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Follow-OnBiologics:

Economic,InnovationandPolicyReflections

TheFuquaSchoolofBusiness

DukeUniversityNovember6-7,2008CharlesDiLibertiV.P.GlobalPharmacokineticsandBioequivalence,BarrLaboratories,Inc.“CommercialOpportunitiesandChallengesforFollow-onBiologics”PresentationOverviewGenericBiologicsCommercialOpportunities&SavingsScience&TechnologyChallengesRegulatory&IntellectualPropertyIssuesSummaryCommercialOpportunities&SavingsBenefitsofGenericCompetitionSignificantCostSavingOpportunitiesSavingsforconsumersandtaxpayersGenericCompetitionWillFuelInnovationBrandcompanieswillhavetheincentiveneededtovigorouslypursuenewbiologics

IncreasingSignificanceofBiologicProductsUSBiologicRevenues1997:$17.4Billion2007:$65.2Billion*400Biologics&VaccinesCurrentlyinClinicalTrialsTargeting>200Diseases**Between2003and2006,biologicsrepresented24%ofallnewchemicalentitiesapprovedbytheUS***

SalesofbiotechproductsintheUSshowedanannualgrowthrateof20%between2001and2006comparedwith6%to8%inthepharmaceuticalmarket****Ernst&Young**BiotechnologyIndustryOrganization***JournalofAmericanMedicalAssociation,October22,2008HighCostofBrandBiologicsAnnualCostperPatient

Enbrel(Arthritis)

$20,000*Cerezyme(GaucherDisease)$200,000**

Remicade(Arthritis)$35,000-$66,000***GenericCompetitionWillReduceTheseCosts*BaltimoreSunJanuary28,2007**BloombergJanuary11,2007***PhiladelphiaInquirerSeptember19,2006SignificantCostSavingsOpportunityGenericBiologicsRepresentSignificantCostSavingsOpportunitiesandStimulateInnovationEpogenMarketBeforeGenericLaunch:$2.5Billion*Brand/YearToday:$9,000**GenericSavings/Yearassuming50%savings:$4,500EnbrelMarketBeforeGenericLaunch:$2.7Billion*Brand/YearToday:$20,000***GenericSavings/Yearassuming50%savings:$10,000*ABNAMROFebruary2008**NationalJournalFebruary10,2007***BaltimoreSunJanuary28,2007GenericCompetition

PriceDropsasNumberofManufacturersIncreasesMarketSizeforSelectBiologicProductsSource:ABNAMROFebruary2008MarketSizeforSelectBiologicProductsSource:ABNAMROFebruary2008Perspective:

HistoricalGrowthinSubstitutionSource:IMSHealth,BancofAmericaSecuritiesLLCestimatesGenericBiologics

OpportunityGenericPharmaceuticals-AVitalPartinHealthCareSystemApproximately67%ofthePrescriptionsDispensedintheUSAreGenerics*BiologicsWorldwideMarketEstimatedaround$75Billion*PerPatientCostforBiologicProductsCanExceed$100,000PerYearGenericBiologicsUSConsumersCouldSave$43BillionBetween2011and2020**EstimatedValueofBiologicsthathavealreadylostPatentProtection:$10Billion***EstimatedValueofBiologicstolosePatentProtectionintheNextTenYears:$20Billion****IMSHealth**CitizensAgainstGovernmentWaste(CAGW)Release,May2,2007***ABNAMROFebruary2008Science&TechnologyChallengesScientificChallengesforGenericBiologicsCharacterizationSafetyAssessmentTherapeuticEquivalenceManufacturingControlsGenericBiologicsGenericbiologics,sometimescalledfollow-onbiologics(FOBs),areproteinproductsthatarepharmaceuticallyandtherapeuticallyequivalentGenericbiologicsdonotutilizethereferenceproduct’sproprietaryprocess,specificationsorclinicaldataForestablishedproducts,therapeuticequivalencecanbedemonstratedusingInvitrostudiesand/orPharmacokineticsand/orSurrogatemarkersand/orClinicaloutcomes dependingonthecharacteristicsoftheproteinInterferon2804atomsMonoclonalAntibody21112atomsrDNATechnologyDrugs:Filgrastim(G-CSF)2659atomsBiologics

