FDA药物流行病学真实世界研究2

FDA药物流行病学_真实世界研究-22024/3/25FDA药物流行病学真实世界研究2October20092FDA药物流行病学真实世界研究2SometerminologyaboutsafetyTherapeuticandNon-therapeuticuseofmedicalproductsMedicationerrors(adversedrugevents)andbiologiceffectsattherapeuticdose(adversedrugreactions)SafetysignalOctober20093FDA药物流行病学真实世界研究2SafetyofmedicalproductsPatientsafetyAsaresultofhumanerror/systemfailureDrug/Vaccine/DevicesafetyToxicityoccurredwhentheproductwasused‘appropriately’GrayareaInappropriateuse(notonlyoff-labeluse)October20094FDA药物流行病学真实世界研究2ByDr.RobertNelson,inHartzema,Tilson,ChanOctober20095FDA药物流行病学真实世界研究2Methodsandobjectives Interventional Observational studies(clinical studies trials)Benefit Efficacy (Comparative) PhaseII/III EffectivenessRisk Pragmatictrial Real-lifeuseof Large&Simpletrial medicalproductsOctober20096FDA药物流行病学真实世界研究2ApplicationsofpharmacoepidemiologySafetyassessmentRelativeandabsoluteriskestimatesRiskfactorsforadverseoutcomesUsagepatternsSafetysignaldetectionComparativeeffectivenessDrugutilization(Developmentofmedicalproducts)October20097FDA药物流行病学真实世界研究2ThreeexamplesfortodayandtomorrowStatinsandrhabdomyolysisRiskfactorsforStevensJohnsonSyndromeAprotininincardiacsurgeryandincreasedriskofend-organdamageOctober20098FDA药物流行病学真实世界研究2Why?Pharmacoepidemiology(Therapeutic)riskmanagementOctober20099FDA药物流行病学真实世界研究2JournaloftheNationalCancerInstitute2005;97:872-3“Thereal

problemin

safetyisoften

notinthe

drugbuthow

itisused,”--RaymondWoosley,

MD,PhD,Critical

PathInstitute“Inmanyways,afteradrugisreleased,therealtrialbegins,”--PaulSeligman,MD,MPH,OfficeofPharmacoepidemiologyandStatisticalScience,FDAOctober200910FDA药物流行病学真实世界研究2ABriefreview:fromlaboratorytobedside(T1andT2)Fromlaboratorytoapproval(FDA)Translationalresearch/oc/initiatives/criticalpath//Fromapprovaltobedside/community(AgencyforHealthcareResearchandQualityAHRQ)SometimescalleddiffusionoftechnologyTheroleofepidemiologyinthisprocessOctober200911FDA药物流行病学真实世界研究2R&DintheindustryResearchBasic/benchresearchAnimal,cellular,andmolecularmodelsDevelopment‘Bringamoleculetothemarket’EvaluationfromclinicalandbusinessperspectiveOctober200912FDA药物流行病学真实世界研究2ClinicaldevelopmentTheroleofsurrogatemarkersandsurrogateendpointsSolidepidemiologydataarerequiredtosubstantiatethecorrelationbetweensurrogateendpointsandimportantclinicaloutcomesEnd-pointtrialsandOutcometrialsMayormaynotbegoodenoughforsafetyassessmentOctober200913FDA药物流行病学真实世界研究2ClinicaldevelopmentPhaseIIIbandIVNewdosageandformulation(supplementaryNDA)Newindications(supplementaryNDA)LongtermoutcomesEffectiveness(vs.efficacy)SafetyQuality-of-life/Functionalstatus/Cost-effectivenessoutcomesOctober200914FDA药物流行病学真实世界研究2What’swrongwiththecurrentsystemfromasafetyperspective?Limitedgeneralizabilityofanimal,cellular,andmolecularmodels/cgi/content/abstract/333/17/1099LimitedutilityofsurrogateendpointsForeffectivenessForsafetyInsufficientknowledgeaboutbackgroundratesandriskfactorsforadverseoutcomesOctober200915FDA药物流行病学真实世界研究2What’swrongwiththecurrentsystemfromasafetyperspective?LimitationsofPhaseIIItrialsComparisongroupDurationPatientpopulationPre-marketingvs.Post-marketingClinicaltrialsvs.ObservationalstudiesThechallengeofcombiningstudies(meta-analysis)MisuseofstatisticsOctober200916FDA药物流行病学真实世界研究2TheScienceofSafety“Weareseeingtheemergenceofascienceofsafety.Thissciencecombinesthegrowingunderstandingofdiseaseanditsoriginsatthemolecularlevel(includingunderstandingofadverseeventsresultingfromtreatment)withnewmethodsofsignaldetection,datamining,andanalysis,enablingresearcherstogeneratehypothesesabout,andconfirmtheexistence,andcausalfactors,ofsafetyproblemsinthepopulationsusingtheproducts.”

