艾昆纬-2022年欧洲生物仿制药竞争的影响（英）-2022.12-44正式版

WhitePaperTheImpactofBiosimilarCompetitioninEuropeDecember2022PERTROEIN,VicePresident,StrategicPartners,IQVIAMAXNEWTON,EngagementManager,GlobalSupplier&AssociationRelations,IQVIAKELSEYSTODDART,Consultant,GlobalSupplier&AssociationRelations,IQVIAAURELIOARIAS,Director,EuropeanThoughtLeadership,IQVIATableofcontentsIntroduction1Keyobservations2Methodology14CountryandtherapyareaKPIs16Humangrowthhormone(HGH)16Epoetin(EPO)18Granulocyte-colonystimulatingfactor(GCSF)20Anti-tumournecrosisfactor(Anti-TNF)22Fertility(Follitropinalfa)24Insulins26Oncology28Low-molecular-weightheparin(LMWH)30Parathyroidhormone(teriparatide)32Opthalmology34Appendix36EMAlistofapprovedbiosimilars36ListofBiosimilarsunderreviewbyEMA38Abouttheauthors40IntroductionThe8thiterationofthe‘ImpactofBiosimilarCompetitioninEurope’reportdescribestheeffectsonprice,volume,andmarketsharefollowingthearrivalofbiosimilarcompetitioninEurope.Thereportconsistsofobservationsoncompetitivemarkets,andasetofKeyPerformanceIndicators(KPIs)tomonitortheimpactofbiosimilarsin23Europeanmarkets.Thereporthasbeenalong-standingsourceofinformationonthestatusofthebiosimilarsmarket.BiosimilarsareacriticalpartoftheEuropeanhealthcaresystem,andareabletobalancespendingbygeneratingsavingsforpayers,createheadroomforinnovation,andexpandaccesstobiologictherapyforpatients.Sincethefirstbiosimilarwaslaunchedin2006,biosimilarmedicineshavebecomeacorecomponentofaneffectivehealthcaresystem,butheadwindsareincreasingwiththechallengesoforphanbiosimilardevelopment,andthedisparityinaccessacrossEuropebecomingmoreacute.Asthereportaddsnewtherapyareas,andasnewclassesemerge,wehavenewchallengesthatwemustadapttoforthisreporttocontinueitsrelevance.Thismeansthatwecontinuetorefinepreviousdefinitionstomakethemrepresentativeofthecurrentenvironment,buildingonthe2020(6threport)whichpermittedtheclassificationhistoricdynamicsinthemarket,andallowspolicymakers,nationalcompetentauthorities,patientgroups,andindustrytoviewthemarketwithgreatergranularity.ThisreporthasbeenpreparedbyIQVIAattherequestoftheEuropeanCommissionserviceswithinitialcontributionsondefiningtheKPIsfromEFPIA,MedicinesforEurope,andEuropaBio.TheobservationshavebeendevelopedsolelybyIQVIAbasedonthedataandanalysesperformed.Theinformationandviewssetoutinthisreportarethoseofitsauthorsandarenottobeattributedto,nornecessarilyreflecttheviewsoftheEuropeanCommissionoranyofitsservices.TheEuropeanMedicinesAgency(EMA)hasacentralroleinsettingtherulesforbiosimilarsubmissions,approving

applications,establishingapprovedindications,andmonitoringadverseevents,andifnecessary,issuingsafetywarnings.Wehave,whenappropriate,quotedtheirinformationandstatements.IQVIAgratefullyacknowledgesthecontributionsofthosewhohavesupportedthedevelopmentofthisseriesovertheyears,notably:AurelioArias,VibhuTewary,MichaelKleinrock,UrvashiPorwal,MarcoTravaglio,KirstieScott,andmany|1IQVIAobservationsImpactofBiosimilarCompetition(2022)BACKGROUNDBiologicmedicinesareanincreasinglyimportantcomponentofpharmaceuticalexpenditure,duetotheirefficacyastreatmentsforcomplexconditions.Biologicsrepresent35%ofmedicinespendinginEuropeatlistpricesandaregrowingata11.3%compoundannualgrowthrate(CAGR)overthepastfiveyears.Thiscomparestoa6.3%CAGRforthetotalmarket.Biologicsareincreasinglyimportantandhavecontinuedtogrowfasterthannon-biologicmedicinesforoveradecade.Theimportanceofbiologicmedicinesandthesustainabilityofbiosimilarcompetitionisanincreasinglycriticalsuccessfactorforhealthcaresystemspre-,andpost-COVID-19.Biosimilarsrepresent€9billionannuallyacrossEurope,butthecompetitiontheyprovidehasfarreachingbenefitsforpatients,payers,andthehealthcaresystem.Exhibit1:TheimportanceofbiologicswithintheEuropeanpharmaceuticalmarketEUspending(%) EUgrowth(YoY,%)100%+0.5%v2021(%)1490%36%280%1270%77651060%850%40%630%420%10%23%Year0%02010202120162017201820192020BiologicsNon-biologics*H2MAT2022Notes:Biologicmarketincludesoriginatorbiologicsandbiosimilars;andEUcountryscope(excludesUK,Switzerland)Source:IQVIAMIDAS(Q22022),Rxonly;BiologicmoleculesexcludeATC-V(vaccines,andvarious)

