpactofTNFαandothercytokinesonapoptosisofTlymphocytesresidinginlaminapropriacancontributetoimmunedysregulationandperpetualmucosalinflammation[38-40].Also,researchintogranulomashasprovidedfurtherevidencefortheroleofTNFαinpromotinginflammationinCD.Granulomasconsistofaggregatesofmacrophages,andassuchrepresentaspecializedtypeofinflammation.Theyappeartoformaroundforeignbodiesthattheimmunesystemisunabletoeliminate.GranulomasarecommonlyfoundinbiopsysamplesfrompatientswithCDandtheformationofthesecellularstructureshasbeenshowntoberegulatedbycomplexinteractionsbetweenTlymphocytesandmacrophagesandtobedependentuponTNFαsignaling[41][30,page27][42].Inconclusion,TNFαisimplicatedinthechronicinflammationinCDandUCandisalsoassociatedwithmucosaldegradation,ulcerationandfistulasinCD[30,page27-29][42,page165].TheprolongedexpressionofTNFαobservedinIBDanditspivotalroleinthepro-inflammatorycytokinecascade

indicatethatTNFαisamajordrivingfactorofchronicinflammationinCDandUC[30,page27][42],page164.b) MechanismofactionofinfliximabInfliximabisachimericIgG1mAbcomposedofavariablemurineFabregionlinkedtoahumanIgG1κconstantregion.InfliximabcanbindtoboththemonomerandtrimerformsofsTNFα[43].ThehighaffinitythatinfliximabdisplaystowardssTNFαsupportsitsuseininflammatorydiseasessuchasRA,PsA,ASandPsO,UCandCDinwhichsTNFαsignalingthroughbindingtoTNFR1andTNFRplaysadominantroleinthepathogenesisofthecondition[44][42,page167].InfliximabexertsitseffectintheameliorationofinflammatorydiseasessuchasCDandUCaswellasRA,AS,PsA,PsOthroughanumberofmechanismsofaction.ThesehavebeenevaluatedintheoriginalNDSincomparisonwiththereferenceproduct.TheywerealsoevaluatedinthesupplementalNewDrugSubmission(sNDS)withinthe3waysimilaritystudiesasdescribedinSection4.1.1. BindingandNeutralizationofSolubleTNFαpreventingitsbindingtoTNFRsandresultingin

blockingsTNFαinducedinflammatoryactivitiesincluding:• Inductionofpro-inflammatorycytokinessuchasinterleukins(IL-1andIL-6)[45]• Enhancementofleukocytemigrationbyincreasingendotheliallayerpermeabilityand

expressionofadhesionmoleculesbyendothelialcellsandleukocytes[46,47]• Activationofneutrophilandeosinophilfunctionalactivity[47-50]• InductionofacutephasereactantssuchasC-reactiveproteinandotherliverproteins[44],as

wellastissuedegradingenzymesproducedbysynoviocytesand/orchondrocytes[51]• Inductionofapoptosisoftissuecellssuchasintestinalepithelialcells[52]throughtheactivityof

sTNFαontheTNFR1receptor[30,page34].2. BindingtoTransmembraneTNFαbyInfliximab:InfliximabisabletobindtotmTNFαlocatedonthe

surfaceofvariouscelltypes.Thisresultsinanumberofeffectsthatinclude:• BlockingtheinteractionoftmTNFαwithTNFRs• Stimulationofreversesignalingpathwaysresultinginsuppressionofsecretionofpro-

inflammatorycytokinessuchasIL-1,IL-10andIL-12frommonocytes[53,54]• Inductionofregulatorymacrophages[55,56]• Stimulationofapoptosisinmonocytes[57]andTcells[58]

3. InductionofRegulatoryMacrophagesandWoundHealing:Macrophagesarepresentinallphasesofadultwoundhealing,andcontributetoinflammation,granulationtissueformation,andmatrixdeposition.Bothpro-inflammatory"M1"macrophagesandanti-inflammatoryorregulatory"M2"macrophagesexist.Pro-inflammatory"M1"macrophagesareproducedbyexposuretoIFN-γandTNFα[59]andsotheirproductionisinhibitedbyanti-TNFagentssuchasinfliximab.InIBDpatients,ithasbeenshownthatlaminapropriamacrophagesarepredominantlyoftheinflammatoryorM1phenotype[60,61].Theanti-inflammatoryM2phenotypeincludesM2a,theregulatorymacrophageswhichareactivatedbyIL-4andIL-13;theotherM2phenotypesareM2bandM2c[62].HencetheratioofM1andM2phenotypesarethoughttobeofimportanceintheetiologyofIBD.“Regulatory”macrophageshavealsobeentermed"woundhealing"macrophages[63],“AlternativelyActivatedMacrophages”[62]and“Mφ2”macrophages[56].RegulatorymacrophageshavebeenshowntoinhibitTcellproliferationviacellcontactand/orthereleaseofsolublemediators[56].

4. Complement-DependentCytotoxicity(CDC):FollowingbindingtotmTNFαonthecellsurface,infliximabmayinducecytotoxicityofthetmTNFαexpressingcellviacomplementactivation[58,64].InfliximabisoftheIgG1classandthereforecanbindcomplementC1q.Activationofthe

complementcascadecanprotectagainstinfectionbutininflammatorydiseasescouldcontributetothepathology.ComplementcomponentscaninduceCDCoftargetcellsresultingincelllysis.

5. Antibody-dependentcellularcytotoxicity(ADCC):ADCCistheimmunedefensemechanismswherebyimmuneeffectorcells(e.g.macrophagesorNK)bindtotheFcregiononantibody-antigencomplexesonthesurfaceoftargetcellsandtherebyactivelypromotetargetcelllysis.Antibody-dependentcell-mediatedcytotoxicityismediatedprimarilythroughasetofcloselyrelatedFcreceptorswhichhavebothactivatingandinhibitoryactivities,withFcγIIIabeingparticularlyimportantinthisrespect.Inconclusion,alltheknownputativemechanismofactionsattributedtoinfliximabhasbeenstudied,andsimilaritytothereferenceproductwasdemonstrated.MinordifferenceswereobservedincertainassaysforADCCactivitythatwerenotdeemedtobeclinicallyrelevant.PleaseseebelowasummarydiscussionoftheADCCevaluation.

c) JustificationofExtrapolation-QualityattributesandBiologicactivityCelltrionhaspresentedtheresultsofthe2-waysimilaritystudiescomparingCT-P13withEU-approvedREMICADE®intheoriginalCDRsubmission.InsupportoftheIBDindication;CELLTRIONhasperformedadditionallargenumberandwiderangeoforthogonal,highlysensitivemethodstoprovideameaningfulfinger-print-likealgorithmtoassesssimilaritybetweenCT-P13,EUandUSapprovedREMICADE®.TheresultsarehighlightedinSection4.1aboveandfurtherdetailsareprovidedinAppendix1.ThecomprehensiveanalyseshaveshownthatCT-P13issimilartoREMICADE®inprimarystructure,higherorderstructure,aggregateandmonomericpurity,andpost-translationalmodificationsnotwithstandingminordifferencesthathavebeendemonstratedtohavenoclinicallymeaningfulimpactonsafety,purityorpotency.TheextensiverangesofinvitroandexvivobiologicalassayshavedemonstratedsimilarbiologicalactivitiesforCT-P13andREMICADE®inassaysmimickingthemechanismsofactionofinfliximabinCDandUC[30,page71].BiologicActivityManyinvitrostudiesreportedintheliterature,havefoundthatinfliximabcaninduceADCCbutallthesestudiesemployengineeredTNFα-overexpressingcelllinesastargetcells[53,58,65].NotablyinfliximabisnotobservedtoinduceADCCinasystemcomprisedofnaturallyderivedcells.Specifically,whenlipopolysaccharide(LPS)stimulatedhumanmonocytesareusedastargetcellsandPBMCasasourceofeffectorcells,noobservableADCCisseeninresponsetoinfliximab[66].ThesefindingshavebeenreplicatedvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvwithpurifiedNKcellsassourceofeffectorcells.SinceLPSstimulatedhumanmonocytesareconsideredrepresentativeofthetargetcellsencounteredinvivointheintestineswheremonocytes/macrophagesareexpectedtobestimulatedbytheLPSpresentonthesurfaceofcommensalbacteria,theseresultssuggestthatADCCisnotlikelytoplayasignificantroleinmediatingthetherapeuticeffectofanti-TNFtherapiesinCDandUC.Interestingly,applyingtheexactsameexperimentalsystembutreplacingactivatedmonocytesasthetargetwithgeneticallyengineeredJurkatcellswhichoverexpressTNFαontheirsurfacecellbyapproximately25folddoesinducemeasurableADCCactivityusinginfliximab.

FurtherevidencethatADCCmaynotplayacriticalroleinefficacyofinfliximabinCDisprovidedbyanalysisoftherapeuticeffectofinfliximabinpatientsofdifferentFcγRIIIagenotypefollowingtreatment,asthebindingaffinityofFcγRIIIaV/VisotypeforFcregionofmonoclonalantibodiesishigherthanthatofthelowaffinityF/Fisotype.ForCD,publisheddatafromseverallargestudies[67-70]shownoassociationbetweenFcγRIIIagenotypeandclinicalresponsetoinfliximabandotherTNFα-antagonists.Althoughdifferenceswerenotedinbiologicalresponse(C-reactiveproteinlevels)intheearlyphasesof

treatmentinseveralCDstudies,thiseffectdidnotpersisttolaterphasesoftreatment,andnodifferencesweredetectedinclinicaloutcome[68,71].

d) JustificationofExtrapolation—PharmacokineticsSimilarityhasbeendemonstratedbetweenCT-P13andREMICADE®withrespecttoPKparametersinASpatientsandRApatients.Also,itseemsscientificallyjustifiedtoextrapolatePKprofilesforCT-P13acrossthedifferenttargetpopulationsgiventhattheCT-P13clinicalstudiesshowsimilarPKpropertiesacrossASpatientsandRApatientsaswellasbetweensingleandrepeatdosing;theappropriatenessoftheextrapolationisfurthersupportedbypublisheddataforREMICADE®showingnomajordifferencesinhalf-life,clearance,volumeofdistributionandotherPKparametersbetweenpatientsubgroupsandacrossalllicensedpopulations[30,pages72-80].Furthermore,thereal-worldexperiencewithCT-P13fromthesponsoredKoreanPMSstudyandnon-sponsoredHungarianNationwideIBDStudy[21],vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.

e) JustificationofExtrapolation—EfficacyandSafetyTheKoreanPMSstudyhasdemonstratedthatCT-P13issafeandeffectiveinpatientswithCD,UCandFCD.InlinewithpublisheddataonREMICADE®,CT-P13hasdemonstratedefficacyintermsofclinicalandendoscopicresponseandremission,fistula-closingandmucosalhealingeffects.Therewerenonewsafetysignalsreportedinthisstudy(pleaserefertoSection4.2aboveforfurtherdetails).

f) JustificationofExtrapolation—ImmunogenicityTheimmunogenicitywithCT-P13andREMICADE®acrossCT-P13clinicalstudieswassimilarinbothRAandASpatients.IncidenceratesofADAsandneutralizingantibodylevelsandtitervaluesweresimilarincontrolledstudiesupto1year.TheratesofIRRsbetweenCT-P13andREMICADE®werealsosimilar.TheefficacywassustainedandthepatternofefficacyandsafetyamongstADA-positiveandADA-negativepatientsweresimilarbetweenCT-P13andREMICADE®.ADAdatainIBDpatientsarenotavailable,howeverlowratesofIRRswereobservedinpost-marketingIBDstudieswithCT-P13.Furthermoreinvitrocross-reactivitydatawithCT-P13andREMICADE®againstserafromADA-positiveIBDpatientsareavailable(pleaserefertoSection4.3aboveforfurtherdetails).Overall,similarandconsistentimmunogenicityprofilewithCT-P13hasbeendemonstratedagainstREMICADE®intwodistinctpatientpopulations.

g) ClinicalDevelopmenttoSupportDoseAdjustmentRecommendationsIntheREMICADE®productmonograph,thereistheoptionforadultpatientswithCDwhorespondtoinfliximabandthenlosetheirresponsetouseanescalateddoseof10mg/kg.ClinicaldatainIBDpatientstreatedwithCT-P13indosesupto10mg/kgwithintheKoreanPMSstudyvvvvvvvvvvvvvvvvvhavebeencollected.vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv.Overall,theefficacyaccordingtoresponseandsafetyofCT-P13administeredathigherdosestovvvvvIBDpatientsappearedtobesatisfactory,vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv[30,page104].