October200917FDA药物流行病学真实世界研究2/Safety/FDAsSentinelInitiative/ucm089474.htmOctober200918FDA药物流行病学真实世界研究2ScienceofEfficacyandScienceofSafetyDifferentparadigmTwosetsofrelatedmethodology,datasources,interpretationoffindings,andregulatoryimplicationsScienceofefficacyHypothesistestingControlledexperimentsSingleendpoint/outcomeScienceofsafetyRiskidentification/Signaldetection(hypothesisgeneration)PublichealthsurveillanceRiskassessment(hypothesistesting)Experimental(clinicaltrial)andobservational(epidemiology)methodsOctober200919FDA药物流行病学真实世界研究2ScienceofSafetyRiskidentification/signaldetectionHypothesisgenerationRiskassessment/signalconfirmationorrefutationHypothesistestingRiskmitigation/managementOctober200920FDA药物流行病学真实世界研究2DatasourcesforsafetysignalsAnimal/cellularmodelClinicaltrials(pre-andpost-marketing)AdverseeventsLaboratorydata(assurrogatemarkers)Numericalimbalancevs.statisticalsignificanceSpontaneousreports(Pharmacovigilance)October200921FDA药物流行病学真实世界研究2SpontaneousAdverseDrugReactionsReportingSystemsVoluntaryFourelementsAnidentifiablepatientAnadverseeventAsuspecteddrug/vaccine/deviceAnidentifiablereporterSensitivityoverSpecificityOctober200922FDA药物流行病学真实世界研究2SeriousAdverseEvents/medwatch/report/DESK/advevnt.htmDeathLifethreateningHospitalization(initialorprolonged)DisabilityCongenitalanomalyRequiresInterventiontoPreventPermanentImpairmentorDamageOctober200923FDA药物流行病学真实世界研究2StrengthsofthespontaneousreportssystemModeratecostsAcaseorcaseseriescantellacompellingstory(temporalsequence,de-challenge&re-challenge)MinimaldelayWorkswellwithpublichealth-orientedcliniciansOctober200924FDA药物流行病学真实世界研究2LimitationsAnecdotalinformation“Thepluralofanecdoteisnotdata”(Usually)poordataqualityCannotconclusivelyestablishcausalityReportingratesaffectedbymanysecularfactorsHypothesisgeneration,notconfirmatoryOctober200925FDA药物流行病学真实世界研究2Hypotheticalcase#1

SuddendeathYear1988,62year-oldmale,noCVriskfactor,survivedacuteMIFrequentprematureventricularcomplexes(PVCs)afterMIPatientwasgivenencainide,aclassIcanti-arrhythmicagent,tosuppressthePVCs6monthslater,patientdiedsuddenlyBackgroundrate:one-yearmortality~10%October200926FDA药物流行病学真实世界研究2Wouldanyonesuspectthatdeathwasprecipitatedbythedrug?WhatiftherewasnoCASTtrial?LearyWE.WarningIssuedon2HeartDrugsAfterDeathsofPatientsinTest.NewYorkTimes,April26,1989,page1A.CardiacArrhythmiaSuppressionTrial(CAST)Investigators.Preliminaryreport:…NEnglJMed1989;321:406-12.(Aug10issue)October200927FDA药物流行病学真实世界研究2Hypotheticalcase#2

LiverfailureYear1999,53year-oldmale,BMI31,socialdrinker,onglyburide,troglitazone,atenolol,simvastatin,anddiclofenacPatientdevelopedacuteliverfailureanddiedwhilewaitingforlivertransplantationLiverfailuremaybecausedbyadrugbutwhichdrugorcombinationofdrugs?October200928FDA药物流行病学真实世界研究2Whatisthedifferencebetweencase#1andcase#2?SuspicionandreportingofAdverseDrugReactionsSeverityofeventPriorknowledgeAlternativeexplanationsBackgroundrateoftheadverseeventRareNotsorareOctober200929FDA药物流行病学真实世界研究2Rareandnot-so-rareadverseeventsRareRhabdomyolysis,DILI,Stevens-JohnsonSyndrome,agranulocytosis,Churg-StraussSyndrome,…Notsorare(especiallyamongcertainpopulations)MyocardialinfarctionTuberculosisamongRApatientsChronicactivehepatitisBexacerbationSuicideamongadolescents,…October200930FDA药物流行病学真实世界研究2Hypotheticalcase#3

AcutemyocardialinfarctionYear2000,49year-oldmale,smoker,BMI33,mildhypertensionandLDLelevationLeftkneeosteoarthritisGivenrofecoxib25mg/dayfortwoweeks,thenthedoseincreasedto50mg/day9monthslater,hadnon-fatalmyocardialinfarctionBackgroundrateofAMI:severalcasesper1,000person-yearsOctober200931FDA药物流行病学真实世界研究2AninterestingquestionCouldtheexistingsystemidentifyCVsafetysignalsassociatedwithrofecoxibiftherewasnoVIGORtrial?PUBMEDsearchonOct24,2005,publishedcasereportsofrofecoxib: hepatitis,interstitialnephritis,colitis,angioedema,anaphylacticshock,gynecomastia,acuterenalfailure,delirium,Stevens-Johnsonsyndrome,congestiveheartfailure,transientvisualimpairment,aquagenicwrinklingofthepalms,…October200932FDA药物流行病学真实世界研究2Epidemiology,ageneraloutlineMeasuresofDiseaseOccurrenceIncidenceandPrevalenceCumulativeincidenceandincidencerateConceptofdynamicpopulationandpersontimeMeasuresofAssociationRelativeriskRateratioOddsratioOctober200933FDA药物流行病学真实世界研究2Epidemiology,ageneraloutlineDescriptiveEpidemiologyCasereportsCaseseriesFrequencyofeventsStudiesprovidingsomeevidence,butnotdefinitiveCross-sectionalstudiesEcologicalstudiesOctober200934FDA药物流行病学真实世界研究2Epidemiology,ageneraloutlineObservationalstudies,selectedmethodsCohortstudiesCase-controlstudiesCase-crossoverstudiesInterventionalstudiesClinicaltrialsforindividualsubjectsClusteredrandomizedtrialsOctober200935FDA药物流行病学真实世界研究2Epidemiology,ageneraloutlineCombininginformationfrommultiplestudiesMeta-analysisDatapoolingOctober200936FDA药物流行病学真实世界研究2SystematicandrandomerrorsValidityconsiderationinepidemiologyConfoundingBiasInformationbiasSelectionbiasAssessmentofrandomerrorinepidemiology:statisticsOctober200937FDA药物流行病学真实世界研究2Commonlyusedtermsinepidemiology Confounder(s)Exposure OutcomeOctober200938FDA药物流行病学真实世界研究2ExposuresinpharmacoepidemiologyDrugsVaccinesMedicaldevicesProceduresProgramse.g.screeningprogramsCodingsystemsforeachofthemOctober200939FDA药物流行病学真实世界研究2AscertainmentofOutcomesOperationaldefinitionsSensitivityandspecificityObjectivecriteriaE.g.hemorrhagicstrokeBlindedadjudicationifpossibleOctober200940FDA药物流行病学真实世界研究2PerformanceofICD-9codesinthestudyofrhabdomyolysisOctober200941FDA药物流行病学真实世界研究2Andradeetal.Healthplanadministrativedatabasescanefficientlyidentifyseriousmyopathyandrhabdomyolysis.JClinEpi2005;58:171-4October200942FDA药物流行病学真实世界研究2CohortstudiesinpharmacoepidemiologySourcepopulationAscertainmentofexposureComparisongroups/cohortsConfounding?AscertainmentofoutcomesInformationBias?ControlforconfoundingEvaluationofeffectmodificationStrengthsandlimitationsOctober200943FDA药物流行病学真实世界研究2ExposureandOutcomeExposuresofinterest/ComparisongroupsHead-to-headcomparisonDrugvs.DiseasecomparisonMultiplecomparisongroupsOutcomesofinterestClinicallyrelevantOctober200944FDA药物流行病学真实世界研究2ArchInternMed2002;162:936-42.ThreestudygroupsAlendronateusers(n=6,432)Womenwithosteoporoticfracture(n=9,776)Age-gendermatchedunexposed(n=33,176)ComparingalendronateusersandunexposedAdjustedrateratio=1.8,95%confidenceinterval0.8–3.9ComparingalendronateusersandwomenwithfractureAdjustedrateratio=1.1,95%confidenceinterval,0.6

