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October2009Hangzhou1Real-lifeStudiesofPharmaceuticalAgents陳建煒,MD,ScD,FISPEHarvardSchoolofPublicHealt

hi3DrugSafetyOctober17-18,2009October2009Hangzhou2October2009Hangzhou3Someterminologyaboutsafety⚫Therapeu

ticandNon-therapeuticuseofmedicalproducts⚫Medicationerrors(adversedrugevents)andbiologiceffectsattherapeuticdose

(adversedrugreactions)⚫SafetysignalOctober2009Hangzhou4Safetyofmedicalproducts⚫Patientsafety⚫Asaresultofhumanerror/systemfailure⚫Drug/Vacci

ne/Devicesafety⚫Toxicityoccurredwhentheproductwasused‘appropriately’⚫Grayarea⚫Inappropriateuse(notonlyoff-labeluse)October2009Hangzhou5ByDr.RobertN

elson,inHartzema,Tilson,ChanOctober2009Hangzhou6MethodsandobjectivesInterventionalObservationalstudies(clinicalstudiestrials)BenefitEffica

cy(Comparative)PhaseII/IIIEffectivenessRiskPragmatictrialReal-lifeuseofLarge&SimpletrialmedicalproductsOctober2009Hangzhou7Applicationsofpharmaco

epidemiology⚫Safetyassessment⚫Relativeandabsoluteriskestimates⚫Riskfactorsforadverseoutcomes⚫Usagepatterns⚫Safetysignaldetection⚫Comparativeeffecti

veness⚫Drugutilization⚫(Developmentofmedicalproducts)October2009Hangzhou8Threeexamplesfortodayandtomorrow⚫Statinsandr

habdomyolysis⚫RiskfactorsforStevensJohnsonSyndrome⚫Aprotininincardiacsurgeryandincreasedriskofend-organdamageOctober2009Ha

ngzhou9⚫Why?⚫Pharmacoepidemiology⚫(Therapeutic)riskmanagementOctober2009Hangzhou10JournaloftheNationalCancerInstitute2005;

97:872-3⚫“Therealprobleminsafetyisoftennotinthedrugbuthowitisused,”--RaymondWoosley,MD,PhD,CriticalPathInstitute⚫“Inman

yways,afteradrugisreleased,therealtrialbegins,”--PaulSeligman,MD,MPH,OfficeofPharmacoepidemiologyandStatisticalScie

nce,FDAOctober2009Hangzhou11ABriefreview:fromlaboratorytobedside(T1andT2)⚫Fromlaboratorytoapproval(FDA)⚫Translationalresearch⚫http://www.fda.gov/oc

/initiatives/criticalpath/⚫http://www.c-path.org/⚫Fromapprovaltobedside/community(AgencyforHealthcareResearchandQualityA

HRQ)⚫Sometimescalleddiffusionoftechnology⚫TheroleofepidemiologyinthisprocessOctober2009Hangzhou12R&Dintheindustry⚫Research⚫Basic/benchre

search⚫Animal,cellular,andmolecularmodels⚫Development⚫‘Bringamoleculetothemarket’⚫EvaluationfromclinicalandbusinessperspectiveOctober2009Hangzhou1

3Clinicaldevelopment⚫Theroleofsurrogatemarkersandsurrogateendpoints⚫Solidepidemiologydataarerequiredtosubstantiatethecorr

elationbetweensurrogateendpointsandimportantclinicaloutcomes⚫End-pointtrialsandOutcometrials⚫Mayormaynotbegoodenoughforsafetyas

sessmentOctober2009Hangzhou14Clinicaldevelopment⚫PhaseIIIbandIV⚫Newdosageandformulation(supplementaryNDA)⚫Newindications(supplementaryNDA)⚫Lon

gtermoutcomes⚫Effectiveness(vs.efficacy)⚫Safety⚫Quality-of-life/Functionalstatus/Cost-effectivenessoutcomesOctober2009Hangzhou15What’swrong

withthecurrentsystemfromasafetyperspective?⚫Limitedgeneralizabilityofanimal,cellular,andmolecularmodels⚫http://content.ne

jm.org/cgi/content/abstract/333/17/1099⚫Limitedutilityofsurrogateendpoints⚫Foreffectiveness⚫Forsafety