SizeDoesMatter...Azithromycin124atomsChemicalDrug:MisinformationCampaignAboutGenericBiologicsMyth:Rawmaterialsofbiologicoriginarehardtosourceandonlybrandbiotechsknowwheretofindthem.Reality:Rawmaterialsareavailabletodayformanygenericbiologicsincludinginsulin,G-CSF,erythropoietin,interferons,etc.MisinformationCampaignAboutGenericBiologicsMyth:Biologicsaretoocomplicatedtobecharacterized.Reality:Numeroushighlysophisticatedanalyticalmethodshavebeendeveloped,permittingcompletecharacterization.Moreadvanceswillbeachievedeachyear.MisinformationCampaignAboutGenericBiologicsMyth:Genericcompanieslackthemedical,scientific,andtechnicalabilitytoproducesafeandeffectivebiotechproducts.Reality:Genericcompaniescananddomakesafeandeffectivebiologics.ManysafeandeffectivebiologicscurrentlyaremadeincontrolledenvironmentsandmarketedbygenericcompaniesoutsidetheU.S.

GenericBiologics(Biosimilars)intheEUTheabilitytomakegenericbiologicsisfarfromatheoreticalpossibility.In2004EUissuedEMEADraftGuidelinesforfourclassesofgenericbiologics,referredtoasbiosimiliarsintheEU.Since2004,theEUhasapprovedseveralbiosimilarproducts.EUBiosimilarApprovals DRUG EUMARKETAUTHORIZATIONDATESandoz’sOmnitrope®

(somatropin) April12,2006

BioPartners’Valtropin®

(somatropin) April24,2006

Sandoz’sBinocrit®Medice’sAbseamed®HexalBiotech’sEpoetinalfaHexal®

(recombinanthumanerythropoietinalfa) August28,2007StadaArzneimittel’sSilapo® Hospira’sRetacrit® (epoetinzeta) December18,2007Teva’sTevagrastim® Ratiopharm’sRatiograstim®Ratiopharm’sFilgrastimratiopharm®CTArzneimittel’sBiograstim® (humanG-CSF) September15,2008currentthroughSeptember25,2008FDAApprovesSandoz’sOmnitropeTherehasbeensomemovementintheUStoapprovegenericbiologics.FDAapprovedOmnitropeinMay2006.FDAstated,however,thatthisapprovaldoesnotcreateapathwayforallgenericbiologics.Omnitropereferencedabrandproduct(Genotropin)approvedundertheFDCA.MisinformationCampaignAboutGenericBiologicsMyth:“TheProductistheProcess.”Reality:“Oldmodelsandmantrasareinhibitingprogress–theproductisnolongertheprocess.”(StatementofMathiasHukkelhoven,Ph.D.,SeniorV.P.,GlobalHead,DrugRegulatoryAffairs,Novartis,Sept.14-15,2004).MisinformationCampaignAboutGenericBiologicsReality(continued):Biotechproductscanbefullycharacterizedandcomparedanalytically.BiotechFirmsroutinelyjustifytheirownprocesschangesviaFDAapprovedcomparabilityprotocols.Developmentof