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2.2October200945FDA药物流行病学真实世界研究2DefiningcohortsMatchingIndividually-matchFrequency-matchMatchingincohortstudyvs.matchingincase-controlstudyRestriction/SelectioncriteriaNew-userdesignIncidentusersvs.PrevalentusersOctober200946FDA药物流行病学真实世界研究2BiasandconfoundingConfoundingChanneling,Confounding-by-Indication,andConfounding-by-SeverityHowtomeasureindicationandseverity?Otherknownriskfactorsfortheoutcomeofinterest(age,gender,smoking…)BiasDetectionbiasasaformofinformationbiasOctober200947FDA药物流行病学真实世界研究2Analyticapproaches‘Atrisk’person-timeImmortalperson-timeCumulativeincidence,incidence,andcorrelatedoutcomesCount,person-time,andtime-to-eventControlforconfoundingMultipleregression,propensityscore,instrumentalvariables,andothersAccountforunmeasuredconfoundersNestedcase-controlstudyOctober200948FDA药物流行病学真实世界研究2StratifiedanalysisControlforconfoundingEffectmodificationSpecificsubgroup(s)Drug-druginteraction

October200949FDA药物流行病学真实世界研究2CohortstudiesinpharmacoepidemiologyStrengthsRelativeriskandAbsoluteriskestimatesMultipleoutcomes(safetysurveillanceformultipleoutcomesandrisk-benefitassessment)LimitationsMitigatedbytheavailabilityofsecondaryand‘hybrid’datasourcesOctober200950FDA药物流行病学真实世界研究2Clinicaltrials‘ClinicalRegimen’trialsvs.‘Clinicalpractice’trialsInclusionandExclusioncriteriaTitration,switching,andstoppingFollow-up/monitoringNewDrugApplicationvs.ClinicalpracticePlacebo-controlledvs.head-to-headcomparisonInternalvalidityvs.GeneralizabilityComorbidityandpotentialdrug-druginteractionOctober200951FDA药物流行病学真实世界研究2Explanatoryvs.PragmaticRolandandTorgerson.Understandingcontrolledtrials:Whatarepragmatictrials?