⚫InsufficientknowledgeaboutbackgroundratesandriskfactorsforadverseoutcomesOctober2009Hangzhou16What’swrongwiththecurrentsystemfromasaf

etyperspective?⚫LimitationsofPhaseIIItrials⚫Comparisongroup⚫Duration⚫Patientpopulation⚫Pre-marketingvs.Post-marketing⚫Clinicaltrialsvs.Observatio

nalstudies⚫Thechallengeofcombiningstudies(meta-analysis)⚫MisuseofstatisticsOctober2009Hangzhou17TheScienceofSafety“Weareseeingtheemergenceofasc

ienceofsafety.Thissciencecombinesthegrowingunderstandingofdiseaseanditsoriginsatthemolecularlevel(includingunderstandingofadverseeventsresul

tingfromtreatment)withnewmethodsofsignaldetection,datamining,andanalysis,enablingresearcherstogeneratehypo

thesesabout,andconfirmtheexistence,andcausalfactors,ofsafetyproblemsinthepopulationsusingtheproducts.”October2009Hangzhou18htt

p://www.fda.gov/Safety/FDAsSentinelInitiative/ucm089474.htmOctober2009Hangzhou19ScienceofEfficacyandScience

ofSafety⚫Differentparadigm⚫Twosetsofrelatedmethodology,datasources,interpretationoffindings,andregulatory

implications⚫Scienceofefficacy⚫Hypothesistesting⚫Controlledexperiments⚫Singleendpoint/outcome⚫Scienceofsafety⚫Riskidentification/Sign

aldetection(hypothesisgeneration)⚫Publichealthsurveillance⚫Riskassessment(hypothesistesting)⚫Experimental(clinicaltrial)

andobservational(epidemiology)methodsOctober2009Hangzhou20ScienceofSafety⚫Riskidentification/signaldetection⚫Hy

pothesisgeneration⚫Riskassessment/signalconfirmationorrefutation⚫Hypothesistesting⚫Riskmitigation/managementOctober2009

Hangzhou21Datasourcesforsafetysignals⚫Animal/cellularmodel⚫Clinicaltrials(pre-andpost-marketing)⚫Adverseevents⚫Labora

torydata(assurrogatemarkers)⚫Numericalimbalancevs.statisticalsignificance⚫Spontaneousreports(Pharmacovigilance)October2009Hangzhou22Sp

ontaneousAdverseDrugReactionsReportingSystems⚫Voluntary⚫Fourelements⚫Anidentifiablepatient⚫Anadverseevent⚫Asuspecteddrug/vaccine/dev

ice⚫Anidentifiablereporter⚫SensitivityoverSpecificityOctober2009Hangzhou23SeriousAdverseEvents⚫http://www.fda.gov/medwatch/report/DESK/advevnt.

htm⚫Death⚫Lifethreatening⚫Hospitalization(initialorprolonged)⚫Disability⚫Congenitalanomaly⚫RequiresInterve

ntiontoPreventPermanentImpairmentorDamageOctober2009Hangzhou24Strengthsofthespontaneousreportssystem⚫Moderatecosts⚫Acaseorcaseseriescantellacompell

ingstory(temporalsequence,de-challenge&re-challenge)⚫Minimaldelay⚫Workswellwithpublichealth-orientedcliniciansOctober2009Hangzhou25Lim

itations⚫Anecdotalinformation⚫“Thepluralofanecdoteisnotdata”⚫(Usually)poordataquality⚫Cannotconclusivelyestablishcausality⚫Reportin

gratesaffectedbymanysecularfactors⚫Hypothesisgeneration,notconfirmatoryOctober2009Hangzhou26Hypotheticalcase#1Suddendeath⚫Year1988,62year-oldma

le,noCVriskfactor,survivedacuteMI⚫Frequentprematureventricularcomplexes(PVCs)afterMI⚫Patientwasgivenencainide,aclas

sIcanti-arrhythmicagent,tosuppressthePVCs⚫6monthslater,patientdiedsuddenly⚫Backgroundrate:one-yearmortality~10%October