ConclusionInsummary,CELLTRIONhasdemonstratedcleartherapeuticcomparabilitybetweenCT-P13andREMICADE®inRAwithsupportiveclinicaldatainASpatients.Inaddition,basedonanextensiveanalysisofthetotality-of-the-evidenceconsideringmechanismsofaction,structuralanalysis,functionalassaysandthesimilarityofpharmacokinetics,efficacy,safetyandimmunogenicity,combinedwithdatafrompost-marketingstudiesCELLTRIONconsidersthatthereissufficientscientificevidencetosupportextrapolationoftheCT-P13toCDandUCindicationsforwhichREMICADE®isregisteredinCanada.Asimilarsafetyprofilewasdemonstratedinatotalofapproximately1,000patientsexposedtotrialmedicationofwhichnearly500receivedCT-P13foruptotwoyearsorforayearfollowingtransitionfromREMICADE®.Additionallysafetydataareavailablefrom518CDandUCpatientswhohavereceivedCT-P13.ThesedatashowingeneralahighlysimilarsafetyprofiletoREMICADE®acrossallofthesepopulations.ImmunogenicityhasbeenshowntobehighlysimilarintwodifferenttherapeuticsettingsnamelyRAandAScoveringtheeffectoftwodifferentdoses(3and5mg/kg)andtheimpactofthepresenceorabsenceofMTX.Cross-reactivitystudiesandsomelimitedexperiencewithimmunogenicityevaluationinCT-P13ofREMICADE®.6.2 HealthCanada’sConclusiononExtrapolationAtthetimeoftheCDRsubmission,theIBDsNDSwasunderreviewbytheBiologicGeneticsTherapiesDirectorate.InJune2016,HealthCanadaauthorizedtheuseofCT-P13fortheIBDindicationsbasedonextrapolationfrompreviouslysubmittedclinicalstudiesinpatientswithRAandAS,comparablepharmacokinetics,andnewlysubmittedphysiochemicalandbiologicaldata.1WhentheNDSwasfiledtoHealthCanadain2012,marketauthorizationwasrequestedforalloftheindicationscurrentlyauthorizedforREMICADE®includingCDandUC.ThefollowingsectionistakenfromtheHealthCanadaSummaryBasisofDecisionforINFLECTRA®[72].“ComparabilitybetweenINFLECTRA®andthereferenceproductwasestablishedbasedoncomparativechemistryandmanufacturingstudies,andcomparativenon-clinicalstudies.Comparativepharmacokineticstudiesandclinicalstudiesinpatientswithrheumatoidarthritisorankylosingspondylitispatientsdidnotidentifyclinicallymeaningfuldifferences.Fortheremainingindicationsanduses,extrapolationwasrequired.Theindicationsforpsoriaticarthritisandplaquepsoriasisweregrantedonthebasisofsimilarityandtheabsenceofmeaningfuldifferences,betweenINFLECTRA®andthereferenceproduct,inproductquality,mechanismofaction,diseasepathophysiology,safetyprofile,anddosageregimenandonclinicalexperiencewiththereferenceproduct.However,extrapolationtoindicationsandusespertainingtoCDandUCcouldnotberecommendedduetodifferencesbetweenINFLECTRA®andthereferenceproductthatcouldhaveanimpactontheclinicalsafetyandefficacyoftheseproductsintheseindications.Thisarosefromtheobserveddifferencesinthelevelofafucosylation,FcγRIIIareceptorbinding,andsomeinvitroAntibody-DependentCell-MediatedCytotoxicity(ADCC)assays.ItwasconcludedthatdifferencesintheabilityofthetwoproductstoinduceADCCcouldnotberuledout.Therefore,sincedifferencesinADCChavebeenobservedbetweenthetwoproductsandbecauseADCCmaybeanactivemechanismofactionforinfliximabinthesettingofIBD,extrapolationfromthesettingsofrheumatoidarthritisandankylosingspondylitistoIBDcouldnotberecommendedduetotheabsenceofclinicalstudiesinIBD.”Pleaseseeabove,Section6.1,forasummaryofdatathathassincebeensubmittedaspartofasNDSfortheIBDindicationstoaddressthepotentialissuesraisedbyHealthCanada.

6.3 InternationalRegulatoryConclusionsonExtrapolationEuropeanMedicineAgency(EMA)TheEMAapprovedCT-P13(INFLECTRA®)fortheIBDindicationsviaextrapolationin2013.AspertheEMACommitteeforMedicinalProductsinHumanUseAssessmentReportforINFLECTRA®[73,page96]:“Inconclusion,byusingarangeofexperimentalmodelsthatareconsideredrepresentativeofthepathophysiologicalconditionsandputativemechanismsofactionofinfliximab,theApplicanthasprovidedconvincingevidencethatthedifferencedetectedintheamountofafucosylatedspecieshasnoclinicallyrelevantimpactontheefficacyandsafetyofCT-P13,inparticularinIBD.AdditionalinvitrodatafromhumanintestinalcellsarefurthersupportingextrapolationoftheclinicaldatatoIBD.”FoodandDrugAdministration(FDA)CT-P13hasbeenapprovedbytheFDAforallindications,includingCDandUCviaextrapolation[74].ThisfollowstherecommendationfromtheUSArthritisAdvisoryCommitteewhichrecommendedtheapprovalofCDandUCviaextrapolationofdata.AsperFDABriefingDocument,[75,pages70-72]:“ExtrapolationofDatatoSupportBiosimilarityinInflammatoryBowelDisease(IBD)Indications:CelltrionprovidedexperimentaldatasupportingaconclusionthatCT-P13andUS-licensedREMICADE®arehighlysimilarbasedonextensivestructuralandfunctionalanalyticalcharacterization.Further,CelltrionaddressedeachoftheknownandpotentialmechanismsofactionofUS-licensedREMICADE®.Asnoted,thereweresmalldifferencesbetweenCT-P13,US-licensedREMICADE®,andEU-approvedREMICADE®inglycosylation(a-fucosylation),FcγRIIIbinding,andsomeNK-basedADCCassays.InconsideringwhethertheapparentfractionalFcγRIIIbinding/ADCCdifferencesmaytranslateintoaclinicallymeaningfuldifferenceinIBD,theAgencyhasconsideredthefollowing:• ThebiologicalfunctionsthatthesubtleFcγRIIIbindingdifferencesmightimpact,namelyADCC,are

withinthequalityrangeofCelltrion’sdataonthereferenceproduct.• ThemechanismofactionofTNFinhibitorsintreatingIBDiscomplexand,ADCCisonlyoneofthe

severalplausiblemechanismsofaction.ItisnoteworthythatproductswithoutanyADCCcapabilityhavebeenapprovedforthetreatmentofpatientswithCD(i.e.certolizumab),whilethepossibleADCCdifferencebetweenCT-P13andUS-licensedREMICADE®issmall.CelltrionhasalsoprovideddatatodemonstrateanalyticalsimilarityinalltheotherpotentialmechanismsofactionofinfliximabinIBD.

• ThehistoricalIBDclinicaltrialdesign,includingthoseforREMICADE®,oftenutilizeddosesandtimingofprimaryendpointassessmentsthatareinthetherapeuticplateau,andthusclinicaloutcomemeasures(e.g.,clinicaleffectofsmalldifferencesinADCCandFcγRIIIbinding.

Therefore,basedontheaboveconsiderations,itisreasonabletoextrapolateconclusionsregardingsimilarefficacyandsafetyofCT-P13andUS-licensedREMICADE®toIBD.Inaggregate,theevidenceindicatesthattheextrapolationofbiosimilaritytotheindicationsforwhichCelltrionisseekinglicensure(PsA,PsO,adultandpediatricCD,andadultandpediatricUC),maybescientificallyjustified.”AustralianTherapeuticGoodsAdministration(TGA)TheTGA,afterevaluationfromtheAdvisoryCommitteeonPrescriptionMedicines(ACPM),approvedandregisteredINFLECTRA®forboththeCDandUCindicationsviaextrapolationinAugust2015.AsperaPublicSummaryDocument:

“TheACPMhasstatedthereweresufficientdatatodeclareINFLECTRA®abiosimilarforREMICADE®andtoextrapolatetheconclusionofequivalentefficacyfromtherheumatoidarthritisandankylosingspondylitisindicationsforwhichevidencewasprovidedtoIBDconditions”[76,page4]6.4 CDRCommentsonExtrapolation

HealthCanadaconsidersseveralfactorswhendecidingontheappropriatenessofextrapolatingauthorizationfromoneindicationtoanother.Thesefactorsinclude:17• similaritybetweenproducts(minor,unimportantdifferencesmayhaveclinicalimpact)• similarityinmechanismofactionforeachcondition• mechanismsofthediseasestobetreated• similaritiesinclinicalexperience• typeanddesignoftheclinicaltrials,populations,andendpointsmeasured• routeofadministration,dosage,andregimen.

HealthCanadareviewsqualityinformationofthebiosimilarcomparedwiththereferenceproduct,assessesthatthemostsensitivepopulationandbestendpointswereincludedinclinicaltrials,andevaluateswhetherthebiosimilarandreferenceproducthavesimilarsafetyandimmunogenicity(>100patientsandsufficientlylongduration).17InCADTH’spreviousreviewofInflectra,18HealthCanada’sdecisionsaboutextrapolatingdatafromtheRAandASindicationstoPsOandPsAwereprovided.ThedecisiontoextrapolatetoPsOandPsAweresupportedbycommondiseasepathologies,commonmechanismofactionofanti-TNFalphadrugsinthesediseases,andsimilaritiesinproductquality,safety,andPK.Atthattime,HealthCanadadidnotsupportextrapolatingdatafromRAandAStoIBDduetodifferencesindiseasemechanisms(roleoftmTNFalphaandADCCinIBD)andsafetyprofilesofinfliximabinIBDversusrheumaticdiseases(higherriskofhepatosplenicT-celllymphomainIBD).18Thesefactorsareexplainedinmoredetailbelow,under“PointsaboutextrapolationidentifiedbyHealthCanada.”InJune2016,HealthCanadaauthorizedtheuseofCT-P13fortheIBDindicationsbasedonextrapolationfrompreviouslysubmittedclinicalstudiesinpatientswithRAandAS,comparablepharmacokinetics,andnewlysubmittedphysiochemicalandbiologicaldata.1HealthCanadaissuedanNOCforInflectrafortheindicationsofCD,FCD,andUConJune10,2016.Theapprovedindicationsareasfollows:19• Reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosal

healing,andreductionofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveCDwhohavehadaninadequateresponsetoacorticosteroidand/oraminosalicylate.Inflectracanbeusedaloneorincombinationwithconventionaltherapy.

• TreatmentofFCD,inadultpatientswhohavenotrespondeddespiteafullandadequatecourseoftherapywithconventionaltreatment.

• Reductionofsignsandsymptoms,inductionandmaintenanceofclinicalremissionandmucosalhealing,andreductionoreliminationofcorticosteroiduseinadultpatientswithmoderatelytoseverelyactiveUCwhohavehadaninadequateresponsetoconventionaltherapy(i.e.,anaminosalicylateand/oracorticosteroidand/oranimmunosuppressant).

TheEMA,FDAandtheAustralianTherapeuticGoodsAdministrationapprovedCT-P13foruseinadultpatientswithCDandUCbasedontheextrapolationofefficacyandsafetydataforRAandAS.20-22ThesejurisdictionshavealsoextendedusetopediatricpatientswithCDorUC;asidefromtheFDAwhichhasnotapprovedCT-P13forpediatricUC.ClinicalTrialEvidenceforRAandAS:Rigorousclinicaltrials,comparingCT-P13withRemicade,havebeenconductedwithPLANET-RAforRAandPLANET-ASforAS.ThisevidencewasevaluatedindetailinthepreviousCADTHsubmissionforInflectra.18PLANET-RAwasaphaseIIIRCTinpatientswithRA(N=606).CT-P13orRemicadewereadministeredat3mg/kgalongwithMTXplusfolicacid.Thetrialdemonstratednodifferencesinefficacy,safety,immunogenicity(developmentofADA),orPK.PLANET-ASwasaphaseIRCTinpatientswithAS(N=250).CT-P13orRemicadewereadministeredat5mg/kg.SimilarPK,efficacy,safety,andimmunogenicityweredemonstrated.18PointsAboutExtrapolationIdentifiedbyHealthCanada:Inthepathologyandmechanismsofactionofanti-TNFalphadrugsforRA,ASandIBD,somedifferencesexistthatpresenteduncertaintiesinextrapolatingbetweenthesediseaseconditions.ThepredominantformofTNFinRAandASissTNFalpha;whereas,inCDandUC,tmTNFalphaplaysanadditionalandcentralrolebyinitiatingreversesignallingpathways.23Also,unlikeRAandAS,inboweldiseasesADCCisanimportantmechanismofactionandismediatedbyafucosylationandFcγIIIareceptorbinding.MinordifferenceshavebeenobservedbetweenCT-P13andthereferenceproductinFcγIIIabindingandADCCactivityusinginvitroassayswithNKcellsfrompatientswithCDandV/VorV/FFcγIIIagenotype(nodifferenceobservedwithF/Fgenotype).InotherassaysusingPBMCsfrompatientswithCDandV/ForF/FFcγIIIagenotype,nodifferenceinADCCactivitywasobserved.24TheclinicalrelevanceofdifferencesinADCCactivitymaybeminor.Etanerceptisanotheranti-TNFalphadrugthatisclinicallyeffectiveinRAbutnotinIBD,possiblybecauseitislessefficientatreversesignallingandapoptosis.23However,thestructureofetanerceptdiffersfrominfliximabandthisresultsinadistinctefficacyprofile.23CT-P13wasshowntobecomparabletothereferenceproductwithrespecttoreversesignallingandapoptosis.19Hepatosplenic-TcelllymphomahasbeenobservedtooccuratahigherincidenceinadolescentandyoungadultmaleswithCDorUCwhoaretreatedwithinfliximabincombinationwithazathioprineor6-mercaptopurine.19OtherConsiderationsAboutExtrapolatingtoIBD:TheclinicalmanagementofIBDdiffersfromRAandAS.Forexample,MTXisanimmunosuppressantthatisnotadministeredasfrequentlyforIBDasitisforRAorAS.TheuseofMTXincombinationwithinfliximabhasbeenshowntoreducethedevelopmentofimmunogenicity(i.e.,theformationofADAagainstinfliximab).23Thedevelopmentofimmunogenicityisacriticalfactorinthelossofresponsetobiologicaldrugtreatment.25TheeffectofothermedicationregimensonimmunogenicitythatareadministeredwithinfliximabinIBD,suchasazathioprine,corticosteroids,or5-ASA,isunclear.Inastudyof174patientswithCD,concomitantadministrationofMTXorazathioprinewithinfliximabwasfoundtoreducetheincidenceofATIformation(46%versus73%withinfliximabmonotherapy);however,nodifferencesinATIformationwereobservedbetweeninfliximabplusMTXandinfliximabplusazathioprine.{44}Furtherinvestigationoftheeffectofimmunosuppressantregimensonimmunogenicityisneeded.Secondly,themaximumdoseofinfliximabforIBDis10mg/kgandishigherthanthedosesusedinPLANET-RAorPLANET-AS.AlthoughinvitrostudieswiththeseraofpatientswithIBDwhodeveloped