BMJ1998;316:285“Trialsofhealthcareinterventionsareoftendescribedaseitherexplanatoryorpragmatic.Explanatorytrialsgenerallymeasureefficacy—thebenefitatreatmentproducesunderidealconditions,oftenusingcarefullydefinedsubjectsinaresearchclinic.Pragmatictrialsmeasureeffectiveness—thebenefitthetreatmentproducesinroutineclinicalpractice.”October200952FDA药物流行病学真实世界研究2SomelargetrialsALLHATstudy/PROVE-IT/TIMI-22study/cgi/content/abstract/350/15/1495CATIE/press/catie_release.cfm/cgi/content/abstract/353/12/1209October200953FDA药物流行病学真实世界研究2ClinicaltrialsforsafetyLargeandSimpleTrialLargeandDirtytrial(Meinert)AhybridapproachRandomizationIndividuallevelGrouplevel‘Real-life’managementandfollow-upImplicationsforcomparativeeffectivenessresearchOctober200954FDA药物流行病学真实世界研究2Exampleofalargeandsimpletrial/ct2/show/NCT00418171LargeSimpleTrial(LST)OfCardiovascularSafetyOfZiprasidoneAndOlanzapine-(ZODIAC)AnInternational,Multicenter,LargeSimpleTrial(LST)ToCompareTheCardiovascularSafetyOfZiprasidoneAndOlanzapineTheprimaryobjectiveofthestudyistoestimatetherelativeincidenceamongusersofziprasidoneandolanzapineofnon-suicidemortalitywithin12months.18,239enrolledpatientsOctober200955FDA药物流行病学真实世界研究2EligibilitycriteriaforZODIACInclusionCriteria:Patientsnewlytreatedforschizophreniaandthosereceivingcontinuingtreatmentwillbeeligibleifthetreatingpsychiatristisreadytoinitiateanewantipsychoticmedication,andwouldconsiderusingeitherziprasidoneorolanzapineasanappropriatetherapy.Age18andolderMaleandfemalepatientswhomeetallcriterialistedbelowareeligibletobeenrolledinthisstudy:DiagnosedwithschizophreniaWillingtoprovideinformationonatleastonealternatecontactpersonforstudystafftocontactregardingpatient'swhereabouts,shouldthepatientbelost-to-follow-upoverthecourseofthestudyExclusionCriteria:ProgressivefataldiseaseofalifeexpectancywhichprohibitsthemfromparticipatinginaoneyearresearchstudyPreviouslyrandomizedtostudymedicationandenrolledinthisstudyOctober200956FDA药物流行病学真实世界研究2Clinicaltrial,statisticalperspectiveOne(andonlyone)pre-specifiedprimaryendpointTypeIandTypeIIerrors,samplesizeestimationErronwhichside?SubgroupanalysisHypothesisgeneration,notconfirmationSuperioritytrialvs.Non-inferioritytrialImplicationsforthechoiceofcomparisongroupMultiplecomparison(no-no!)October200957FDA药物流行病学真实世界研究2SubgroupanalysisHortonR.Fromstarsignstotrialguidelines.Lancet2000;355:1033-34ISIS-2Collaborationgroup.Randomisedtrialofintravenousstreptokinase,oralaspirin,both,orneitheramong17,187casesofsuspectedmyocardialinfarction.Lancet1988;ii:39-60“TheanalysisshowedthataspirinwasbeneficialinallpatientsexceptthosewiththestarsignsofLibraandGemini.”October200958FDA药物流行病学真实世界研究2DifferencebetweenpharmacoepidemiolgyandothertopicsinepidemiologyFocusExposurevs.OutcomeConfoundersBiasAgreementwithclinicaltrialsRegulatoryimplications

October200959FDA药物流行病学真实世界研究2Whatiftheclinicaltrialsresultsdifferfromtheobservationalfindings?Women’sHealthInitiative,hormonereplacementtherapy,andcardiovascularoutcomes/cgi/content/abstract/288/3/321/cgi/content/abstract/297/13/1465/cgi/content/abstract/356/25/2591October200960FDA药物流行病学真实世界研究2Clinicaltrialsandobservationalstudies“Rethinkingthehierarchyofevidence”–VandenbrouckeObjectivesofstudyIntendedeffectoftherapy(confirmation)Unintendedeffectoftherapy(discovery)October200961FDA药物流行病学真实世界研究2Aspecialmethodinpharmacoepidemiology:Registries./reports/topic.cfm?topic=0&sid=2&rType=11&sType=3Aregistryisbasicallyaprospectivelyidentifiedcohort,definedbyDiseaseExposureOutcomeOctober200962FDA药物流行病学真实世界研究2RegistriesinpharmacoepidemiologyDiseaseregistrye.g.cancer,diabetes,rheumatoidarthritis,multiplesclerosis,myocardialinfarction(NationalRegistryofMyocardialInfarction)…Exposure(medicalproductsandprocedures)CoronaryrevascularizationSpecialpopulationPregnancyregistryAdverseoutcomesAcuteliverfailureOctober200963FDA药物流行病学真实世界研究2Lancet2002;359:1173–77October200964FDA药物流行病学真实世界研究2SomeregistryexamplesOctober200965FDA药物流行病学真实世界研究2Antiepilepticdrugpregnancyregistry/WyszynksiD.F.,NambisanM.,SurveT.,AlsdorfR.M.,SmithC.R.,HolmesL.B.Increasedrateofmajormalformationsinoffspringexposedtovalproateduringpregnancy.Neurology2005;64:961-965.HolmesL.B.,WyszynskiD.F.NorthAmericanAntiepilepticDrugPregnancyRegistry.Epilepsia2004;45(11):1465.HolmesL.B.,WyszynskiD.F.,LiebermanE.S.,TheAED(AntiepilepticDrug)PregnancyRegistry:A6-YearExperience.ArchNeurol.2004;61:673-678.October200966FDA药物流行病学真实世界研究2Registry,surveillance,andsafetyassessmentRegistryofdiseaseInternalcomparisongroupsSeculartrendintermsofclinicalepidemiologyandtreatmentTreatmentregistryLimitedbyavailabilityofexternalcomparisongroupsAdverseoutcomeregistryWell-suitedforcasecontrolstudyOctober200967FDA药物流行病学真实世界研究2CasecontrolstudiesinpharmacoepidemiologyIdentifyingthecasesCompletecaseascertainment?SelectionofcontrolsNestedcase-controlstudies(fromadefinedstudypopulation)Non-nestedcase-controlstudiesHospitalbasedCommunitybasedAscertainmentofexposureAscertainmentofpotentialconfoundersOctober200968FDA药物流行病学真实世界研究2Case-controlstudiesConfoundingConfoundingbyindication/severityBiasSelectionbiasInformationbias(recallbias)October200969FDA药物流行病学真实世界研究2Asthmadeaths/1995/05/10/obituaries/teresa-teng-singer-40-dies-famed-in-asia-for-love-songs.htmlPearce&Hensley.Epidemiologicstudiesofbetaagonistsandasthmadeaths.EpidemiolRev1998;20:173-86October200970FDA药物流行病学真实世界研究2Outcomeregistryandcase-controlstudyNEnglJMed1995;333:1600-7