2009Hangzhou27Wouldanyonesuspectthatdeathwasprecipitatedbythedrug?⚫WhatiftherewasnoCASTtrial?⚫LearyWE.WarningIssuedon2HeartDrugsAfterDeat

hsofPatientsinTest.NewYorkTimes,April26,1989,page1A.⚫CardiacArrhythmiaSuppressionTrial(CAST)Investigators.Preliminaryreport

:…NEnglJMed1989;321:406-12.(Aug10issue)October2009Hangzhou28Hypotheticalcase#2Liverfailure⚫Year1999,53year-oldmal

e,BMI31,socialdrinker,onglyburide,troglitazone,atenolol,simvastatin,anddiclofenac⚫Patientdevelopedacuteliverfailure

anddiedwhilewaitingforlivertransplantation⚫Liverfailuremaybecausedbyadrug⚫butwhichdrugorcombinationofdrugs?October2009Hangzhou29Whatisthediffere

ncebetweencase#1andcase#2?⚫SuspicionandreportingofAdverseDrugReactions⚫Severityofevent⚫Priorknowledge⚫Alternati

veexplanations⚫Backgroundrateoftheadverseevent⚫Rare⚫NotsorareOctober2009Hangzhou30Rareandnot-so-rareadverseevents⚫Rar

e⚫Rhabdomyolysis,DILI,Stevens-JohnsonSyndrome,agranulocytosis,Churg-StraussSyndrome,…⚫Notsorare(espe

ciallyamongcertainpopulations)⚫Myocardialinfarction⚫TuberculosisamongRApatients⚫Chronicactivehepatiti

sBexacerbation⚫Suicideamongadolescents⚫,…October2009Hangzhou31Hypotheticalcase#3Acutemyocardialinfar

ction⚫Year2000,49year-oldmale,smoker,BMI33,mildhypertensionandLDLelevation⚫Leftkneeosteoarthritis⚫Givenrof

ecoxib25mg/dayfortwoweeks,thenthedoseincreasedto50mg/day⚫9monthslater,hadnon-fatalmyocardialinfarction⚫BackgroundrateofAMI:severalcasesper1,000p

erson-yearsOctober2009Hangzhou32Aninterestingquestion⚫CouldtheexistingsystemidentifyCVsafetysignalsassociatedwithrofec

oxibiftherewasnoVIGORtrial?⚫PUBMEDsearchonOct24,2005,publishedcasereportsofrofecoxib:hepatitis,interstitialnephritis,colitis,angioedema,anaphylact

icshock,gynecomastia,acuterenalfailure,delirium,Stevens-Johnsonsyndrome,congestiveheartfailure,transientvisualimpairment,aqua

genicwrinklingofthepalms,…October2009Hangzhou33Epidemiology,ageneraloutline⚫MeasuresofDiseaseOccurrence⚫IncidenceandPrevalence⚫Cumulativeinci

denceandincidencerate⚫Conceptofdynamicpopulationandpersontime⚫MeasuresofAssociation⚫Relativerisk⚫Rateratio⚫OddsratioOc

tober2009Hangzhou34Epidemiology,ageneraloutline⚫DescriptiveEpidemiology⚫Casereports⚫Caseseries⚫Frequencyo

fevents⚫Studiesprovidingsomeevidence,butnotdefinitive⚫Cross-sectionalstudies⚫EcologicalstudiesOctober20

