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JointMeetingoftheArthritisandDrugSafetyandRiskManagementAdvisoryCommittees,February16-18,2005,太原房产网,LeonardM.Baum,RPh,VicePresident,RegulatoryAffairsBayerHealthCareConsumerCareDivision,Agenda,RegulatoryOverviewNaproxenADAPTTrialSafetyEvaluationClinicalPharmacologyClinicalStudiesPostmarketingSurveillanceObservationalStudiesConclusions,Roche/BayerPresentersandResponders,Presenters:LeonardM.Baum,RPhVicePresident,RegulatoryAffairsBayerHealthCareMartinH.Huber,M.D.VicePresident,GlobalHeadDrugSafetyRiskManagementHoffmannLa-RocheInc.Responders:SusanSacks,Ph.D.GlobalHead,EpidemiologyHoffmannLa-RocheInc.BharatThakrar,Ph.D.SeniorEpidemiologistHoffmannLa-RocheInc.,ErnstWeidmann,M.D.Head,GlobalSafetyBayerHealthCareSteveZlotnick,Pharm.D.Director,MedicalAffairsBayerHealthCare,OutsideExperts,KayBrune,M.D.ProfessorandChairmanDepartmentofExperimentalandClinicalPharmacologyandToxicologyFriedrich-AlexanderUniversityErlangen-NurembergIanM.Gralnek,M.D.,MSHSAssistantProfessorofMedicine,DivisionofDigestiveDiseasesDavidGeffenSchoolofMedicineatUCLA,RegulatoryOverview,NaproxenavailableintheUnitedStatessince1976PrescriptioncurrentlymarketedbymultiplemanufacturersforthetreatmentofRA,OA,ankylosingspondylitis,gout,juvenileRA,dysmenorrhea,tendinitis,bursitis,andpainAleve(OTC)approvedin1994CurrentlymarketedbyBayerHealthCarefortemporaryreliefofminorachesandpains,andforthetemporaryreductionoffeverMultiplegenericversions,Naproxen,Naproxen,anonsteroidalanti-inflammatorydrug(NSAID),belongstothechemicalclasspropionicacidderivativesNaproxenhasanti-inflammatory,analgesicandantipyreticpropertiesNaproxenknowntoinhibitplateletaggregationThemajordifferencesbetweenmembersoftheNSAIDclassarepotencyandpharmacokinetics,ClassesofNSAIDS,SalicylicacidderivativesAspirin,sodiumsalicylate,cholinemagnesiumtrisalicylate,salsalate,diflunisalPara-aminophenolderivativesAcetaminophenIndoleandindeneaceticacidsIndomethacin,sulindacHeteroarylaceticacidsTolmetin,diclofenac,ketorolacPropionicacidsNaproxen,ibuprofen,flurbiprofen,ketoprofen,fenoprofen,oxaprozinAnthranilicacids(fenamates)Mefenamicacid,meclofenamicacidEnolicacidsOxicams(piroxicam,meloxicam)AlkanonesNabumetoneCoxibsCelecoxib,valdecoxib,rofecoxib(withdrawn),Source:GoodmanandGilmansThePharmacologicalBasisofTherapeutics,10thedition,RelevanceofNaproxenData,ThesafetyprofilefornaproxeniswellknownNaproxenisareferencedrugformanyanalgesicclinicaltrialsNaproxenandothernon-selectiveNSAIDs,areimportanttreatmentoptionsforabroadrangeofpatientsandconditions,NaproxenExposureData(RxandOTC),*coursesoftherapy(2tabx10days),TheADAPTTrial,NIHsponsoredstudyBayerprovidednaproxensodiumforinvestigationaluseStudyDesignNaproxensodium220mgbidCelecoxib200mgbidPlaceboPatientPopulation2400patients,age70yearsorolder,forpreventionofAlzheimersdiseaseStudyDurationBeganin2001,plannedfor7years,suspendedafter3years,Sources:NIHNewsDec20,2004;WFeb1,2005,writtenbyWoloshinSetal.,PubliclyReportedEventsLeadingtotheSuspensionofADAPT,DSMBreviewonDec.10,2004didnotrecommendstoppingthestudyTheAPCstudywassuspendedduetoindicationsofanincreaseincardiovascularandcerebrovascularriskofcelecoxibvs.placebo(Dec.17,2004)NIAannouncedADAPTtrialsuspension(Dec.20,2004)Informationreleasedtopublicbystudygroup,werebasedonpreliminaryfindings,notthroughpeer-reviewedjournals,Sources:CelebrexNewsReleaseDec17,2004;NIHNewsDec20,2004;WFeb1,2005,writtenbyWoloshinSetal.,Summary,Naproxenisanon-selectiveCOX-1/COX-2inhibitorWidelyusedEstablishedsafetyprofileReferencestandardUnadjudicatedpreliminaryfindingsofADAPTneedstobelookedatincontextofthewidebodyofdataonnaproxen,MartinH.Huber,MD,GlobalHead,DrugSafetyHoffmann-LaRocheInc.,SafetyEvaluation,ClinicalPharmacologyClinicalStudiesPost-MarketingSafetySurveillancePost-MarketingClinicalStudiesObservationalStudies,PharmacologicalDifferencebetweenNaproxenandCOX-2Inhibitors,Naproxenisanon-selectiveCOX-1/COX-2inhibitorNaproxenisknowntoinhibitplateletaggregationandthus,isnotexpectedtohaveanincreasedriskofmyocardialinfarction,ClinicalTrialsandPost-MarketingSurveillance,ClinicaltrialsintheprescriptionandOTCnaproxenNDAsdidnotprovideanyevidenceofanincreasedriskofmyocardialinfarctionorstrokeAreviewofpostmarketingsurveillancedatashowednosignalforMIorcerebrovascularaccidentwithexposurestoprescriptionnaproxenofmorethan110,000,000patientsAreviewOTCpostmarketingsurveillancedatadidnotidentifyasignalforMIorCVAwithanestimateof550,000,000coursesoftherapy,ProportionalReportingRate(PRR),Source:EvansSetal.PharmacoepidemiologyandDrugSafety2001;10:483-86,Post-MarketingClinicalTrials,VIGORRandomizedRApatients50yo(or40yoandreceivinglong-termglucocorticoidtherapy)intoeitherrofecoxib50mgqd(N=4,047)ornaproxen500mgbid(N=4,029)OverallrateofcardiovasculareventsreportedinassociationwithnaproxenisconsistentwiththatexpectedinthispopulationMI:Rofecoxib(0.4%)vs.naproxen(0.1%)Ischemiccerebrovascularevents:0.2%inbotharms,Source:BombardierCetal.NEJM2000;343:1520-8,Post-MarketingClinicalTrials,TARGETRandomizedOApatients50yointoeitherlumiracoxib400mgqd(N=9,156),naproxen500mgbid(N=4,754)oribuprofen800mgtid(N=4,415)NaproxenarmshowedlowerratesforcerebrovasculareventsandMI:Stroke:Lumiracoxib(0.34%)vs.naproxen(0.25%)Ischemicstroke:Lumiracoxib(0.32%)vs.naproxen(0.23%)Hemorrhagicstroke:0.02%inbotharmsAcuteMI:Lumiracoxib(0.38%)vs.naproxen(0.23%),Source:FarkouhMEetal.Lancet2004;364:675-84,Post-MarketingClinicalTrials,TARGET(cont.)RateofMIeventswaslowerfornaproxenthanibuprofen,usinglumiracoxibasthereferencepointforbothstudies,Source:FarkouhMEetal.Lancet2004;364:675-84,*Giveninpercentofpatientswithconfirmedorprobablecardiovascularandcerebrovascularevents,AdditionalPost-MarketingClinicalTrials,AlzheimersTrialRandomizedmildtomoderateADpatients(meanage:74yo)intoeitherrofecoxib25mgqd,naproxensodium220mgbid,orplacebo,Source:AisenPSetal.JAMA2003;289:2819-26,TrialswithCelecoxib,Pooledanalysisof41celecoxibclinicaltrials(Whiteetal)2271naproxenpatients1non-fatalstroke1fatalstroke2non-fatalMIsNaproxen(relativetocelecoxib):4/393(1.01per100patientyears)Celecoxib(relativetoNSAIDs):56/4,969(1.13per100patientyears)Placebo(relativetocelecoxib):3/200(1.5per100patientyears)ThereisnoevidenceofanincreasedriskofMIorstrokecomparedtoeithercelecoxiborplacebo,Source:Whiteetal.AmJCardiology2003;92:411-18,ObservationalStudies,CasecontrolstudiesandretrospectivecohortstudiescanbeperformedinashorterperiodoftimeOpportunitytodetect/evaluaterelativelyinfrequenteventsReflect“realworld”useofthedrugMoreheterogeneouspopulationsConcomitantmedications,concurrentillnessesValueofobservationalstudiesincreaseswhenthesestudiesaredoneinmultiplepopulations,Source:StromB,Pharmacoepidemiology2000;WileyandSons,SummaryofobservationalstudiesofnaproxenandMI,Source:Junietal.Lancet2004;364:2021-29,SensitivityAnalysisofObservationalStudies,Meta-analysisincludedmultiplestudiesfromsamedatabasesPerformedanalysisincludingonlyonestudyfromGPRDandonestudyfromTennesseeMedica