Biologics,CAGR(2016-2022):11.3%TotalEUmarket,CAGR(2016-2022):6.3%Smallmolecules,CAGR(2016-2022):3.4%2021 2022*Thepast5yearshavebeenasignofthematurationofthebiosimilarsmarket.Thenumberofnewbiologicmoleculeswithabiosimilardoubledinthepast5yearperiodcomparedtothe10yearsprior,andthenumberofcompetitorswithineachmarkethasincreasedsignificantly.By2022atotalof18moleculesnowhavedirectbiosimilarcompetitionandhaveanaverageof3.8competitorsauthorised,ledbyadalimumabwhichalonehas10marketedbiosimilarmedicinesauthorisedinEurope.2|TheImpactofBiosimilarCompetitioninEuropeExhibit2:CentrallyapprovedbiosimilarsandnewmoleculesopentocompetitionCentrallyapprovedbiosimilarsbymoleculetype(2006–2022)181614141approvals121114991central118113#of6514414614333211141122211112112311112221111110120062007200820092010201120122013201420152016201720182019202020212022Source:IQVIAanalysisofEMAEPARlist(lastaccessedNovember2022)TheImpactofBiosimilarCompetitioninEurope2022;PreparedforEuropeanCommission(DGSANTE)December2022

insulinhuman(rDNA)ranibizumabinsulinaspartbevacizumabpegfilgrastimadalimumabtrastuzumaboldestteriparatidetoinsulinlispronewestetanerceptenoxaparinsodiumOrder:insulinglargineinfliximabfollitropinalfafilgrastimepoetinzetaepoetinalfasomatropinBackground:Cumulative#ofnewmoleculeswithbiosimilarsSincethecreationofthisseriesofreports,IQVIAhasprovided5observationsonthemarket.Thethemesoftheseobservationshavebeenonsavings,prices,access,strategy,andcompetition,whicharethecentraltenantsofbiosimilarcompetition.Eachyeartheaimistoprovidenovelinsightsonthemarket.Previousyears’insightsremainvalidandarenowreferencedforposteritysuchaschangingoriginatorstrategies(2019),theestimatesofthenetsavingsasaproportionofhealthcareexpenditure(2020),andthelocationofemergingbiosimilarmanufacturers(2021).Exhibit3:IQVIA’shistoric5observationsonthebiosimilarmarket(2015–2021)2015 2016 2017 2018 2019 2020 2021CompetitiondrivesCompetitiondrivesTheentranceofTheentranceofBiosimilarcompetitionBiosimilarcompetitionThepandemichasdownpricedownpricebiosimilarsincreasesbiosimilarsincreaseshasasignificantcontinuestoofferimpactedcertainThecorrelationbetweenThecorrelationbetweenpricecompetitionpricecompetitionpotentialimpactonopportunitiestomakesegmentsofthebiologicbiosimilarsmarketsharebiosimilarsmarketshareInsometherapeuticBiosimilarshavetheoveralldrugspendhealthcaresavingsmarketandpricereductionisandpricereductionisclasses,loweringthepotentialtoimproveMajorproductsseefastSomecountriesarenotThesavingsfromweakweakpriceofthereferencedpatientaccessoftheuptakeandlargepriceincreasingusagebiosimilarcompetitionCompetitioncanalsoCompetitioncanalsoproductcanlimitthetotalmarketreductionsdespitepricereductionsreachanall-timehighmarketpenetrationofInsomecountries,Originatormanufactur-ThevariationofDevelopmentofaccessinfluencetheinfluencetheoriginator’sbehavioursoriginator’sbehavioursthebiosimilarbiosimilarshaveershavechangedoriginatorresponsetotobiologicmedicinesLowerpriceshastheLowerpricesincreaseThereisafirsttomarketcompletelytakenoverstrategytostayprotectionexpiryremainschallengingadvantageinbiosimilarInsometherapeuticcompetitivemostimpactonusagepatientaccessinSeveralmodelscanworkThecompetitionmarketsclasses,loweringtheAccessisnotyet(patientaccess)incountrieswithlowinitialtosupportcompetitiveenvironmentinEuropecountrieswithlowinitialusageBiosimilarshavethepriceofthereferencedincreasingforallmarketsischangingproductcanlimitthemoleculesandinallusageTheproductprofilepotentialtoimproveTherealimpactofEnsuringpreparednessmarketpenetrationofcountriesafterpatientaccessoftheTheproductprofiledifferencesinclassesthebiosimilarbiosimilarintroductionbiosimilarcompetitionisforthefutureoftotalmarketdifferencesinclassescanexplaindifferencesThespeedofuptakehasMoreisneededtojustbeginningbiosimilaropportunitycanexplaindifferencesinimpactontheKPIsincreasedforsomeofcreateasustainableinimpactontheKPIsthemorerecentmarketforbiosimilarbiosimilarlaunchesmanufacturersSource:IQVIA/IMSHealth,TheImpactofBiosimilarcompetitioninEurope(2015-2021)TheImpactofBiosimilarCompetitioninEurope2022;PreparedforEuropeanCommission(DGSANTE)December2022|3In2022theseobservationsfocusontheEuropeanCommission’spriorityareasandhaveanincreasedfocusontheareasofaccess,affordability,andcompetitorentry.ThereportcontinuestotracktheimpactofCOVID-19onbiologic(andbiosimilar)prescribingtrendsandconsidersthechallengesforallstakeholderstobeensuringthecontinuedsuccessofthemarketforfuturebiologiclossofexclusivity(LOE)events.Theobservationsareasfollows:COVID-19:Biologicprescribinghasrebounded,butmacroeconomicchallengesloomSavings:Thesavingsfrombiosimilarcompetitionreachanall-timehighAccess:AccessisimprovingbutagrowingdisparityisoccurringacrosscountriesCompetition:NotalloriginatorswillseecompetitionFuture:LOEwilltripleinthenext5yearsversustheprevious5OBSERVATION1:COVID-191.1BiologicprescribinghasreboundedsincethepandemicCOVID-19hadamarketeffectonpatients,populations,andhealthcaresystems.Accesstohealthcareprofessionalswasrestricted,andprescribinghabitschangedtoasthepriorityofhospitalcarechangedtosupportthoseaffectedbyCOVID-19.Therewasdebateintheacademicliteratureofthepotentialrisksofbiologictreatmentduringthepandemic,withnewguidelinesbeingprovidedatthebeginningofthepandemic,andunexpectedbeneficialeffectsofanti-TNFagentsforCOVID-19protectionandtreatmenti.Initiationofnewpatientsontobiologictherapyhasbeenchallengedinmanycountries.Forexample,inFrancebiologicinitiationsweregreatlyreducedduringthelockdownforanti-TNFsii,andwereobservedwherethepandemicwasmorepronounced.PsoriasispatientsinItalybeingprescribedbiologictherapiesforimmunomodulationfacedvariableadvicetostoptreatmentorfaceddifficultiesinobtainingsuppliesoftheirmedicinesduetothelockdowniii.Exhibit4:ImpactofCOVID-19pandemicontherapyclassesopentobiosimilarcompetitionIndex(Q12019=100)

180160140120100806040200

+18ptssincepre-COVID-192019 2020 2021 2022Anti-tumournecrosisfactor(ANTI-TNF)Epoetin(EPO)Granulocyte-colonystimulatingfactor(GCSF)Humangrowthhormone(HGH)

Index(Q12019=100)

180160140120100806040200

+2ptssincepre-COVID-192019 2020 2021 2022Fertility(FOLLITROPINALFA)InsulinsLow-molecular-weightheparin(LMWH)OncologyParathyroidhormonesSource:IQVIAMIDASJune2022MATNotes:Ophthalmologytherapyareaexcludedduetotheimpactofnewproductentrieswithintheclassskewingtheindex4|TheImpactofBiosimilarCompetitioninEuropeAssessingthetotalEuropeanmarketbytherapyclass,theanalysisshowsthatthemajorityoftreatmentclasseswithinthisreporthavereboundedtoabovetheirpre-COVID-19prescribinglevels(anti-TNFs,EPO,GCSF,andHGH).Thishasnotoccurredequally,withnoticeabledropsinmosttherapyclassesatthestartofthepandemic,andnoticeableincreasesassecondaryusesforbiologictherapiesweretested.Fertilitytreatmentsfacedasignificantdeclineastheabilitytoaccessnon-urgentcaredeclineandriskofCOVID-19andpregnancywasconsidered.1.2.COVID-19ledtomacroeconomicpressuresthatimpacthealthcaresystemsItremainstobeseenhowthepopulationandhealthcaresystemscancombatCOVID-19pandemicduringthe2022–2023winter,butthepandemichashadabroaderimpactonpatients,payers,andindustry.Ontopofthis,inflationintheEurozonereached10%inNovember2022iv(downfrom10.6%inOctober)primarilydrivenbyenergyprices,asaresultofthewarinUkraine.Thesecondarydriverofthiswasthefragilityofglobalsupplychains,whichcausedanimpactonconsumergoods.Whileeconomistssuggestthisenergycrisiswillnotbealong-term,theimpactofinflationaffectsallstakeholdersaspricesremainhigh.Fromapatient’sperspective,countrieswherepatientspayfortheirbiologictreatmentsoutofpocketorwithco-pay(e.g.Poland)willfinditincreasinglydifficulttoaffordtheirmedications,smallermanufacturersofbiosimilarsrecordincreasesinthecostofpackaginganddistributionofmedicinesv,andpayerswillhaveanincreasedneedtomakethesavingstoreducethelong-termimpactthattheCOVID-19pandemichadonhealthcaresystems.Inmarketswithvisiblenetprices(e.g.Sweden),theexpectationdoesnotalwaysmeetthereality;pricesformedicinescontinuetofall,althoughthefulleffectremainstobeseen.Exhibit5:Broaderimpactonhealthcaresystems,andtheimpactofinflationonbiologicRxUpfrontcostistothecompanies,specicallyforsmallermanufacturersinEuropeanmarkets,ashospitaldistributionislessexposedtotherapidincreaseinsupplychaincosts

PatientcostsAbilitytopayformedicineswillfallwithlowerdisposableincome(OTC,andco-paymarketse.g.Poland)Theripple,notthesplashProductioncostsareanimportantbutsmallerproportionoftotalcosts,butcapsandclawbacksactaslimitsIncreasedfocusoncostRequirementformarketstomakesavingscanincreasedfocusonLOE,butsuccessdependswhetheritsthroughincreasingcompetitionorpricereductiononlySource:IQVIAperspectives,[1]MedicinesforEuropeOpenletter:/wp-content/uploads/2022/06/EPSCO-Council-_-Medicines-for-Europe-Executive-Committee-OPEN-letter-on-inflation-impacting-the-supply-of-essential-medicines.pdfOBSERVATION2:SAVINGS2.1SavingsfromtheimpactofbiosimilarcompetitioncontinuestogrowUsingthe‘pre-biosimilar’prices,itispossibletocalculatethelistpricesavingsthataregeneratedon‘post-biosimilar’volume.Biosimilarsprovidednearly4.5billionpatienttreatmentdaystoEuropeanpatientsandcontinuetogrowyear-on-year.Inthepastyear,850millionpatienttreatmentdayswereattributedtobiosimilartherapies,upfrom750millionin2021.However,thetruecostofbiologictherapy(originatororbiosimilar)iscommerciallysensitive,butlistpricesacrossEuropeactasabase-casetoestimatesavingsgeneratedinEuropeanmarkets.In2012,estimatessuggestedsavingscouldbeintherangeof€12–€34billionby2020vi.Asof2022,thecumulativesavingsatlistpricesfromtheimpactofbiosimilarcompetitioninEuropereachedover€30|5Anumberofdifferentmechanismscanbeusedtostimulatesavings.Savingsfromareductioninlistpricesoccursautomaticallyinmanymarkets,othersregulatepricereductions,andmarketforcescreatepricedifferentials,andamixofbiosimilarpoliciesandlevers.ThemodelsuggeststhatGermanysaved€3.6billioninsavingssince2015onanti-TNFsvii.Exhibit6:SavingsfromtheimpactofbiosimilarcompetitionatlistpricesValue(Euros,Mn)