October200971FDA药物流行病学真实世界研究2NEnglJMed1996;335:609-16October200972FDA药物流行病学真实世界研究2Case-controlstudiesofcongenitalanomalyNEnglJMed2003;349:2556-59October200973FDA药物流行病学真实世界研究2NEnglJMed2000;343:1608-14.October200974FDA药物流行病学真实世界研究2SloneEpidemiologyCenter“Since1976,theSloneEpidemiologyUnitBirthDefectsStudyhasinterviewedmothersoflive-borninfantswithmalformationsin80maternityortertiarycarehospitalsinthegreatermetropolitanareasofBoston,Philadelphia,andToronto,and,between1983and1985,inpartofIowa.Since1988,womenwhohadstillborninfantsandthosewhosefetuseswereabortedbecauseofamalformationhavealsobeenincluded.Studysubjectsareidentifiedthroughthereviewofadmissionsanddischargesatmajorreferralhospitalsandclinicsandthroughregularcontactwithnew-bornnurseriesincommunityhospitals(toidentifyinfantswithmalformationswhosemothersmaynothavebeenreferredtomajorcenters).”October200975FDA药物流行病学真实世界研究2Case-crossoverdesignSimilartoacrossovertrialEvaluationofshortterm/‘triggering’effectMittlemanetal.TriggeringofAcuteMyocardialInfarctionbyHeavyPhysicalExertion--ProtectionagainstTriggeringbyRegularExertion.NEnglJMed1993;329:1677-83Hunteretal.Recentdiureticuseandtheriskofrecurrentgoutattacks:theonlinecase-crossovergoutstudy.JRheumatology2006;33:1341-5October200976FDA药物流行病学真实世界研究2October200977FDA药物流行病学真实世界研究2JRheumatol2006;33:1341–5October200978FDA药物流行病学真实世界研究2Datapoolingandmeta-analysisJAMA2001;286:954-9October200979FDA药物流行病学真实世界研究2Datapoolingandmeta-analysisJAMA2005;294:2581-6.October200980FDA药物流行病学真实世界研究2PostingofclinicaltrialdatainthepublicdomainOctober200981FDA药物流行病学真实世界研究2/files/pdf/3104.pdfRationale:AspartofGSK’songoingpharmacovigilanceprogram,anevaluationoftheassociation(ifany)betweenrosiglitazone(RSG)andcardiovasculareventswasundertakenforeventsofcongestiveheartfailure(CHF)andforeventsrelatedtomyocardialischemia.Twodistinctapproacheshavebeenusedinthisevaluation.OneapproachexaminedeventsofCHFaswellaseventsrelatedtomyocardialischemiautilizingaretrospectivestatisticalanalysisofintegratedclinicaltrials.ThemajorityofpatientsinthisanalysiswererandomizedtoafixeddoseofRSGaddedtobackgroundtherapyvsmaintenanceofthebackgroundtherapyalone.Thesecondapproachexaminedeventsrelatedtomyocardialischemia(hospitalizationsformyocardialinfarctionand/orcoronaryrevascularization)utilizingalarge,well-balancedretrospectiveobservationalstudy.ComparisonsweremadebetweenmatchedcohortsofpatientsinitiatingantidiabetictherapyasoralmonotherapyororaldualtherapyorcombinationswithinsulininwhichpatientsweretreatedinaUSclinicalpracticeenvironment.October200982FDA药物流行病学真实世界研究2Lancet2009;373:2125-35.321peopleintherosiglitazonegroupand323intheactivecontrolgroupexperiencedtheprimaryoutcomeduringamean5.5-yearfollow-up,…HRwas0.84(0.59-1.18)forcardiovasculardeath1.14(0.80-1.63)formyocardialinfarction0.72(0.49-1.06)forstrokeOctober200983FDA药物流行病学真实世界研究2/bbs/topics/NEWS/2007/NEW01597.htmlThroughoutFebruaryandMarch2007,NovartisreportedtoFDAtheresultsofanewanalysisof29short-term(1-3months)randomized,controlledclinicaltrialsofZelnorm.FDAhasconcluded,basedonthesedatathatformostpatientsthebenefitsofthisdrugnolongeroutweightherisks.Theanalysisincludedmorethan11,600patientstreatedwithZelnormandover7000patientstreatedwithplacebo.Thedatashowedthattheriskofseriouscardiovascularadverseevents(e.g.,angina,heartattacks,andstrokes)associatedwithuseofZelnormishigherthanwithplacebotreatment.ThirteenZelnorm-treatedpatients(or0.1%)hadconfirmedcardiovascularischemicevents,andonly1placebo-treatedpatient(or0.01%)withanevent.October200984FDA药物流行病学真实世界研究2DatapoolingconductedbydrugcompaniesOctober200985FDA药物流行病学真实世界研究2Tegaserod