GenericBiologicsStrictlyControlledProcess(Validated)ExtensiveAnalyticalComparability(Characterization)ComparableBiologicalActivity(InVitro/InVivo)Non-ClinicalComparability(Safety,Immunogenicity...)Comparablepharmacokinetics(bloodconcentrationprofile)ComparableClinicalEfficacyandSafetyDevelopmentConsiderationsProductComplexityFromDevelopmentToClinicalCharacterizationBiosynthesis,In-ProcessandFinishedProductNomenclatureLackofStrictDefinition,INNIssueHighCostofDevelopmentMarketingRequirementsandCostPost-MarketingSafetySurveillanceIPStrengthRegulatory&IntellectualPropertyIssuesChallengesforGenericBiologicsRegulatoryCongressneedstocreateanabbreviatedapprovalpathwayIntellectualPropertyBrandexclusivityGenericexclusivityResolutionofpatentlitigationpriortogenericlaunchRegulatoryIssuesRegulatoryFrameworkComplicatedByExistenceofTwoLawsForBiologicsFDCAforNDAProductsPHSAforBLAProductsNDAProductsGenericPathwayExits,ButFDAImplementationIsUnclear BLAProductsThreeIssuesNeedToBeResolvedMechanicsofApprovalPathwayNeedToBeDefinedBrand/GenericExclusivityAnEfficientPatentDisputeResolutionMechanismAbbreviatedGenericPathwayUnderPHSAAGenericPathwayShould:GiveFDAAuthorityToDecideApprovalRequirementsForGenericProductsAdoptExclusivityProvisionsNoGreaterThanThoseFoundInHatch-WaxmanPermitPre-LaunchAdjudicationofCertainPatentDisputesAbbreviatedGenericPathwayUnderPHSAFDAshouldbepermittedtodecidewhattests/dataarenecessaryforapprovalasacomparableorinterchangeablegeneric.Congressshouldnotimposeunnecessarybarrierstogenericapprovals,e.g.,mandatoryguidanceorrule-makingrequirements;mandatoryclinicaltrials;requirementthatgenericsseekapprovalforallapprovedbranduses.AbbreviatedGenericPathwayUnderPHSACongressshouldcarefullyconsideranynew,additionalexclusivitiesawardedtobrandbiologics.Considerableincentivesalreadyexistforbrandbiotechcompanies.ExistingIncentivesforBrandBiotechCompaniesAbbreviatedGenericPathwayUnderPHSAIfCongressdecidestogiveadditionalexclusivitiestobrandcompanies,Hatch-Waxmanestablishesthemaximumlengthandnumberofexclusivitiesthatcanbejustified:

-5yearsfortrulynew,innovativeproducts -3yearsforcertainimprovementstoalready-approvedbrandproductsAbbreviatedGenericPathwayUnderPHSAUnliketheincentivesthatalreadyexisttodevelopnewbrandbiologics,noincentivesexisttodevelopgenericbiologics.Genericbiologicslegislationshouldincludeanincentive,justasHatch-Waxmandoesforsmallmoleculedrugs,forthedevelopmentofgenericbiologics.AbbreviatedGenericPathwayUnderPHSAEffectivegenericbiologicslegislationwillincludeamechanismforexpeditiousresolutionofpatentdisputes.Hatch-Waxmanhasshownthatpatentmechanismscanbeabusedtodelaygenericmarketentry.AbbreviatedGenericPathwayUnderPHSAOnlythosepatentdisputesthatwouldcausethegenericcompanytodelaylaunchshouldbelitigatedsimultaneouslywiththeFDAapprovalprocess.Disputesoveranyotherpatentthatthebrandownsshouldwaituntilthegenericcompanyactuallylaunches.AbbreviatedGenericPathwayUnderPHSASuchaprocessensuresthatbrandcompaniescannotuseweakorsuspectpatentstodelaygenericmarketentry.Atthesametime,theprocessprotectsalllegitimatepatentrights–itallowslitigationoverallpatents,butcontrolswhenthatlitigationcanstartsothatgenericmarketingisn’tundulydelayed.NegotiationsAreOngoingMuchMomentumGainedinDebateOptimisticforUltimateResolutionRegulatoryIssues

U.S.ProposedLegislationSummaryGenericBiologicsinUSSignificantMomentuminUSCongressFailedtoPassin2007-08Session;LikelytoBeOnLegislativeAgendain2009StrongConsensusforGenericBiologicsAmongPayers,ConsumerGroupsDebateCentersOnThreeIssuesMechanicsofPathwayHowtoResolveIPIssuesExclusivityIssueStateGovernors

Broad,BipartisanSupportforaWorkablePathwayforGenericBiologics1、Geniusonlymeanshard-workingallone'slife.(Mendeleyer,RussianChemist)

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