ADAafterRemicadewerefoundtobecross-reactivewithCT-P13,suggestingsimilarfeaturesofimmunogenicity(Section4.4),theimmunogenicsimilarityofthehigherdoseofCT-P13withregularorhigherdosesofRemicadeisuncertain.ThereisalsoamicrobiologicalcomponenttoIBDthatisabsentinRAorAS.PatientswithIBDareathighriskforbacteremia/sepsisandinfectionssuchasshingles,skininfections,andpneumoniaandrequireclosemonitoring,especiallyduringtreatmentwithinfliximab.

7. COSTCOMPARISONTheInflectra100mg/vialdrugproductwillcarrya44%lowerprice($525.0000)relativetothecurrentlylowest-listedpriceofRemicade100mg/vial,whichisat$940.0000pertheRégiedel'assurancemaladieduQuébec(RAMQ).Consequently,the44%costdifferentialequatesto$415.0000savingsper100mgvial.PleasenotethattheListPriceofREMICADE®inallotherProvincesinCanada(excludingQuebec)is$987.0000per100mgvial.ThereforethecostsavingsofINFLECTRA®versusREMICADE®inprovincesoutsideQuebec(47%or$462lessexpensivethanREMICADE®)isactuallygreaterthanwhatisshowninthefollowingtables

TABLE5:COSTCOMPARISONOFINFLECTRAANDREMICADEFORCROHN’SDISEASE(FIRSTYEAR)

Drug/Comparator Strength DosageForm Price($) RecommendedDosec

AverageDrugCost($)/Year

Inflectra 100mg/vial Lyophilizedpower $525.0000a 5mg/kg $16,800Remicade 100mg/vial Lyophilizedpower $940.0000b 5mg/kg $30,080

aPublicprice.bRAMQListofMedications,updated2016-02-08.cInflectraandRemicadeproductmonograph.

TABLE6:COSTCOMPARISONOFINFLECTRAANDREMICADEFORCROHN’SDISEASE(SUBSEQUENTYEAR)

Drug/Comparator Strength DosageForm Price($) ExpectedDosec

aPublicpricebRAMQlistofMedications,updated2016-02-08cInflectraandRemicadeproductmonograph

TABLE7:COSTCOMPARISONOFINFLECTRAANDREMICADEFORULCERATIVECOLITIS(FIRSTYEAR)

Drug/Comparator Strength DosageForm Price($) RecommendedDosec

aPublicprice.bRAMQlistofMedications,updated2016-02-08.cInflectraandRemicadeproductmonograph.

TABLE8:COSTCOMPARISONOFINFLECTRAANDREMICADEFORULCERATIVECOLITIS(MAINTENANCEATEVERY7WEEKSA),(SUBSEQUENTYEAR)

Drug/Comparator Strength DosageForm Price($) ExpectedDosec

aPublicprice.bRAMQlistofMedications,updated2016-02-08.cInflectraandRemicadeproductmonograph.

CDRReviewerCommentsRegardingCostInformationSummaryoftheManufacturer’sAnalysisSEBinfliximab(Inflectra)isavailableasa100mg/vialsolutionforintravenousinfusionatamanufacturersubmittedpriceof$525.00pervial.27ThemanufacturersubmittedacostcomparisonbetweenInflectraandreferenceinfliximab(Remicade)forthreeindications:adultpatientswithmoderatelytoseverelyactiveCD,FCD,andUC.27Themanufacturerassumedaweight-baseddoseof5mg/kgforInflectraandRemicadeforthethreereviewedindications.Undertheassumptionofsimilareffectandusageoftheinterventions,thecostsavingsofInflectracomparedwithRemicadewerereportedtobe44%ofthemanufacturer’sbasecase;usingtheRAMQ(Quebec)listpriceforRemicade($940.00per100mgvial).FortheotherCanadianjurisdictions,thedifferencewasreportedtobeupto47%ofthemanufacturer’sbasecase(Remicadeprice:$987.00per100mgvial).27CDRAssessmentoftheManufacturer’sCostComparison• UsingtheOntarioExceptionalAccessProgram(EAP)priceofRemicadeasareference,28theannual

costofInflectrais47%lowerthanthatofRemicade(refertoTable9).

TABLE9:INFLIXIMABDOSINGBASEDONTHEMANUFACTURERSCOSTCOMPARISONTreatment/Indications

TimePeriod RecommendedDosea

NumberofTreatments/Yeara

Priceper100mgVial($)b

AnnualCost($)c

Inflectra/CDandUC

Firstyear 5mg/kg 8 525.0000 16,800Subsequentyears

5mg/kg 6.5 525.0000 13,650

Remicade/CDandUC

Firstyear 5mg/kg 8 987.5600 31,601Subsequentyears

5mg/kg 6.5 987.5600 25,677

CD=Crohn’sdisease;UC=ulcerativecolitis.aInflectraandRemicadeproductmonograph.bManufacturersubmittedpriceforInflectra;27OntarioEAPpriceforRemicade.28cAssumespatientweightisbetween60kgto80kg.IssuesforConsideration• GiventhecomplexitiesofmanagingIBD,theclinicalexpertnotedthatphysiciansandpatientsmay

bereluctanttoswitchfromRemicadetoInflectrawhenapatientisadequatelymanagedonRemicade.Asaresult,InflectramaybemorelikelytobeusedinpatientswhoarenewlystartinginfliximabratherthanthoseswitchingfromRemicade.

• ThemanufacturerofRemicadesponsorsinfusioncentresfortheadministrationofRemicade,andcoverscostsofpatientfollow-upandmonitoring.ThesecostsareexpectedtobesimilarlycoveredbythemanufacturerofInflectra,therefore,thisisnotexpectedtoresultinadditionalcoststothepubliclyfundedhealthcarepayer.10

• ThedosageofInflectraisbasedonpatientweight.ConsideringthatInflectraandRemicadehavesimilarpharmacokinetics,pharmacodynamics,clinicalefficacyandharms,andsharethesamedosingstrategies,therelativecostdifferencebetweenthedrugsisthereforelikelytobemaintainedregardlessofpatientcharacteristicsorrequireddailydose.

• Basedontheproductmonograph,thedoseofinfliximabinpatientswithUCandCDcanbeincreasedtoupto10mg/kg.19DoseescalationwouldsimilarlyimpactthecostofbothInflectraandRemicade,therelativecostdifferencewouldthereforenotbeaffected.However,thiscouldaffect

thecostdifferentialwithothertreatmentsfortheseindications.• Inflectra(SEBinfliximab)waspreviouslyreviewedbyCADTHforfourindications:RA,AS,PsA,and

PsO.ItwasrecommendedthatInflectrabelistedinaccordancewiththeHealthCanadaindicationandinasimilarmannertoRemicade.29

• ThelistingcriteriaforRemicadedifferacrosspubliclyfundeddrugplansinCanada;whereas,Remicadeisavailableasarestrictedbenefitwithspecificlistingcriteria(Appendix2).TheexpectedsavingsfromInflectracomparedwithRemicadearebasedontheassumptionthatthelistingcriteriaforRemicadewouldbeappliedtoInflectra.

ConclusionAtthesubmittedprice,theannualcostofInflectrais47%lessthanthereferenceproductinfliximab(Remicade)whenusingtheOntarioEAPpriceforRemicade($987.56)asareference.

8. DISCUSSION

BiologicaldrugsareimportanttreatmentoptionsforinducingandmaintainingremissionofCDandUC.InCanada,thethreeanti-TNFalphadrugsapprovedforIBDareinfliximab,adalimumab,andgolimumab.23Thesedrugsmaybeusedinstep-uporstep-downtreatmentapproaches.Inthestep-upapproach,5-ASAisprescribedinitially,followedbycorticosteroids(e.g.,topicalfoams,budesonide,prednisone),immunosuppressants(e.g.,azathioprine,MTX),andanti-TNFalphadrugsifsymptomsarenotcontrolled.Inthestep-downapproach,drugsatthehigherendofthetreatmentladderareinitiatedfirst,followedbydownwardtitrationtothedrug(s)thatofferthemostfavourableprofileofsymptomcontrolandminimizationofadverseeffects.30CT-P13isabiosimilarofthereferenceinfliximabproduct,Remicade,andoffersanother,potentiallycost-effective,treatmentoptionforCDandUC.Abiosimilarproductisdesignedtobesimilartoareferenceproductthatisalreadybeingusedinclinicalpractice.Themolecularcomplexityofbiologicscomparedwithotherdrugsrequiresclosescrutinyofthebiosimilar’sPK,efficacy,safety,andimmunogenicity.TheclinicalevidencefortheuseofCT-P13inIBDwasbasedonobservationaltrials.NodirectcomparisonswithRemicadeinthispatientpopulationwereavailable.Datafrominvitrostudiessuggestsimilarimmunogenicity,sTNFalphaandtmTNFalphabinding,andADCCactivityusingPMBCsamongCT-P13andRemicade,althoughdifferencesinADCCactivityusingNKcellswereobserved.SomedifferencesbetweenIBDandRAorASexist,suchasthegreaterrolesoftmTNFalphaandADCC,higherinfliximabdosingrequirements,andadministrationofdifferentimmunosuppressanttreatmentregimensinIBD.TheresultsoftheongoingRCT(CT-P133.4)areanticipatedtoprovideadditionalevidencetoassesstheefficacyandsafetyofCT-P13comparedwithRemicadeinIBD.Inaddition,theexperiencesofjurisdictionsthatarealreadyusingCT-P13forIBD,suchastheUS,Korea,andvariousEuropeancountries,canbeusedasaguidefortheongoingassessmentofitsefficacyandsafety.Nonewsafetysignalshaveemerged,althoughcontinuedlong-termmonitoringisneeded.TheCanadianAssociationofGastroenterologyhasissuedapositionstatementonSEBsforIBD.31Theysupporttheuseofbiosimilarsaspotentiallyeffectiveandcost-savingoptions,butemphasizethatevidencefromclinicaltrialsrelevanttoCanadiansshouldbeavailabletosupporttheiruseinpractice.PatientgroupsforIBDhavealsovoicedtheirconcernsabouttherapiesbeingchosenbasedsolelyonconsiderationsofcost(Appendix3).Theyhaveindicatedthatdiseaseremissioncanbedifficulttoobtainandthatchangestotherapy,includingswitchingfromaninnovatorproducttoanSEB,shouldnotbemadewithoutapatient’sconsent.Expertknowledge,open-dialogue,andpatientchoicewillbeintegraltoeffectivelyimplementingCT-P13inclinicalpractice.HealthcareprovidersandpatientsshouldbeprovidedwithinformationaboutHealthCanada’sSEBregulatoryprocess,theclinicalevidenceavailableforCT-P13,andtherationalebehindextrapolation.Post-marketingdataofCT-P13willbecriticalformonitoringexpectedandnewsafetysignalsandtoensurethatbenefitsoutweighrisksinbothtreatment-naiveandtreatment-switchpatients.Assessmentofimmunogenicityandincidenceofserioussideeffects,suchashepatosplenicT-celllymphoma,willbeneededforevaluatingCT-P13’srisk-benefitprofile.GiventheinterimnatureoftheCT-P13PMSstudy,itwillbeimportanttoassessiftheobservedresultsremainstableoverseveralyears.