/bbs/topics/NEWS/2007/NEW01597.html"ThisdecisionreflectstheFDA'scommitmenttocontinuouslymonitorapproveddrugsthroughouttheirmarketinglife,andtakeactionwhenwebelievetherisksexceedthebenefits,"saidDr.DouglasThrockmorton,DeputyDirectorfortheCenterforDrugEvaluationandResearch."Here,apotentialriskofveryseriousharmtopatientswhohavethisnon-life-threateningconditionwasrecentlyidentified,makingthisactionnecessary."October200986FDA药物流行病学真实世界研究2Risk-benefitcalculusAlternativesNaturalhistoryofdiseaseCharacterizeandquantifythebenefitEfficacyANDEffectivenessCharacterizeandquantifytherisksUtility/ValueassessmentPopulationlevelvs.individuallevelOctober200987FDA药物流行病学真实世界研究2Anotherdatapoolingexercise:TiotropiumandstrokeOctober200988FDA药物流行病学真实世界研究2/cder/drug/early_comm/tiotropium.htmBoehringerIngelheimreportedtotheFDAthatithasconductedananalysisofthesafetydatafrom29placebocontrolledclinicalstudies(“pooledanalysis”).

In25oftheclinicalstudies,patientsweretreatedwithSpirivaHandiHaler.

Intheother4clinicalstudiespatientsweretreatedwithanotherformulationoftiotropiumapprovedinEurope,SpirivaRespimat.

The29clinicalstudiesincludedapproximately13,500patientswithCOPD.

Basedondatafromthesestudies,thepreliminaryestimatesoftheriskofstrokeare8patientsper1000patientstreatedforoneyearwithSpiriva,and6patientsper1000patientstreatedforoneyearwithplacebo.

ThismeansthattheestimatedexcessriskofanytypeofstrokeduetoSpirivais2patientsforeach1000patientsusingSpirivaoveraoneyearperiod.October200989FDA药物流行病学真实世界研究2/cder/drug/early_comm/tiotropium.htmItisimportanttointerpretthesepreliminaryresultswithcaution.

FDAhasnotconfirmedtheseanalyses.

Pooledanalysescanprovideearlyinformationaboutpotentialsafetyissues.

However,theseanalyseshaveinherentlimitationsanduncertaintythatrequirefurtherinvestigationusingotherdatasources.

ThisearlycommunicationisinkeepingwithFDA’scommitmenttoinformthepublicaboutitsongoingsafetyreviewsofdrugs.

October200990FDA药物流行病学真实世界研究2EarlyCommunicationaboutanOngoingSafetyReviewofTiotropium(marketedasSpirivaHandiHaler)Update10/07/2008:

FDA’sEarlyCommunicationAboutanOngoingSafetyReviewi