35,000530,0004Biosimilar25,00015,0003volume(TD,20,000Nohistoricsalesdatapre-2011*10,000Bn)5,0001002006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 20212022*Salesvalue(€,listprices)SavingsVolume(TD)Caveats:Thisfigureisnotequivalenttoallsavings.Andisthereforeanunder-estimate.Thedatadoesnotincludetheimpactofrebatesordiscounts,whichmayhavebeenpresentpriortotheintroductionofbiosimilarsinsmallquantities,andarehighlysignificantpost-biosimilarentryasitisbasedonpubliclyavailablelistprices..Source:IQVIAMIDAS™datafrom2006–2022,usingEurosatconstantexchangerates;valueincludesalloriginatorproductswithapprovedbiosimilarsfrom2006–2022,coveringthefullEuropeanEconomicArea(33CTYs),calculatedvolumeisintreatmentdaysdeterminedbyWHO-DDD,andwherevaluesareunavailableviaOncologyDynamicsPhysicianSurvey(2017)DDDestimates.VolumeissolelybiosimilartreatmentdaysSource:IQVIAMIDASJune2022MAT2.2Savingsareafunctionofmultiplecomponents:rebates,usage,uptake,policies,andprogressBiosimilaruptakehasincreasedmarkedlywithnewnewerbiologicsthathavelostexclusivity.InEurope,theaverageuptakerateinthefirst-yearpost-biosimilarentryhasincreasedfrombetween5–40%foruptonearly75%forbevacizumabbiosimilars.Thisreflectsanincreasingcomfortwithbiosimilarprescribingamongstphysicians,andimprovementsinbiosimilarpolicies.However,notallareasseeequivalentbiosimilaruptake,andthereforearenotequivalentcontributorstothetotalsavingscalculations.Theretailmarketforbiologicsseessignificantlylowerpenetrationofbiosimilarmedicines,lowerlistpriceschange,andagreaterchallengetogeneratingsavingsthroughtheretailchannel.IrelandandsomeNordicmarketsemployamethodologytopermitretaildispensingofhospitalfundedmedicines(viaHigh-TechDrugSchemeandequivalents)tonavigatethis.Competitionbetweenmanufacturersbeforebiosimilarentry(inclasseslikeInsulins,LMWHs,andHGH)meanthatbiosimilaruptakeislowerduetothealreadycompetitivenatureofthemarketandtheloweropportunityforbiosimilarmanufacturers.Fromapayer’sperspective,savingsareone,ifnotthe,greatestbenefitofbiosimilarcompetition.Toimproveuponthis,healthcaresystemsmustconsider:1.theusageoftheoriginatormoleculewhichactsasacapforthesavingsthatcanbeachievedwithoutincreasedtreatment,2.biosimilarcompetitionwhichisaprecursorforuptake,andcreatingarobustsetofpoliciesthatsupportacompetitive,andsustainablemarketforbiosimilarcompetition.EachcountryisEuropehasauniqueprofileofpoliciesrelatedtobiosimilarswhichcanbeimprovedupontosupportsavings,access,andcreateheadroomforinnovation.IQVIA,TheImpactofBiosimilarCompetitioninEuropereports(2019,page5;2020,page3)6|TheImpactofBiosimilarCompetitioninEuropeExhibit7:SelectedKPIstoillustratevolumeshare,priceevolution,andvolumeevolutioninselectedEuropeancountriesHOSPITALMIXEDINSULINSinfliximabetanerceptrituximabrituximabIVtrastuzumabtrastuzumabIVpegfilgrastimbevacizumabteriparatideadalimumabInsulinGlargineInsulinLisproGermany83%80%86%93%83%94%56%93%45%74%16%6%France84%50%75%97%45%98%79%99%53%41%28%0%Italy95%78%88%99%79%99%85%92%71%80%15%11%Spain82%53%73%96%69%95%87%78%60%63%18%0%Netherlands90%44%97%99%84%100%95%94%68%66%34%16%Denmark99%93%86%100%95%99%100%99%17%97%29%0%Finland98%50%93%100%54%100%66%90%16%58%4%44%Norway99%94%94%199%92%100%98%91%75%92%22%5%Poland100%68%99%99%38%100%100%96%0%99%28%27%HighuptakeLowuptakeSource:IQVIAMIDASMTHJune2022Netpricesareconfidentialforcompetativereasons.Therebatescanbepublished(orleaked)incertaincases,andtheseofferafurtheralargecomponentofthesavingsavailablefrombiosimilarmanufacturers,andincreasinglyfromorigionatormanufacturerstoobeyondthelistpricereductionsseenuponcompetitorentry.PreviousestimatesfromIQVIAsuggestthattheoverallcostreductionimpactofrebatesfrombiologicswithbiosimilarcompetitioncanbebetween2%–8%ofthetotaldrugbudget.Rebatesvaryandcanbeupto90%ofthelistprice,althoughthisvariesbyclass,product,originalpricelevel,andcountry.OBSERVATION3:ACCESS3.1AccessisincreasinginallcountriessignallingprogressBiosimilaruptakeremainsauseful,butoverall,limitedperformancemetrictoaccessthefullbenefitstopayersandpatientsofbiosimilarcompetition.Withchangingapproachesfromoriginatormanufacturerswhonowcompetedirectlyonpriceandcanprovidelowerpricesthanbiosimilarmanufacturersinsometenders,focussingonuptakeremainsonepartofacountry’stoolkittogeneratesavings.Usinganti-TNFclassasanexample,prescribingofanti-TNFmoleculeshasincreasedanaverageof11%acrossEurope(~0.5treatmentdayspercapita)sincetheentryofbiosimilars.Highergrowthrates(7-yearCAGR)areseenincountriesthatstartfromalowerbaselevelofprescribing,butnoticeablytheabsolutegrowthissignificantlylowerthanthoseinthehighusagecountriespre-biosimilarcompetitionoftenwithonlyanominaldifferenceinthetreatmentdayspercapitaprescribed(e.g.,Poland+0.07).IQVIAInstitute,Spotlightonbiosimilars:OptimisingtheSustainabilityofHealthcareSystems,publishedJune2021|7Exhibit8:DevelopmentofAnti-TNFclassusageacrossEuropeanmarketsExample:Anti-TNFstreatmentdaydevelopmentNorway2.22.0IrelandSweden1.8Belgium1.6DenmarkNetherlandsTD/capita1.4Finland1.2SwitzerlandAustria1.0France0.8UKSpain0.6Slovenia0.4GermanySlovakia0.2Portugal0.0CzechItaly-10+1+2+3+4+5+6BulgariaNormalisedyearssincebiosimilarcompetitionHungaryRomaniaPolandNotes:Calculationisbasedonthenormalizedyearbeforebiosimilarentryforeachmoleculeintheanti-TNFclass,andthetreatmentdaysbeforeandsincetheLOEdateinEuropeSource:IQVIAMIDASJune2022MAT