PotentialPlaceinTherapy2Thereferenceinfliximabproduct,Remicade,iscurrentlyusedforpatientswithmoderatetosevereCDandUCaloneorincombinationwithimmunomodulatorssuchasazathioprine.Itiseffectiveintreatingperianaldiseaseaswellasluminalinflammation.OccasionallypatientsarestartedonRemicadeimmediatelyupondiagnosis,butmoreoftenbothprivateinsurersandpublicdrugplansindicatethatpatientsshouldfirsthavebeeninadequatelymanagedwith5-ASA,steroids,andimmunomodulatorssuchasazathioprine.Remicadehasasimilaractionandefficacytootheranti-TNFalphadrugs,andisadministeredundersupervisionatinfusioncentres.Forsomepatients,contactwithhealthprovidersonaregularbasisishelpful,whileforothers,self-administrationispreferred,inwhichcaseanotheranti-TNFalphadrugs,suchasadalimumab,maybeused.CT-P13isanSEBthatdoesnotaddtoavailabletherapyoptionsbutprovidesalessexpensivealternativetoanestablishedtherapy.Itisnotdesignedtobenovelbuttobesimilartothereferenceproduct(Remicade).AsignificantpercentageofpatientswithIBDdonothaveinsuranceforthecostofmedications,oftenbecausethediseaseaffectsyoungerindividualswhomaynotyethavedrugplaninsurance.32Followingdiseaseonset,insuranceisverydifficulttoobtain.Therefore,thepotentialcostsavingsofCT-P13inthispopulationwouldbeadvantageous.Bothprivateandpublicdrugplanshaveguidelinesinplacethatstipulatewhichpatientsareeligiblefortreatmentwithanti-TNFalphadrugs,andCT-P13willfitwithinthatframework.Animportantquestion,whichwillneedtobeaddressedifthedrugisintroduced,iswhetherpatientswhoarestableonRemicadewillhavethedrugsubstitutedwithCT-P13orwhetheritwillonlybeusedintreatment-naivepatients.Endoscopicevaluationofdiseaseactivitymayberequiredinpatientswhoexperienceadiseaseflareafterswitching,andtherearesignificantbarrierstothatintermsofaccesstoendoscopyprocedures.Observationalcohortstudiesfromdifferentcountriessuggestthatdiseaseactivityandadverseeffectsaresimilarbeforeandafterswitching.However,giventhelimitationsofobservationalstudies,theassessmentandpredictionofpatientresponseuponswitchingfromRemicadetoCT-P13willrequireclosemonitoring.

2ThisinformationisbasedoninformationprovidedindraftformbytheclinicalexpertconsultedbyCDRreviewersforthepurposeofthisreview.

9. CONCLUSION

CT-P13providescliniciansandpatientswithanotherpotentiallycost-effectivechoiceofabiologicaldrugforIBD.ThefocusofthisCDRreviewofCT-P13(Inflectra)isfortherecentlyapprovedindicationsofCD,FCD,andUCinadultpatients.TheNoticeofCompliance(NOC)fortheCD,FCD,andUCindicationswasgrantedsubsequenttoanearlierNOCforCT-P13fortheindicationsofRA,AS,PsO,andPsA.Ofnote,HealthCanadaapprovedtheindicationsofPsOandPsAbasedontheextrapolationofdatafromstudiesconductedwithpatientswithRAandAS.AllclinicalevidencecurrentlyavailableforCT-P13inpatientswithIBDisbasedonobservational,open-labelstudiesfromKoreaorEuropeinsmallnumbersofpatients.Thepivotalstudy,CT-P13PMS,isanobservational,open-labelstudyconductedinSouthKoreainpatientswithIBD,witha30-weekinterimanalysis.NaiveindirectcomparisonsofCT-P13withstudiesofRemicade(infliximab)suggestsimilarefficacyandsimilarsafetyforsomesafetyendpointsinpatientswithCDorUC.Nonetheless,intheabsenceofdatafromRCTs,theclinicalsimilarityofCT-P13andRemicadeforIBDintheCanadianpopulationremainsuncertain.GiventhattheresultsofCT-P13PMSarebasedonaninterimanalysis,theongoingmonitoringofCT-P13inpatientswithIBDwillbeimportantforevaluatinglong-termefficacyandsafety.

APPENDIX1:ADDITIONALDATAPleaseincludeanylargetablesorfiguresinthissectionofthetemplate.Pleaseensurethefollowingisincluded:• Allitemsinthissectionmustbewell-labelled(e.g.,Table6:AdverseEventsfromStudyX).Allitemsinthissectionmustbeclearlyreferencedinthemainbodyofthetemplate.Forexample,“pleaseseeTable6inAppendix1forcompletedetailsregardingtheadverseeventsreportedintheStudyX.”TABLE10:HIGHLEVELOVERVIEWOFTHETESTSANDCONCLUSIONSFORTHEOLIGOSACCHARIDEPROFILINGANDBIOLOGICACTIVITYCOMPARISONBETWEENCT-P13ANDREMICADE®

Typeofstudy(s) Briefoverviewoftestsandconclusions ReferencesBindingofsolubleandtransmembraneTNFαOligosaccharideprofiling • HPAEC-PADTest

• Tocharacterizetheglycanmicro-heterogeneityassociatedwiththesinglesiteofN-glycosylation(Asn300),glycanswereenzymaticallycleavedusingPNGaseFandresolvedusingchromatography.

• TheHPAEC-PADdatarevealthatthetypeandproportionoftheunchargedglycansisreasonablyconservedbetweenCT-P13,EUandUSapprovedREMICADE®.

• Minordifferencesinafucosylatedglycans:meanvaluesofMan5+G0,forEUandUSapprovedREMICADE®byHPAEC-PADwerevvvvvvvvvvvvv,respectively,comparedtovvvvvFORCT-P13.

CTDModule3.2.R.2.7

EffectofblockingsolubleTNFαinvitroIBDmodel

• InhibitionofInflammatoryCytokines(IL-8)fromCaco-2cellstest

• TheabilityofCT-P13,EUandUSapprovedREMICADE®toinhibitreleaseofinflammatorycytokines(IL-8)fromanintestinalepithelialcelllinefollowingstimulationwithcytokines(TNF-α,IL-1,LPSandIFN-γ)wasevaluated.

• Thedataindicatethatthe3productsarecomparableinrelativesuppressionofcytokineinCaCo-2cellswithmean±SDvaluesforCT-P13,EUandUSapprovedREMICADE®.

CTDModule3.2.R.2.8.1.6

tmTNFαReceptorSignalingStudies

• Suppressionofcytokinereleasebyreversesignalingtest• Thismethodwasdevelopedtomeasurereversesignaling

resultingfromsamplesbindingtotmTNFαandresultingininhibitionofLPS-inducedcytokinerelease(TNFα)fromPeripheralBloodMononuclearcells(PBMCs).

• PBMCsfromhealthysubjectswereisolatedandthenincubated,withsamplesoverarangeofconcentrations.

• TherelativeinhibitionofcytokinereleaseinducedbyreversesignalingonbindingofCT-P13issimilartothatofEUandUSapprovedREMICADE®.Themeanvaluesforeachconcentrationalsoindicatecomparableactivityofthe3productsininhibitionofcytokinereleasebyreversesignaling.

Typeofstudy(s) Briefoverviewoftestsandconclusions References• Inductionofapoptosisbyreversesignalingtest• Apoptoticactivity,resultingfromantibody-induced

signalingafterbindingtotransmembranewasconductedusingtherecombinantJurkatcelllinewhichstablyexpressestmTNFα.

• TheapoptosisassaywasperformedusingacommerciallyavailablekitwhichlabelscellsusingAnnexin-V/PItodeterminethenumberofapoptoticcells.

• TherelativeinductionofapoptosisthroughreversesignalingofCT-P13,EUandUSapprovedREMICADE®aresimilar.

Fcf(ab’)2relatedEvaluationofRegulatoryMacrophageFunction

• EffectofInfliximabonSuppressionofTCellProliferationbyRegulatoryMacrophagesinMixedLymphocyteReaction(MLR)Assay

• TheMLRrequiresmixingofHumanLeukocyteAntigendisparatePBMCfrom2individualsthatarenonethelessmatchedforFcγRIIIagenotype.

• CT-P13,EUandUSapprovedREMICADE®inducedregulatorymacrophagesintheMLRassay.SimilaritywasobservedbetweenCT-P13andEUandUSapprovedREMICADE®atallconcentrations.

CTDModule3.2.R.2.8.2

• QuantitationofInfliximab-InducedRegulatoryMacrophagesbyFACS

• Adose-dependentinhibitionofTcellproliferationofPBMCsfromhealthydonorswasinducedbyCT-P13EUandUSapprovedREMICADE®.

• Similaractivitywasdetectedforthe3products.• EffectofWoundHealingbyRegulatoryMacrophages• Theeffectoftheinducedmacrophagesonscratchesina

colorectalcelllayer(HCT116)wasdeterminedinawoundhealingassay.

• Woundhealingmodelsusingbidirectional(V/F+V/F)MLRwithPBMCfromhealthydonorsanddemonstratedthattherewascomparableactivityforCT-P13andEUandUSapprovedREMICADE®withrespecttotheabilityofinducedregulatorymacrophagestopromotewoundhealing.

CDCStudies • Complement-dependentcytotoxicity(CDC)Activity• C1q-bindingisfollowedbyactivationofC1qenzymatic

activityandsubsequentactivationofthedownstreamcomplementcascade.Thelevelofcytotoxicactivitywasmeasuredbyviablecellcountingusingakit.

• ThemeanrelativebindingvaluesforCT-P13,EUandUSapprovedREMICADE®weresimilar.

• C1qbindingaffinity(ELISA)• BindingaffinityofCT-P13EUandUSapproved

REMICADE®toC1qwasmeasuredbyELISA.• ThemeanrelativebindingvaluesCT-P13,EUandUS

approvedREMICADE®weresimilarforC1qbinding

Typeofstudy(s) Briefoverviewoftestsandconclusions Referencesaffinity.

FcγreceptorBindingStudies

• ComparativebindingtoFcγreceptors:FcγRIbindingaffinity(ELISA),FcγRIIa,FcγRIIbandFcRnbindingaffinity

• ThemeanrelativebindingaffinityvaluesFORCT-P13,EUandUSapprovedREMICADE®showthatthe3productshavecomparableinFcγRIIa,FcγRIIbandFcRnbindingaffinityThethreeproductshavebeendemonstratedtohavesimilarbindingaffinity.

CTDModule3.2.R.2.8.4

• ComparativebindingtoFcyreceptors:FcγRIIIa(VandFhemizygotes)andFcγRIIIbbindingaffinity(SPR)

• Usingthevvvvvvvvvinstrument,thebindingofCT-P13,EUandUSapprovedREMICADE®wasmeasuredinrealtimeat3concentrationstotheimmobilizedFcγRIIIa(Vtype)ligandbymeasuringchangesintherefractiveindex.

• TheresultsdemonstratethattheFcγRIIIa(Vtype)bindingaffinityofEUandUSapprovedREMICADE®batcheswassignificantlyhigherthanforCT-P13,confirmingthedataobtainedinthepreviousstudysubmittedintheNDSshowingFcγRIIIa(Vtypepolymorphicvariant)bindingaffinityisdependentontheafucosylationlevel(CTDModule3.2.R.5,Sequence0000).

• ThisdifferenceinbindingbetweenCT-P13andREMICADE®ismuchsmallerthanthedifferenceinbindingtoFcγRIIIaofdifferentgenotypes.Studieshavefailedtodiscernaclinicaldifferenceinresponse(Crohn’sDiseaseActivityIndex[CDAI])followinginfliximabtreatmentbetweenCDpatientsexpressingthelowaffinityF/FgenotypecomparedtothoseexpressingthehighaffinityV/Vgenotype[67].

• ThemeanrelativebindingaffinityvaluesINFLECTRA®,EUandUSapprovedREMICADE®indicatesomedifferenceinbindingaffinitytoFcγRIIIbalthoughvvvvvvvvbatchesofINFLECTRA®werewithinthemean±3SDofEUapprovedREMICADE®batchesandvvvvvvvvbatcheswerewithinthemean±3SDofUSapprovedREMICADE®batches.

• TheclinicalrelevanceofanypossibledifferencesinFcγRIIIbbindingaffinitywereinvestigatedinpreviousstudiessubmittedintheNDScomparingtheabilityofCT-P13andEUapprovedREMICADE®tobindtoNeutrophils,whichexpresspredominantlyFcγRIIIbonthecellsurface.ThesestudieswerepresentedinCTDModule3.2.R.5(Sequence0000)anddemonstratedthatthereisnodifferenceinbindingofCT-P13andEUapprovedREMICADE®toneutrophilsfromhealthyvolunteersandCDpatients.Thus,anydifferenceobservedinbindingaffinitytoFcγRIIIbbySPRappearstohavenoclinicalsignificance.

CTDModule3.2.R.2.8.4.1CTDModule3.2.R.2.8.4.2

Typeofstudy(s) Briefoverviewoftestsandconclusions References• ComparativebindingtoRcyreceptors:Exvivoassay(NK

cellsfromHealthyPBMC• ToassessifthedifferencesbetweenCT-P13,EUandUS

approvedREMICADE®inFcγRIIIa(V-typeandF-typepolymorphicvariants)bindingasdeterminedbySPRtranslateintofunctionaldifferencesrelatedtobindingtotheFcγRIIIapresentonNKcells,exvivoNKcellbindingstudieswereconductedinthe3-wayabridgedstudy.NKcellsareknowntoexpressFcγRIIIaontheircellsurfaceandserveassuitableexvivomodelfortheassessmentofFcγRIIIabinding.