09Hangzhou35Epidemiology,ageneraloutline⚫Observationalstudies,selectedmethods⚫Cohortstudies⚫Case-controlstudies⚫Case-crossoverst

udies⚫Interventionalstudies⚫Clinicaltrialsforindividualsubjects⚫ClusteredrandomizedtrialsOctober2009Hangzhou36Epidemiology,a

generaloutline⚫Combininginformationfrommultiplestudies⚫Meta-analysis⚫DatapoolingOctober2009Hangzhou37Systematicandrandomer

rors⚫Validityconsiderationinepidemiology⚫Confounding⚫Bias⚫Informationbias⚫Selectionbias⚫Assessmentofrandomerrorinepidemiology:statisti

csOctober2009Hangzhou38CommonlyusedtermsinepidemiologyConfounder(s)ExposureOutcomeOctober2009Hangzhou39Exposuresi

npharmacoepidemiology⚫Drugs⚫Vaccines⚫Medicaldevices⚫Procedures⚫Programs⚫e.g.screeningprograms⚫Codingsystemsforeachofthem

October2009Hangzhou40AscertainmentofOutcomes⚫Operationaldefinitions⚫Sensitivityandspecificity⚫Objectivecriteria⚫E.g.hemo

rrhagicstroke⚫BlindedadjudicationifpossibleOctober2009Hangzhou41PerformanceofICD-9codesinthestudyofrhabdomyolysisOctober

2009Hangzhou42Andradeetal.Healthplanadministrativedatabasescanefficientlyidentifyseriousmyopathyandrhabdomyolysis.JClinEpi2005;58:171-4

October2009Hangzhou43Cohortstudiesinpharmacoepidemiology⚫Sourcepopulation⚫Ascertainmentofexposure⚫Comparison

groups/cohorts⚫Confounding?⚫Ascertainmentofoutcomes⚫InformationBias?⚫Controlforconfounding⚫Evaluationofeffec

tmodification⚫StrengthsandlimitationsOctober2009Hangzhou44ExposureandOutcome⚫Exposuresofinterest/Comparisongroups⚫Head-to-headco

mparison⚫Drugvs.Diseasecomparison⚫Multiplecomparisongroups⚫Outcomesofinterest⚫ClinicallyrelevantOctober2

009Hangzhou45ArchInternMed2002;162:936-42.⚫Threestudygroups⚫Alendronateusers(n=6,432)⚫Womenwithosteo

poroticfracture(n=9,776)⚫Age-gendermatchedunexposed(n=33,176)⚫Comparingalendronateusersandunexposed⚫Adjustedrateratio=1.8,95%confidenceinterval0.8–3

.9⚫Comparingalendronateusersandwomenwithfracture⚫Adjustedrateratio=1.1,95%confidenceinterval,0.6-2.2October2009Hangzhou46Definingcohorts⚫Matching⚫Ind

ividually-match⚫Frequency-match⚫Matchingincohortstudyvs.matchingincase-controlstudy⚫Restriction/Selectioncriteria⚫New-userd

esign⚫Incidentusersvs.PrevalentusersOctober2009Hangzhou47Biasandconfounding⚫Confounding⚫Channeling,Confounding

-by-Indication,andConfounding-by-Severity⚫Howtomeasureindicationandseverity?⚫Otherknownriskfactorsfortheoutcomeofinterest(age,gender,smoking…)⚫Bias

⚫DetectionbiasasaformofinformationbiasOctober2009Hangzhou48Analyticapproaches⚫‘Atrisk’person-time⚫Immortalperson-time⚫Cumulativeincidence,incid

ence,andcorrelatedoutcomes⚫Count,person-time,andtime-to-event⚫Controlforconfounding⚫Multipleregression,propensityscore,instrumenta

lvariables,andothers⚫Accountforunmeasuredconfounders⚫Nestedcase-controlstudyOctober2009Hangzhou49Stratifiedanalysis⚫Controlforcon

founding⚫Effectmodification⚫Specificsubgroup(s)⚫Drug-druginteractionOctober2009Hangzhou50Cohortstudiesinpharmac

oepidemiology⚫Strengths⚫RelativeriskandAbsoluteriskestimates⚫Multipleoutcomes(safetysurveillanceform

ultipleoutcomesandrisk-benefitassessment)⚫Limitations⚫Mitigatedbytheavailabilityofsecondaryand‘hybrid’datasourcesOctober2009Hangzhou51