%growth(7yearCAGR)Absgrowth11%1.1212%1.1010%0.848%0.6912%1.027%0.5912%0.773%0.2033%1.059%0.519%0.519%0.478%0.348%0.357%0.2912%0.3715%0.385%0.1424%0.354%0.113%0.0515%0.073.2ThedisparityinaccessacrossEuropeisexpandingAccesstomedicinesisacriticalpriorityforallstakeholders.However,theabilityforcountriestocapitaliseofthepromiseofbiosimilarcompetitionhasnotoccurredevenly,andnotallhavehadanequivalentstartingpoint.Inaddition,thedifferentapproacheshavebeendocumentedroutinely,butthedeltabetweenthehighestandlowestprescribingcountrieshasgrown,highlightedbytheanti-TNF,oncology,andinsulinclasses.Exhibit9:AgrowingdeltabetweenhighaccessandlowaccessmarketsinEuropeTD/capita

Anti-TNFs Oncology Insulins114%50%1220%2.0Increasein0.25IncreaseinIncreaseinaccessdisparityaccessdisparity11accessdisparity1.5TD/capita0.20TD/capita10+0.0891.0+1.50.15+0.128+4.1+4.90.5+0.70.10650.0-10+1+2+3+4+5+6Year*0.05-10+1+2+3+4Year*4-10+1+2+3+4+5Year*High-accesscountriesHigh-accesscountriesHigh-accesscountries(NO,IE,SE,BE,DK)(BE,FR,AT,CH,FI)(FI,DE,CZ,HU,SE)Low-accesscountriesLow-accesscountriesLow-accesscountries(IT,BU,HU,RO,PO)(SK,CZ,DE,PO,RO)(BU,PO,IT,IE,CH)*Normalisedtotheyearoffirstrecordedbiosimilarsalesineachcountry,toaccountformarketsthataredelayedinusingbiosimilarsafterlossofpatentprotectionChartnotes:IncludesTDforallmarketsegments(Non-accessible,Non-referenced,Referenced,Biosimilars);AllcountriesarerankedbasedonTD/Capitaat+6yearsandthetop-5andbottom-5countriesincludesinthisanalysis.Source:IQVIAMIDASJune2022MAT.8|TheImpactofBiosimilarCompetitioninEuropeOBSERVATION4:COMPETITORENTRY4.1RecentbiologicshavereceivedbiosimilarcompetitionBiologicmoleculesareunliketraditionalgenericsintherequirementforclinicalequivalencestudies,thecostofdevelopment,andthecostforcomparatorsduringtrials.Theincreasedcostofdevelopmentmeansthatnotallmoleculesarecurrentlysuitabletargetsforthedevelopmentthemultiplebiosimilarsthatarerequiredtocreateacompetitivemarket.Thisanalysisincludesallbiologicmedicinesthathavelostexclusivityinthepast5years,theirglobalsales(asanindicatorofoverallattractiveness),andtheirEuropeansalesforcontext.Allhighvaluebiologicswhichwerevaluedatabove€100millionintheiryearbeforelossofexclusivityeitherhavebiosimilarsorhavebiosimilarsindevelopment.Therearelowervaluemedicines,oftenthosethattreatrareconditions,thathavelimitedsalesvalueandwouldnotsupportmultiplecompetitorseffectivelyinthecurrentframework.Thesemedicinesaremostlyrecombinanthormonesorrecombinantenzymesthathaveverylimitedrevenueorarehighlycomplextomanufacture,especiallyintheU.S.whichhassignificantweightininvestmentdecisionsglobally.Inaddition,somebiologicsinthisanalysisaredefinedas‘verysimilar’or‘veryslightlydifferent’viiibytheEMAtootherbiologicsandarethereforeunlikelytowarranttheirownuniquebiosimilar.Exhibit10:StatusofcompetitorentryforrecentbiologicLOEs(2016–2021)Salesinglobalmarkets(yearbeforeLoP)

100,000,000,00010,000,000,0001,000,000,000100,000,00010,000,000

Recentlossofexclusivities(2016–2021)High-valuebiologics:competitorsordevelopmentexistsinallcasesUniquecasesofLowvaluebiologics similarityalreadytolackscompetitorsor anotherbiologicdevelopment1,000 1,000,000100,000,0001,000,000,00010,000,000,000SalesinEUmarkets(yearbeforeLoP)BiologicwithcompetitionBiologicswithproductsindevelopmentBiologicswithoutcompetitorsSource:IQVIAInstitute,ProtectionExpiryandJourneyintotheMarket:PharmaceuticalproductsinEurope(September2022)/insights/the-iqvia-institute/reports/protection-expiry-and-journey-into-the-market4.2HighnumbersofbiosimilarsarewithdrawnorhavedevelopmentdiscontinuedThetopbiologicsbyspendinEuropealreadyhavebiosimilarsoradevelopmentpipeline.Thelargestbiologicmoleculesbyspendarevaluedat~€36billionin2022alone.Anumberofthesebiologicsarenotyeteligibleforcompetitionduetotheirprotectionstatus,andothershavehadcompetitionformanyyears.Competitionwithinthebiosimilarmarketisincreasinglyfierce,withmultiplecompetitorsenteringforthelargermolecules.Adalimumabalonehashad17potentialcompetitors,whileasignificantnumberwereeitherwithdrawnfromthemarketordiscontinuedbytheirdevelopers.Thenumberofwithdrawals/discontinuationssignalsanemergingsaturationforsome|9Exhibit11:CompetitorstatusfortopbiologicmoleculesandpipelineEuropeanspending(2022,LCEuros)Numberofbiosimilars(by