• ThemeanrelativebindingofCT-P13,EUandUSapprovedREMICADE®inthepresenceof1%bovineserumalbuminshowsomedifferencebetweenCT-P13andREMICADE®.Howeverinthemorephysiologicallyrepresentativeconditionsinthepresenceof50%humanserum,themeanrelativebindingofCT-P13,EUandUSapprovedREMICADE®havecomparablebindingtoFcγRIIIaonNKcells,althoughonebatchofINFLECTRA®withavalueofvvvrelativebindingtoNKcellsexvivoin50%serumwasbelowthemean-3SDofUSapprovedREMICADE®ofvvvvv.

• ThedifferenceobservedinexvivoNKcellbindingbetweenCT-P13andEUapprovedREMICADE®issmallincomparisontothedifferenceinbindingofEUapprovedREMICADE®toFcγRIIIaofdifferentgenotypes.

ADCCPotencystudiesusingdifferenteffectorandtargetcells

• ADCCusingPBMCfromHealthydonors• TheADCCassayusingtransfectedtmTNFαJurkatcellsas

targetcellsandPBMCfromhealthydonorofV/FFcγRIIIagenotypeaseffectorcellswasconductedusingvvbatcheseachproduct.

• PBMCofFcγRIIIagenotypeswereusedinthisstudyADCCusingPBMCfromHealthydonors.

• ThemeanrelativeADCCactivityofCT-P13,EUandUSapprovedREMICADE®showsimilarADCCactivitybetweenINFLECTRA®andREMICADE®usingtransmembraneTNFαJurkattargetcellsandPBMCeffectorcells.AllbatchesofINFLECTRA®werewithinthemean±3SDrangeofbothEUandUSapprovedREMICADE®batchesusingthisassaysystem.

• ADCCusingNKcellsfromHealthdonors• TheADCCassayusingtransfectedtmTNFαJurkatcellsas

targetcellsandNKcellisolatedfromPBMCofV/FFcγRIIIahealthydonorsaseffectorcells.

• ThemeanrelativeADCCactivityofCT-P13,EUandUSapprovedREMICADE®indicatesomeslightdifferenceinADCCactivitybetweenCT-P13andREMICADE®usingtransmembraneTNFαJurkattargetcellsandNKeffectorcells.

CTDModule3.2.R.2.8.5.1CTDModule3.2.R.2.8.5.2

• ADCCusingLipopolysaccharide(LPS)-stimulatedmonocytesastargetcells

Typeofstudy(s) Briefoverviewoftestsandconclusions References• TheabilityoftheLPS-stimulatedmonocytesisolated

fromhealthydonortoactastargetsinanADCCassaywasinvestigatedamongCT-P13,EUandUSapprovedREMICADE®.

• ThedatashownoADCCactivitywasdetectableforCT-P13,EUandUSapprovedREMICADE®.

• ThesefindingssuggestthatLPS-stimulatedmonocytes,supposedtoberepresentativeofinflammatoryfociinvivo,donotexpresssufficientamountsoftmTNFαtoinduceaneffectiveADCCinresponsetothepresenceofCT-P13,EUandUSapprovedREMICADE®.

• ExvivotmTNFαExpressionLevelinIBDPatients• Biopsymaterialwasobtainedfromvvpatientswithmild

tosevereUCorCDandtheleveloftmTNFexpressiononLaminaPropriaMononuclearCellsfromtheseIBDpatientshasbeeninvestigated.

• ThedataclearlyshowthatmonocytesandmacrophagesinthelaminapropriaofIBDpatientsexpresslowlevelsoftmTNF.TheexpressionoftmTNFonmonocytes/macrophageswasapproximatelyvvvvvlowerthanonmonocytes/macrophagesfromLPSstimulatedPBMCsfromhealthydonorsandtmTNFwasexpressedatonly2%(50foldlower)ofthelevelobtainedwithtmTNFαJurkatcells.

• ThesedataconfirmthatlowlevelsoftmTNFαareexpressedonmonocytes/macrophagesinlaminapropriaofIBDpatientsandtogetherwithdatafromADCCstudiessuggestthatADCCishighlyunlikelytocontributetotherapeuticeffectinIBD.

REMICADE®PHARMACOKINETICLINEARITYConcentrationVersusTimeCurveofInfliximabtreatmentwithandwithoutMethotrexate(MTX):DatafortheseruminfliximablogconcentrationversustimecurveforRApatientstreatedwith3and10mg/kginfliximabsupportsadose-proportionalPKprolife,regardlessofthepresenceorabsenceofMTX[77,78].IntheCO168T14trial,assessing101RApatientstreatedwith1,3or10mg/kgorplaceboeitheraloneorincombinationwith7.5mg/kgMTX,therewasnoapparentdose-orconcentration-efficacyresponsefor3or10mg/kgdosingatevery4weeksorevery8weeks[79,80].TheplasmaconcentrationofinfliximabwasslightlyincreasedwiththeuseofMTX,withthemostprofoundeffectseenwithlowdose1mg/kg[77-80].Adramaticdecreaseinseruminfliximabconcentrationwasobservedforthe1mg/kgdosegivenwithoutMTX,andthoughttobearesultofincreasedinfliximabclearanceduetoHumanAnti-chimericAntibodyformation[77-80].RegardlessofMTXadministration,theinfliximab3and10mg/kgdoseswereassociatedwithsimilarefficacy.Thedurationofclinicalresponseinthe1mg/kgdosewithoutMTXwasmarkedlyshorterthan1mg/kgwithMTX[77].ThepivotalPhaseIIIATTRACTtrial,assessing428patientstreatedwith3or10mg/kg(withMTX)orplacebo(withMTX)at4-or8-weekintervals,showedmaximuminfliximabserumconcentrationstobedirectlyproportionaltointravenousdoseovera3mg/kgto10mg/kgrange[81].Theinfliximabmedium

serumconcentrationwas3.2-3.3-foldhigherfor10mg/kgdosecomparedto3mg/kgdose,administeredevery8weeksthrough14weeksoftreatment[80].InfliximabserumAccumulation:Infliximabcouldbedetectedintheserumofmostpatientsforatleast8weeksafterasingledoseof5mg/kgforCrohn’sdiseaseandtheRAmaintenancedoseof3mg/kgevery8weeks[82].Repeatedadministrationofinfliximab(5mg/kgat0,2and6weeksinfistulisingCrohn´sdisease,3or10mg/kgevery4or8weeksinRA)resultedinaslightaccumulationofinfliximabinserumaftertheseconddose[83].Nosystemicaccumulationofinfliximabwasobservedincontinuedrepeatedtreatmentwith3mg/kgor10mg/kgat4-or8-weekintervalsinRApatientsorinsevereCrohn’sdiseasepatientsretreatedwith4infusionsof10mg/kgat8weekintervals[11,82][12].InfliximabVolumeofDistributionandClearance:Thevolumeofdistributionofinfliximabatsteadystate(4-5.6Lina70kgindividual)isnotdependentontheadministereddoseandindicatesthatinfliximabisdistributedprimarilywithinthevascularcompartment[11,84][12].Thereisaverylowsystemicclearanceofinfliximabofabout11-15mL/hourandtheeliminationhalf-lifeofinfliximabcanrange7.7-14.7days[11,77,82].Therearenospecificstudiesassessingthemetabolismorexcretionofinfliximabinhumans[77].Itisbelievedthatinfliximabiseliminatedinasimilarmannertootherproteins[11].Therearenomajordifferencesinclearanceorvolumeofdistributionofinfliximabinpatientssubgroupedbyageorweight[11,12,78].Anti-drugantibodydevelopmenthasbeenassociatedwithincreasedclearanceofinfliximabinUCpatients[12],whilehigherserumalbuminconcentrationswereassociatedwithdecreasedclearanceofinfliximabinpatientswithUC[12].HumanAnti-chimericAntibodyformationisassociatedwithincreasedclearanceofinfliximabandadecreasedexposure,basedonareaunderthecurve,whenMTXisnotco-administered[78,79,81].Thisincreaseinclearanceisdose-dependentandthehighestlevelofclearanceisobservedwiththe1mg/kgdose[78,79,81]

CommonDrugReview November2017 51

APPENDIX2:DRUGPLANLISTINGSTATUSFORREFERENCEPRODUCTForeachindicationthatisapprovedbyHealthCanadafortheSEB(orlikelytobeapproved,inthecaseofasubmissionfiledonapre-NOCbasis),pleaseprovidethepubliclyavailablelistingstatusandcriteriaforthereferenceproduct.

Step1:Usethefollowingabbreviationstocompletethetable.Useaseparaterowforeachindicationandaddmorerowsifnecessary.

Abbreviation DescriptionEX Exceptionitemforwhichcoverageisdeterminedonacase-by-casebasisFB FullbenefitNB NotabenefitRES Restrictedbenefitwithspecifiedcriteria(e.g.,specialauthorization,exceptiondrugstatus,limitedusebenefit)UR Underreview

ListingStatusforREMICADE®

Indication(s) CDR-ParticipatingDrugPlans

BC AB SK MB ON NB NS PE NL YK NT NIHB DND VACCrohn’sDisease RES RES RES RES RES RES RES RES RES RES RES RES RES RES

UlcerativeColitis NB RES RES RES RES NB NB NB NB RES NB NB NB NB

AB=Alberta,BC=BritishColumbia,DND=DepartmentofNationalDefence;MN=Manitoba;NIHB=Non-InsuredHealthBenefitsProgram;NL=NewfoundlandandLabrador;NS=NovaScotia;NT=NorthwestTerritories;ON=Ontario;PE=PrinceEdwardIsland;SK=Saskatchewan;VAC=VeteransAffairsCanada;YK=Yukon.

Step2:Forallrestrictedbenefitentries(RES),pleasestatethecriteriausedbyeachdrugplan.Useaseparatetableforeachindicationandaddordeleterowsasnecessary.

RestrictedBenefitCriteriaforREMICADE®forthetreatmentofCrohn’sDisease

DrugPlan CriteriaforRestrictedBenefitBC TreatmentofmoderatetosevereactiveCrohn'sdiseaseorfistulisingCrohn’sdiseaseaccordingtoestablishedcriteriawhen

prescribedbyagastroenterologistActiveCrohn’sDiseaseCURRENTHARVEYBRADSHAWINDEXgreaterthan8Resistant,dependent,contraindicatedorintoleranttocorticosteroids-corticosteroidresistant:lackofasymptomaticresponsedespiteacourseoforalprednisone40-60mg/day(orequivalent)foraminimumof14days.-corticosteroiddependent:unabletowithdraworalcorticosteroidwithin3monthsofinitiationwithoutarecurrenceofsymptoms;asymptomaticrelapsewithin3monthsofstopping;ortheneedfortwoormorecoursesofcorticosteroidswithinoneyear.-corticosteroiduseiscontraindicated(specify):-intolerant/sideeffect(s)(specify):FORPATIENTSWITHFISTULIZINGCROHN’SFailurewith,intolerancetoorcontraindicationto:Ciprofloxacinatmaximallytolerateddoses(min3weektrial)Metronidazoleatmaximallytolerateddoses(min3weektrial)ForRenewalCURRENTHARVEYBRADSHAWINDEXSCOREWHILEONTREATMENTREQUIRESHBISCORE<5ORADECREASEINSCORE>4.

AB ModeratelytoSeverelyActiveCrohn'sDiseaseandFistulisingCrohn'sDisease:"SpecialauthorizationcoveragemaybeapprovedforcoverageofinfliximabforthereductioninsignsandsymptomsandinductionandmaintenanceofclinicalremissionofModeratelytoSeverelyActiveCrohn'sDiseaseand/ortreatmentof

DrugPlan CriteriaforRestrictedBenefitFistulisingCrohn'sDiseaseinpatientswhomeetthefollowingcriteria:-InfliximabmustbeprescribedbyaSpecialistinGastroenterologyoraphysicianappropriatelytrainedbytheUniversityofAlbertaortheUniversityofCalgaryandrecognizedasaprescriberbyAlbertaBlueCrossforinfliximabforcoverageforthetreatmentofModeratelytoSeverelyActiveCrohn'sDiseaseand/orFistulisingCrohn'sDiseasepatients(`Specialist').-Patientsmustbe18yearsofageoroldertobeconsideredforcoverageofinfliximab.-Patientswillbelimitedtoreceivingonedoseofinfliximabperprescriptionattheirpharmacy.-Patientsmaybeallowedtoswitchfromonebiologicagenttoanotherfollowinganadequatetrialofthefirstbiologicagentifunresponsivetotherapy(bothprimarylossofresponseandsecondarylossofresponse)orduetoseriousadverseeffectsorcontraindications.Anadequatetrialisdefinedasataminimumthecompletionofinductiondosing(e.g.initialcoverageperiod).-Patientswillnotbepermittedtoswitchbacktoapreviouslytrialedbiologicagentiftheyweredeemedunresponsivetotherapy.-Patientsarelimitedtoreceivingonebiologicagentatatimeregardlessoftheconditionforwhichitisbeingprescribed.PriortoinitiationofinfliximabtherapyforNewPatients:'NewPatients'arepatientswhohaveneverbeentreatedwithinfliximabbyanyhealthcareprovider.ModeratelytoSeverelyActiveCrohn'sDisease:Priortoinitiationofinfliximabtherapy,NewPatientsmusthaveacurrentModified(withoutthephysicalexam)HarveyBradshawIndexscoreofgreaterthanorequalto7(NewPatient'sBaselineScore),ANDbeRefractory.Refractoryisdefinedasoneormoreofthefollowing:1)Seriousadverseeffectsorreactionstothetreatmentsspecifiedbelow;OR2)Contraindications(asdefinedinproductmonographs)tothetreatmentsspecifiedbelow;OR3)Previousdocumentedlackofeffectatdosesandfordurationofalltreatmentsspecifiedbelow:a)mesalamine:minimumof3grams/dayforaminimumof6weeks;ANDrefractoryto,ordependenton,glucocorticoids:followingatleastonetaperingdosingscheduleof40mg/day,taperingby5mgeachweekto20mg,thentaperingby2.5mgeachweektozero,orsimilar;Note:PatientswhohaveusedtheabovetreatmentsincombinationwillnotberequiredtobechallengedwithindividualtreatmentsasmonotherapyAND

DrugPlan CriteriaforRestrictedBenefitb)Immunosuppressivetherapyasfollows:-Azathioprine:minimumof2mg/kg/dayforaminimumof3months;OR-6-mercaptopurine:minimumof1mg/kg/dayforaminimumof3months;OR-Methotrexate:minimumor15mg/weekforaminimumof3months.OR-Immunosuppressivetherapydiscontinuedatlessthan3monthsduetoseriousadverseeffectsorreactions.Applicationsforcoveragemustincludeinformationregardingthedosagesanddurationoftrialofeachtreatmentthepatientreceivedadescriptionofanyadverseeffects,reactions,contraindicationsand/orlackofeffect,aswellasanyotherinformationrequestedbyAlbertaBlueCross.FistulisingCrohn'sDisease:Priortoinitiationofinfliximabtherapy,NewPatientsmusthaveactivelydrainingperianalorenterocutaneousfistula(s)thathaverecurredorpersisteddespite:a)Acourseofanappropriatedoseofantibiotictherapy(e.g.ciprofloxacinormetronidazole)foraminimumof3weeks;ANDb)Immunosuppressivetherapy:-Azathioprine:minimumof2mg/kg/dayforaminimumof6weeks;OR-6-mercaptopurine:minimumof1mg/kg/dayforaminimumof6weeks;OR-Immunosuppressivetherapydiscontinuedatlessthan6weeksduetoseriousadverseeffectsorreactions.[Note:PatientswhohaveusedtheabovetreatmentsincombinationforthetreatmentofFistulisingCrohn'swillnotberequiredtobechallengedwithindividualtreatmentsasmonotherapy]Applicationsforcoveragemustincludeinformationregardingthedosagesanddurationoftrialofeachtreatmentthepatientreceivedadescriptionofanyadverseeffects,reactions,contraindicationsand/orlackofeffect,aswellasanyotherinformationrequestedbyAlbertaBlueCross.CoverageCriteriaforModeratelytoSeverelyActiveCrohn'sDiseaseAND/ORFistulisingCrohn'sDisease-NewPatientsmustmeetthecriteriaabovepriortobeingconsideredforapproval.-Allapprovalsarealsosubjecttothefollowingapplicablecriteria.

DrugPlan CriteriaforRestrictedBenefitInductionDosingforNewPatients:-CoverageforInductionDosingmayonlybeapprovedforNewPatients(thosewhohaveneverbeentreatedwithinfliximabbyanyhealthcareprovider).-'InductionDosing'meansamaximumofone5mg/kgdoseofinfliximabperNewPatientateach0,2and6weeks(foramaximumtotalofthreedoses).-NewPatientsareeligibletoreceiveInductionDosingonlyonce,afterwhichtimetheMaintenanceDosingforNewPatientsandContinuedCoverageforMaintenanceDosingcriteriawillapply.MaintenanceDosing:'MaintenanceDosing'meansone5mg/kgdoseofinfliximabperpatientprovidednomoreoftenthanevery8weeksforaperiodof12monthsto:-NewPatientsfollowingthecompletionofInductionDosing;OR-ExistingPatients,whoarepatientsthatarebeingtreated,orhavepreviouslybeentreated,withinfliximab.MaintenanceDosingforNewPatientsafterCompletionofInductionDosing:-TheNewPatientmustbeassessedbyaSpecialistbetweenweeks10and14aftertheinitiationofInductionDosingtodetermineresponsebyobtainingaModifiedHarveyBradshawIndexscoreforpatientswithModeratelytoSeverelyActiveCrohn'sDiseaseand/orclosureofindividualfistulasasevidencedbynoorminimalfistuladrainagedespitegentlefingercompressionoffistulasthatweredrainingatbaselineforFistulisingCrohn's;AND-TheSpecialistmustconfirmtheModifiedHarveyBradshawIndexscoreshowsadecreasefromtheNewPatient'sBaselineScoreofgreaterthanorequalto3pointsforpatientswithModeratelytoSeverelyActiveCrohn'sand/orconfirmclosureofindividualfistulasasevidencedbynoorminimalfistuladrainagedespitegentlefingercompressionoffistulasthatweredrainingatbaselineforFistulisingCrohn's.MaintenanceDosingforExistingPatients:-ThepatientmustbeassessedbyaSpecialistatleast4to8weeksafterthedaythelastdoseofinfliximabwasadministeredtothepatientandpriortoadministrationofthenextdosetoobtain:aModifiedHarveyBradshawIndexScore(ExistingPatient'sBaselineScore)forModeratelytoSeverelyActiveCrohn'sand/orclosureofindividualfistulasasevidencedbynoorminimalfistuladrainagedespitegentlefingercompressionoffistulasthatweredrainingatbaselineforFistulisingCrohn's;AND-thesemeasuresmustbeprovidedtoAlbertaBlueCrossforassessmentforcontinuedcoverageformaintenancedosing.(ForexistingpatientswithModeratelytoSeverelyActiveCrohn'sDiseasewithanincompleteresponseorforexistingpatients

DrugPlan CriteriaforRestrictedBenefitwithFistulisingCrohn'swhorespondthenlosetheirresponse,thedosemaybeadjustedto10mg/kgbymakinganadditionalspecialauthorizationrequesttoAlbertaBlueCrossfortheincreaseddose.)ContinuedCoverageforMaintenanceDosing:Continuedcoveragemaybeconsideredforone5mg/kgdoseofinfliximabperpatientprovidednomoreoftenthanevery8weeksforaperiodof12months,ifthefollowingcriteriaaremetattheendofeach12monthperiod:-TheNewPatientortheExistingPatientmustbeassessedbyaSpecialistatleast4to6weeksafterthedaythelastdoseofinfliximabwasadministeredtothepatientandpriortotheadministrationofthenextdosetoobtainaModifiedHarveyBradshawIndexScoreforModeratelytoSeverelyActiveCrohn'sand/orclosureofindividualfistulasasevidencedbynoorminimalfistuladrainagedespitegentlefingercompressionoffistulasthatweredrainingatbaselineforFistulisingCrohn's;AND-ForNewPatients:TheSpecialistmustconfirmthatthepatienthasmaintainedagreaterthanorequalto3pointdecreasefromtheNewPatient'sBaselineScoreforModeratelytoSeverelyActiveCrohn'sand/orclosureofindividualfistulasasevidencedbynoorminimalfistuladrainagedespitegentlefingercompressionoffistulasthatweredrainingatbaselineforFistulisingCrohn's;OR-ForExistingPatients:TheSpecialistmustconfirmthatthepatienthasmaintainedtheExistingPatient'sBaselineScoreand/orclosureofindividualfistulasasevidencedbynoorminimalfistuladrainagedespitegentlefingercompressionoffistulasthatweredrainingatbaselineforFistulisingCrohn's.(FornewandexistingpatientswithModeratelytoSeverelyActiveCrohn'sDiseasewithanincompleteresponseorfornewandexistingpatientswithFistulisingCrohn'swhorespondthenlosetheirresponse,themaintenancedosemaybeadjustedto10mg/kgbymakinganadditionalspecialauthorizationrequesttoAlbertaBlueCrossfortheincreaseddose.)"Allrequests(includingrenewalrequests)forinfliximabforModeratelytoSeverelyActiveCrohn'sDiseaseandFistulisingCrohn'sDiseasemustbecompletedusingtheAdalimumabforCrohn's/InfliximabforCrohn's/FistulisingCrohn'sDiseaseSpecialAuthorizationRequestForm(ABC31200).

SK ModeratetosevereCrohn'sDisease:-Fortreatmentofpatientswhodemonstratecontinuingsymptomsdespitetheuseofoptimalconventionaltherapiessuchas5-ASAagents,glucocorticoidsandimmunosuppressivetherapy.-Fortreatmentofpatientswhoareintoleranttoconventionaltherapyincluding5-ASAagents,glucocorticoidsandimmunosuppressivetherapy.

DrugPlan CriteriaforRestrictedBenefitFistulisingCrohn'sDisease:-Fortreatmentofpatientswithsymptomaticenterocutaneousorperinealfistulae,enterovaginalfistulaeorenterovesicalfistulae(i.e.anytypeoffistulisingCrohn’sDisease).Clinicalresponseshouldbeassessedaftertheinductiondose.Ongoingcoveragewillonlybeprovidedforthosewhorespondtotreatment.Patientsundergoingthistreatmentshouldbereviewedeverysixmonthsbyaspecialistinthisarea.

MB ForthetreatmentofmoderatetoseverelyactiveCrohn'sDiseaseand/orFistulisingCrohn'sDiseaseinpatientsrefractoryorwithcontraindicationstoanadequatecourseof5-aminosalicyclicacidandcorticosteroidsand/orotherimmunosuppressivetherapy.Requestforcoveragemustbemadebyaphysicianwhoisaspecialistingastroenterology.

ON TreatmentoffistulisingCrohn’sDiseaseinpatientswhohave:-Activelydrainingperianalorenterocutaneousfistula(e)thathaverecurredorpersisteddespiteacourseofantibiotictherapy(ciprofloxacinand/ormetronidazole)andimmunosuppressivetherapy(azathioprineor6-mercaptopurine).Note:Anyintolerance(s)orcontraindication(s)totreatmentwithrequiredalternative(s)mustbedescribedindetail.Renewalwillbeconsideredforpatientswithresolutionoffistulae.Theplanneddosingregimenfortherequestedbiologicshouldbeprovided.TherecommendeddoseforthetreatmentofCrohn’sDiseaseis5mg/kg/doseat0,2and6weeksfollowedby5mg/kg/doseevery8weeks.Initial:3monthsFirstrenewal:1yearSecondandsubsequentrenewals:2years

NB -FormoderatelytoseverelyactiveCrohn'sdiseaseinpatientswhoarerefractoryorhavecontraindicationstoanadequatecourseof5-aminosalicylicacidandcorticosteroidsandotherimmunosuppressivetherapy.Initialapprovalwillconsistof3dosesof5mg/kggivenatweeks0,2and6.ClinicalNote:-Infliximabwillnotbereimbursedincombinationwithotheranti-TNFagents.ClaimNotes:-Ongoingcoverageformaintenancetherapywillonlybereimbursedforrespondersandforadosenotexceeding5mg/kgevery8weeks.Coveragemustbereassessedannuallyandisdependentonevidenceofcontinuedresponse.-Mustbeprescribedby,orinconsultationwith,agastroenterologistorphysicianwithaspecialtyingastroenterology

NS FortreatmentofCrohn’sdiseaseinadults,whenprescribedbyagastroenterologistorphysicianwithaspecialtyingastroenterology:-inpatientswithmoderatetosevereactivediseaserefractoryto5-ASAproductsANDglucocorticoids(e.g.,prednisone)ANDimmunosuppressivetherapy(azathioprineor6-mercaptopurineormethotrexate)**.Initialapprovalofinfliximabwillbefora

DrugPlan CriteriaforRestrictedBenefitsingleinfusionof5mg/kg/dose.Asecondinfusionmaybewarrantedinpatientsnotrespondingtothefirstinfusionorinpatientsrespondinginitiallybutthenworseningbeforemaintenancetherapyiseffective.Requestforapprovalbeyondinductiontherapywillbeconsideredonacase-by-casebasis-inpatientswithfistulisingdiseasewhohaveactivelydrainingperianalorenterocutaneousfistula(e)thathaverecurredorpersisteddespiteacourseofappropriateantibiotictherapy(e.g.,metronidazole+/-ciprofloxacinforaminimumof3weeks)ANDimmunosuppressivetherapy(azathioprineor6-mercaptopurineormethotrexate)**.Initialapprovalisforthreeinfusionsofinfliximabof5mg/kg/doseat0,2and6weekintervals**PatientswhoareveryillandnotcandidatesforsurgerymayqualifyforinfliximabtherapywithoutatrialofAZA,6-MPorMTX,astheymayrequireamorerapidonsetofresponse

PE ForthetreatmentofmoderatetosevereCrohn=sDiseaseinpatientswho:1. HaveaHarveyBradshawIndexscoreof7ormore,AND2. Havenotrespondedto5-ASAproducts(minimumtrialof3gramsperdayfor6weeks),AND3. Havenotrespondedtoorareintoleranttoglucocorticosteroidtherapy(e.g.Prednisone)orwheresuchtherapyis

contraindicated,AND4. Havenotrespondedtoorareintoleranttoimmunosupressivetherapy(Azathioprine,MercaptopurineorMethotrexate)

orwheresuchtherapyiscontraindicated.InitialapprovalforInfliximabwillallowfor3dosesof5mg/kg/doseadministeredat0,2,and6weeks.RenewalofcoveragewillrequirereassessmentofthepatientandsubmissionofanewCrohn=sDiseaseSpecialAuthorizationform.Continuedcoveragewillbeapprovedatadosenotexceeding5mg/kgevery8weeksForthetreatmentoffistulisingCrohn’sDiseaseinpatientswho:1. HaveaHarveyBradshawIndexscoreof7ormore,AND2. Haveanactivelydrainingperianalorenercutaneiousfistula(e)thathaverecurredorpersisteddespiteacourseof

appropriateantibiotictherapy(e.g.CiprofloxacinwithorwithoutMetronidazoleforaminimumof3weeks),AND3. Havenotrespondedtoorareintoleranttoimmunosupressivetherapy(Azathioprine,MercaptopurineorMethotrexate)

orwheresuchtherapyiscontraindicated.InitialapprovalforInfliximabwillallowfor3dosesof5mg/kg/doseadministeredat0,2,and6weeks.RenewalofcoveragewillrequirereassessmentofthepatientandsubmissionofanewCrohn’sDiseaseSpecialAuthorizationform.Continuedcoveragewillbeapprovedatadosenotexceeding5mg/kgevery8weeks.

NL Forthetreatmentofpatientswithmoderateorsevereactivedisease*withcontraindicationstoornotachievingremissionwithglucocorticosteroidsANDimmunosuppressivetherapy.

DrugPlan CriteriaforRestrictedBenefitInitialrequestmustincludecurrentCrohn’sDiseaseActivityIndex(CDAI)ortheHarvey-BradshawIndexAssessment(HBI)score.Initialapproval,3infusionsofinfliximab5mg/kgatweek0,2&6.Continuedcoveragedependentonevidenceofresponseusingcriteriasuchthe100pointreductioninCrohn’sDiseaseActivityIndex(CDAI)ortheHarvey-BradshawIndexAssessment(HBI)withascoreof5orlessoradecreaseinscoreof4ormore.Coveragecanbereassessedannuallydependentonevidenceofresponse(asoutlinedabove)Themaximumapproveddoseis5mg/kgevery8weeks.*Patientsveryill&notcandidatesforsurgerymayqualifyforimmediateinfliximabinductiontherapy,astheymayrequireamorerapidresponse.Concurrentuseofbiologicsnotapproved.WrittenrequestbyGastroenterologistorphysicianwithaspecialtyingastroenterology

YK FormoderatetoseverelyactiveCrohn'sDiseaseonrecommendationofaspecialist.Consulttobeprovided.ForpatientswithacurrentHarveyBradshawIndex(HBI)>7,whoareintolerantorrefractoryto5-ASA(3gdailyforatleast6weeks)ANDarerefractory,intolerantordependantonglucocorticoids,ANDwhoarerefractoryorintoleranttoatleastoneofazathioprine,6-mercaptopurineormethotrexateaftera3monthtrial.

ForfistulisingCrohn'sDiseaseonrecommendationofaspecialist.Consulttobeprovided.Forpatientswithactivelydrainingfistula(s)despitea3weektrialofciprofloxacinormetronidazole,ANDatleasta6weektrialofazathioprineor6-mercaptopurine

NT FistulisingCrohn’sdiseaseaccordingtoestablishedcriteria.-ForadultpatientswithmoderatelytoseverelyactiveCrohn’sDiseasewhohavehadaninadequateresponsetoconventionaltherapy.ForthetreatmentofFISTULIZINGCROHN’SDISEASECriteriaforinitialforoneyear:-PrescribedbyagastroenterologyspecialistTheinitialcoveragewillallowfor3dosesof5mg/kg/dose,administeredat0,2and6weeks.Forcontinuedcoverage,patientmustbereassessedaftertheinitialdoses.Patientmeetsallthefollowingcriteria:-Patientisanadultwithactivelydrainingperianalorentercutaneousfistula(e)thathaverecurredorpersisteddespite:-acourseofappropriateantibiotictherapy(e.g.ciprofloxacinwithorwithoutmetronidazoleforaminimumof3weeks)PLUS-immunosuppressivetherapy:

DrugPlan CriteriaforRestrictedBenefit-azathioprine2to2.5mg/kg/dayforaminimumof6weeksortreatmentdiscontinuedbefore6weeksduetosevereadversereactions.OR-6-mercaptopurine,50-70mg/dayforaminimumof6weeksortreatmentdiscontinuedbefore6weeksduetosevereadversereactions.ORForthetreatmentforSEVEREACTIVECROHN`SDISEASECriteriaforinitialforoneyear:-PrescribedbyagastroenterologyspecialistTheinitialcoveragewillallowfor3dosesof5mg/kg/dose,administeredat0,2and6weeks.Forcontinuedcoverage,patientmustbereassessedaftertheinitialdoses.Patientmeetsthefollowingcriteria:PatientisanadultwithsevereactiveCrohn’sdiseasethathasrecurredorpersisteddespite:-Therapywith5-ASAproducts(atleast3g/dayforaminimumof6weeks).PLUS-Glucocorticoidsequivalenttoprednisone40mg/dayforaminimumof2weeks.OR-TreatmentdiscontinuedduetoseriousadversereactionsOROR-Contraindicationtoglucocorticoidtherapy.PLUS-Azathioprine2to2.5mg/kg/dayforaminimumof3months.OR-6-mercaptopurine50to70mg/dayforaminimumof3months.OR-Methotrexate15to25mg/weekforaminimumof3months.

NIHB FistulisingCrohn’sdiseaseaccordingtoestablishedcriteria.-ForadultpatientswithmoderatelytoseverelyactiveCrohn’sDiseasewhohavehadaninadequateresponsetoconventionaltherapy.ForthetreatmentofFISTULIZINGCROHN’SDISEASECriteriaforinitialforoneyear:

DrugPlan CriteriaforRestrictedBenefit-PrescribedbyagastroenterologyspecialistTheinitialcoveragewillallowfor3dosesof5mg/kg/dose,administeredat0,2and6weeks.Forcontinuedcoverage,patientmustbereassessedaftertheinitialdoses.Patientmeetsallthefollowingcriteria:-Patientisanadultwithactivelydrainingperianalorentercutaneousfistula(e)thathaverecurredorpersisteddespite:-acourseofappropriateantibiotictherapy(e.g.ciprofloxacinwithorwithoutmetronidazoleforaminimumof3weeks)PLUS-immunosuppressivetherapy:-azathioprine2to2.5mg/kg/dayforaminimumof6weeksortreatmentdiscontinuedbefore6weeksduetosevereadversereactions.OR-6-mercaptopurine,50-70mg/dayforaminimumof6weeksortreatmentdiscontinuedbefore6weeksduetosevereadversereactions.ForthetreatmentforSEVEREACTIVECROHN`SDISEASECriteriaforinitialforoneyear:-PrescribedbyagastroenterologyspecialistTheinitialcoveragewillallowfor3dosesof5mg/kg/dose,administeredat0,2and6weeks.Forcontinuedcoverage,patientmustbereassessedaftertheinitialdoses.Patientmeetsthefollowingcriteria:PatientisanadultwithsevereactiveCrohn’sdiseasethathasrecurredorpersisteddespite:-Therapywith5-ASAproducts(atleast3g/dayforaminimumof6weeks).PLUS-Glucocorticoidsequivalenttoprednisone40mg/dayforaminimumof2weeks.OR-TreatmentdiscontinuedduetoseriousadversereactionsOROR-Contraindicationtoglucocorticoidtherapy.PLUS-Azathioprine2to2.5mg/kg/dayforaminimumof3months.OR-6-mercaptopurine50to70mg/dayforaminimumof3months.OR

DrugPlan CriteriaforRestrictedBenefit-Methotrexate15to25mg/weekforaminimumof3months.

DND Crohn’sDisease:-whenprescribedbyagastroenterologistforpatientswithmoderatetosevereCrohn’sDiseasewhoarerefractoryorintolerantto:-5-ASAproductsat3g/dayfor6weeksANDprednisone40mg/dayfor2weeksANDImmunosuppressivetherapyasfollows:-azathioprine2-2.5mg/kg/dayfor3monthsOR-mercaptopurine50-75mg/dayfor3monthsOR-methotrexate15-25mg/weekfor3monthsOR-Immunosuppressivetherapydiscontinuedatlessthan3monthsduetoseriousadverseeffectsorreactionsFistulisingCrohn’s:-whenprescribedbyagastroenterologistforpatientswithactivedrainingfistulasdespite:-ciprofloxacin+metronidazolefor3weeksAND-azathioprineforaminimumof6weeksOR-6-mercaptopurinefor6weeks

VAC CriteriaNotPublicallyAvailableviaVACWebsite

RestrictedBenefitCriteriaforREMICADE®forthetreatmentofUlcerativeColitis

DrugPlan CriteriaforRestrictedBenefitBC NotaBenefit

AB SpecialauthorizationcoveragemaybeprovidedforthereductioninsignsandsymptomsandinductionandmaintenanceofclinicalremissionofUlcerativeColitisinadultpatients(18yearsofageorolder)withactivedisease(characterizedbyapartialMayoscore>4priortoinitiationofbiologictherapy)andwhoarerefractoryorintolerantto:-mesalamine:minimumof4grams/dayforaminimumof4weeksAND-corticosteroids(failuretorespondtoprednisone40mgdailyfor2weeks,or;steroiddependenti.e.failuretotaperoffsteroidswithoutrecurrenceofdiseaseordiseaserequiringaseconddoseofsteroidswithin12monthsofpreviousdose).'Refractory'isdefinedaslackofeffectattherecommendeddosesandfordurationoftreatmentsspecifiedabove.'Intolerant'isdefinedasdemonstratingseriousadverseeffectsorcontraindicationstotreatmentsasdefinedinproductmonographs.Immunosuppressivetherapyasfollowsmayalsobeinitiatedifintheclinician'sjudgmentatrialiswarranted:i)Azathioprine:minimumof2mg/kg/dayforaminimumof2months;ORii)6-mercaptopurine:minimumof1mg/kg/dayforaminimumof2monthsForcoverage,thisdrugmustbeprescribedbyaSpecialistinGastroenterologyoraphysicianappropriatelytrainedbytheUniversityofAlbertaortheUniversityofCalgaryandrecognizedasaprescriberbyAlbertaBlueCross('Specialist').Initialcoveragemaybeapprovedforthreedosesof5mg/kgofinfliximabat0,2and6weeks.-Patientswillbelimitedtoreceivingaonedoseofinfliximabperprescriptionattheirpharmacy.-Patientswillbepermittedtoswitchfromonebiologicagenttoanotherfollowinganadequatetrialofthefirstbiologicagentifunresponsivetotherapy,orduetoseriousadverseeffectsorcontraindications.Anadequatetrialisdefinedasataminimumthecompletionofinductiondosing(e.g.initialcoverageperiod).-Patientswillnotbepermittedtoswitchbacktoapreviouslytrialedbiologicagentiftheyweredeemedunresponsivetotherapy.-Patientsarelimitedtoreceivingonebiologicagentatatimeregardlessoftheconditionforwhichitisbeingprescribed.Forcontinuedcoveragebeyondthreedoses,thepatientmustmeetthefollowingcriteria:1)ThepatientmustbeassessedbyaSpecialistbetweenweeks10and14aftertheinitiationoftherapytodetermineresponse.2)TheSpecialistmustconfirminwritingthatthepatientisa'responder'thatmeetsthefollowingcriteria:-adecreaseinthepartialMayoscoreofgreaterthanorequalto2pointsFollowingthisassessment,continuedcoveragemaybeapprovedfordoseof5mg/kgevery8weeksforaperiodof12months.Ongoingcoveragemaybeconsideredonlyifthefollowingcriteriaaremetattheendofeach12-monthperiod:1)ThepatienthasbeenassessedbyaSpecialistinGastroenterologytodetermineresponse;

DrugPlan CriteriaforRestrictedBenefit2)TheSpecialistmustconfirminwritingthatthepatienthasmaintainedaresponsetotherapyasindicatedby:-adecreaseinthepartialMayoscoreofgreaterthanorequalto2pointsfromthescorepriortoinitiationofinfliximabtherapyNote:Forpatientswhoshowedaresponsetoinductiontherapythenexperiencedsecondarylossofresponsewhileonmaintenancedosingwith5mg/kg,themaintenancedosemaybeadjustedfrom5mg/kgto10mg/kgbymakinganadditionalspecialauthorizationrequesttoAlbertaBlueCrossfortheincreaseddose.Allrequests(includingrenewalrequests)forinfliximabforUlcerativeColitismustbecompletedusingtheInfliximabforUlcerativeColitisSpecialAuthorizationRequestForm(ABC60008).

SK Fortreatmentofulcerativecolitisinpatientsunresponsivetohighdoseintravenoussteroids.NOTE:Clinicalresponseshouldbeassessedafterthethree-doseinductionphasebeforeproceedingtomaintenancetherapy.Ongoingcoveragewillonlybeprovidedforthosewhorespondtotherapy.Patientsundergoingthistreatmentshouldbereviewedeverysixmonthsbyaspecialistinthisarea.3)Adequateresponsetotreatmentassessedat12weeksdefinedasatleast50%reductioninpre-treatmentbaselineBASDAIscoreorby>2unitsANDareductionof>2cminthespinalpainVAS.NOTE:Coveragewillnotbeprovidedwhenapatientswitchestoanotheranti-TNFagentifthepatientfailstorespondorifthereisalossofresponsetothefirstagent.Requestsforcoverageforthisindicationmustbemadebytherheumatologist.Asecondapplicationwouldalsoberequiredafter12weekstoassessandwouldneedtoshowanimprovementtothepatient’sconditiononeitherofthesemedications.PleaserefertotheFormularywebsitefortheapplicationform.Subsequentannualrenewalrequests(beyond15months)willbeconsideredforpatientswhoseBASDAIscoresdonotworsen(i.e.remainswithintwopointsofthesecondassessment).Foralloftheaboveindicationsthisproductshouldbeusedinconsultationwithaspecialistinthisarea.(h)Fortreatmentofulcerativecolitisinpatientsunresponsivetohighdoseintravenoussteroids.NOTE:Clinicalresponseshouldbeassessedafterthethree-doseinductionphasebeforeproceedingtomaintenancetherapy.Ongoingcoveragewillonlybeprovidedforthosewhorespondtotherapy.Patientsundergoingthistreatmentshouldbereviewedeverysixmonthsbyaspecialistinthisarea

MB Forthetreatmentofpatientswithmoderatelytoseverelyactiveulcerativecolitiswhohavehadaninadequateresponsetoconventionaltherapyincluding5-aminosalicylatecompoundscorticosteroidsandimmunomodulators.Requestforcoveragemustbemadebyaphysicianwhoisaspecialistingastroenterology

ON Induction1.Milddiseasea.Mayoscore<6ANDb.Patientswithmilddiseasewillbeconsideredonacase-by-casebasisBUTsubmissionmustincludetherationaleforcoverage

DrugPlan CriteriaforRestrictedBenefit2.Moderatediseasea.Mayoscorebetween6and10(inclusive)ANDb.*Endoscopicsubscoreof2ANDc.Failed2weeksoforalprednisone≥40mg(orIVequivalentforatleast1week)AND3monthsofAzathioprine(AZA)/6-Mercaptopurine(6MP)(orwheretheuseofimmunosuppressantsiscontraindicated)ORd.Stabilizedwith2weeksoforalprednisone≥40mg(ora1weekcourseofIVequivalent)buttheprednisonedosecannotbetapereddespite3monthsofAZA/6MP(orwheretheuseofimmunosuppressantsiscontraindicated)3.Severediseasea.Mayoscore>10ANDb.*Endoscopysubscore≥2c.Failed2weeksoforalprednisone≥40mg(or1weekIVequivalent)ORd.Stabilizedwith2weeksoforalprednisone≥40mg(or1weekofIVequivalent)buttheprednisonedosecannotbetapereddespite3monthsofAZA/6MP(orwheretheuseofimmunosuppressantsiscontraindicated)*Theendoscopyproceduremustbedonewithinthelastyearbutdoesnothavetobefullendoscopy.MaintenanceCriteria:1.After3loadingdosesofREMICADE®:a.Mayoscore<6ANDb.50%reductioninprednisonefromthestartingdoseApproval:3monthsat5mg/kg/doseevery8weeksIfpatientiscompletelyoffsteroids.Approval:12monthsat5mg/kg/doseevery8weeks2.Subsequentrenewals:a.Mayoscore<6;ANDb.Mustbeoffsteroids(Patientswhoremainonsteroidswillbeconsideredonacase-by-casebasis)Approval:12monthsat5mg/kg/doseevery8weeks

DrugPlan CriteriaforRestrictedBenefitNB NotaBenefit

NS NotaBenefitPE NotaBenefit

NL NotaBenefitYK ForUlcerativeColitisonrecommendationofaspecialist.Consulttobeprovided.ForpatientswithaMayoscore>6ANDanendoscopic

subscore≥2(withinlast12months

ANDfailed2weeksoforalprednisone≥40mg(or1weekIVequivalent)AND3monthsofazathioprineor6-mercaptopurine

ORstabilizedonprednisoneasabovebuttheprednisonedosecannotbetapereddespite3monthsofDMARDS.

Onlyonemonth'sdosetobedispensedatatime.Approvalfor12monthperiodNT NotaBenefitNIHB NotaBenefit

DND NotaBenefit

VAC NotaBenefit

APPENDIX3:SUMMARYOFPATIENTINPUT

1.DescriptionofPatientGroupsSupplyingInput:Twopatientgroupsprovidedinputforthissubmission:TheGastrointestinal(GI)SocietyandCrohn’sandColitisCanada(CCC).ThemissionoftheGISocietyistoprovideevidence-basedinformationonconditionsrelatedtotheGItractandliver,improvethelivesofpeoplelivingwiththeseconditions,supportresearch,advocateforhealthcareaccess,andpromoteGIandliverhealth.TheGISocietyprovidespamphletsandonlineinformation,deliverslectures,andrespondstoinformationrequestsfrompatientsandhealthcareprofessionals.English(www.badgut.org)andFrench(www.mauxdeventre.org)websitesareavailable.Financialcontributionsarereceivedfrompharmaceuticalcompanies(Pfizer,AbbVieCorporation,Actavis,AstraZenecaCanadaInc.,InnovativeMedicinesCanada,FerringInc.,GileadSciencesCanadaInc.,GlaxoSmithKlineInc.,JanssenCanada,MerckCanadaInc.,PfizerCanadaInc.,ShireCanadaInc.,andTakedaCanadaInc.),governments,foundations,andindividuals.Noconflictofinterestwasdeclaredinpreparingthepatientinputforthissubmission.CCCisanational,volunteer-basedcharitythatworksonfindingcuresforCrohn’sdisease(CD)andulcerativecolitis(UC),improvingthelivesofpeoplelivingwiththeseconditions,providingpatientprograms,advocatingonbehalfofpatients,andincreasingawareness.Itisamongtheforemostcharityfundersofinflammatoryboweldisease(IBD)researchintheworld.Theorganizationhaschaptersin45communitiesacrossCanada.During2014-2015,11%ofCCC’srevenueswerefromcorporatedonations.Majorsupporterswere:AbbVieCorporation,JanssenInc.,TheLeonaM.andHarryB.HelmsleyCharitableTrust,M&MMeatShops,TakedaCanadaInc.,andVertexPharmaceuticals(Canada)Inc.Noconflictofinterestwasdeclaredinpreparingthepatientinputforthissubmission.2.ConditionRelatedInformation:TheCCCobtainedinformationfromCCCpublishedreports,CCCsurveys,andeducationalbrochuresavailableontheorganization’swebsite(www.crohnsandcolitis.ca).ThesourcesofinformationconsultedbytheGISocietywerenotprovided.TheGISocietyindicatedthattherearedifferencesbetweenUCandCDwithrespecttotheextentandareasofinflammationexperiencedbypatientswiththeseconditions.TheinflammationofCDaffectsmoreareasoftheintestinaltractandisdeeperinextentcomparedwithUC.InadditiontoGIsymptoms,patientswitheitherUCorCDmayexperienceextra-intestinalmanifestations,suchasfever,inflammationofeyesorjoints,ulcersofmouthorskin,tenderandinflamednodulesontheshins,anxiety,andstress.Symptomsmayhaveprofoundeffectsonthephysical,social,andemotionalaspectsofpatients’lives.Patientsalsoreportbeingconstantlyconcernedaboutdiseaseflare-ups,whichmaybeworseinseveritycomparedwithpreviousflaresandoccurunpredictably.Thiscausesgreatdisruptiontopatients’lives.Sustainedremissionortreatmentresponse,therefore,isdesiredbypatients.TheCCCreportedthatthemostunbearablesymptomsexperiencedbypatientsarelackofcontroloverbowelmovementsandurgentandfrequentneedtousethebathroom.ACCC2011surveyfoundthat73%ofpatientsexperienced5to20ormorebowelmovementsperday.Althoughpatientsindicatedbloodinthestoolandabdominalpainasimportantsymptoms,thedominatingconcernwasaccesstoawashroom.Somepatientswerealsoconcernedabouttheincreasedriskofcoloncancer.Limitationsin

leisureactivities(e.g.,goingoutfordinners,movies,andconcerts),physicalactivities,useofpublictransportation,andworkwerereported.Accordingtoonerespondent,“Yousimplycan’tleadanormallifeofworkingandgoingtotheoffice.”Thirty-fourpercentfrequentlymissedplayingsports,22%missedschooltrips,20%skippedfamilyvacations,40%avoidedparties,and22%didnotattendspecialeventssuchasgraduationsorfamilyweddings.Inaddition,patientsreportedexperiencinggreaterscrutinyfrombossesduetofrequentwashroombreaksorsickdays.IBDsareattachedwithstigma,whichmakesitdifficultforpatientstoopenlytalkabouttheircondition.Caregiversarealsoaffectedbythecondition,oftenactingasadvocatesfortheirlovedoneanddevotingtimeandresourcestohelpmanagethepotentiallimitationsincarryingoutday-to-dayactivities.Theprocessofcaring,however,mayaffectthecaregiver’smentalandphysicalhealth,andoftenexertsfinancialburdenincludingout-of-pocketexpensesassociatedwithdiseasemanagement.3.CurrentTherapy-RelatedInformation:TheCCCobtainedinformationfrompatientreportsofinnovatordrugs,whichwereincludedinpreviousdrugsubmissionstoCADTH.ThesourcesofinformationconsultedbytheGISocietywerenotprovided.AsurveywasconductedbytheGISocietyin2015ontheirEnglishandFrenchwebsitestounderstandtheperspectivesofpatientswithIBDorcaregiversofapersonwithIBDregardingsubsequententrybiologics(SEBs).Atotalof423respondentsparticipated,fromallprovincesandterritories.Thegoalsoftherapyareinductionofremissionandmaintenanceofremission.Thisisachievedbyusingtreatmentsthatcontrolinflammationintheintestinaltract.Oldertreatmentsinclude5-aminosalicylicacid(5-ASA),corticosteroids,andimmunosuppressivedrugs.AccordingtotheGISociety,theintroductionofbiologicdrugswaslife-changingand“revolutionary”whenoldertreatmentsfailedtoachievethegoalsoftherapy.However,biologicsdohavesideeffectsandrisksand,therefore,areprescribedonlyiftheyarethebestoptionforcontrollinginflammation.ThecourseofIBDisoftenunpredictableanduniqueamongpatientsand,thus,treatmentmustbeindividualized;atreatmentregimenthatworksforonepatientmaynotbesuitableforanother.Availabilityandchoiceofdifferenttreatmentsoptionsareamust.SincethereisnocureforIBD,isitimportanttomaintainongoingmedicalcare,propernutrition,andmedication.PatientswhoreportedtotheCCCindicatedthattheyrespondedwelltotheinnovatorbiologic.Afterfailureoffirst-linetreatments,innovatorbiologicdrugshaveallowedpatientstoachieveremissionandexperienceareductioninthenumberofbowelmovements,decreasedfatigue,lesspain,andlesspsychologicalstressassociatedwithneedforwashroomaccess.Accordingtoonerespondent,“withsteroidsIwasat60%butwith[innovatorbiologics]I’mat95%.”Patientsreportedthatinnovatorbiologicshelpedthemachieveasclosetoanormallifeaspossible.Biologicdrugsofferanalternativetosurgerywhenothertreatmentshavefailed.Thispreventsthecomplicationsofsurgery,suchascontinence/soiling,poorpouchfunction,pouchitis,sexualdysfunction,andlossoffertilityinfemales.4.ExpectationsfortheDrugBeingReviewed:TheinformationforthissectionwasobtainedfromthesurveyconductedbytheGIsociety.Patientsexpectthattreatmentwillimprovetheirqualityoflife,whichmeansreliefofsymptoms,alleviationofanxietyandstress,abilitytoleadanormallifewithfamily,career/education,andwithoutinterruptionsduetoflare-ups.TheyexpectthatanapprovedSEBhasbeenproventobesafeandeffective,specificallyinIBD.

PatientsexpressedconcernsaboutthesafetyandefficacyofSEBs,theregulatoryprocessofSEBsinCanada,andswitchingbetweeninnovatorandSEBtreatments,especiallywithouttheirconsent.Theydonotwantcosttobetheonlyconsiderationwhendecidingwhichbiologictouse.Inaddition,itwasimportantforpatientsthatthephysicianchoosesinconsultationwiththemthebestdrugfortheircondition(andthatthechoiceisnotjustmadebyagovernmentordrugplan).PatientsexpectthatSEBregulationsconsider,inorderofpriority:safety,areviewandapprovalprocessthatisasrigorousasfortheinnovator,thattheSEBistestedforallindications/diseases,theimportanceofmoretreatmentoptions,andthattheSEBisclinicallytestedinCanadians.

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