Clinicaltrials⚫‘ClinicalRegimen’trialsvs.‘Clinicalpractice’trials⚫InclusionandExclusioncriteria⚫Titration,switching,andst

opping⚫Follow-up/monitoring⚫NewDrugApplicationvs.Clinicalpractice⚫Placebo-controlledvs.head-to-headcomparison⚫Internalvalidityvs

.Generalizability⚫Comorbidityandpotentialdrug-druginteractionOctober2009Hangzhou52Explanatoryvs.PragmaticRolandandTorgerson.U

nderstandingcontrolledtrials:Whatarepragmatictrials?BMJ1998;316:285“Trialsofhealthcareinterventionsareoftendes

cribedaseitherexplanatoryorpragmatic.Explanatorytrialsgenerallymeasureefficacy—thebenefitatreatmentproducesunderidealconditi

ons,oftenusingcarefullydefinedsubjectsinaresearchclinic.Pragmatictrialsmeasureeffectiveness—thebenefitthetreatmen

tproducesinroutineclinicalpractice.”October2009Hangzhou53Somelargetrials⚫ALLHATstudy⚫http://allhat.ut

h.tmc.edu/⚫PROVE-IT/TIMI-22study⚫http://content.nejm.org/cgi/content/abstract/350/15/1495⚫CATIE⚫http://www.nimh.nih.gov/press/catie_release.cf

m⚫http://content.nejm.org/cgi/content/abstract/353/12/1209October2009Hangzhou54Clinicaltrialsforsafety⚫LargeandSimpleTrial⚫LargeandDirtytrial(Mein

ert)⚫Ahybridapproach⚫Randomization⚫Individuallevel⚫Grouplevel⚫‘Real-life’managementandfollow-up⚫Implicationsforcomparativeeffectivenessresearch

October2009Hangzhou55Exampleofalargeandsimpletrial⚫http://clinicaltrials.gov/ct2/show/NCT00418171⚫LargeSimpleTrial(LST)OfCardiovascula

rSafetyOfZiprasidoneAndOlanzapine-(ZODIAC)⚫AnInternational,Multicenter,LargeSimpleTrial(LST)ToCompareTheCardiovascularSafetyOfZiprasidone

AndOlanzapine⚫Theprimaryobjectiveofthestudyistoestimatetherelativeincidenceamongusersofziprasidoneandolanzapin

eofnon-suicidemortalitywithin12months.⚫18,239enrolledpatientsOctober2009Hangzhou56EligibilitycriteriaforZODIAC⚫Inclu

sionCriteria:⚫Patientsnewlytreatedforschizophreniaandthosereceivingcontinuingtreatmentwillbeeligibleift

hetreatingpsychiatristisreadytoinitiateanewantipsychoticmedication,andwouldconsiderusingeitherziprasidoneorolanzapineas

anappropriatetherapy.⚫Age18andolder⚫Maleandfemalepatientswhomeetallcriterialistedbelowareeligibletobeenrolledinthisstudy

:⚫Diagnosedwithschizophrenia⚫Willingtoprovideinformationonatleastonealternatecontactpersonforstudystafftocontactregardingpati

ent'swhereabouts,shouldthepatientbelost-to-follow-upoverthecourseofthestudy⚫ExclusionCriteria:⚫Progressivefata

ldiseaseofalifeexpectancywhichprohibitsthemfromparticipatinginaoneyearresearchstudy⚫Previouslyrandomizedtostudymedicationandenrolle

dinthisstudyOctober2009Hangzhou57Clinicaltrial,statisticalperspective⚫One(andonlyone)pre-specifiedprimaryendpoint⚫TypeIandTypeIIerrors,s

amplesizeestimation⚫Erronwhichside?⚫Subgroupanalysis⚫Hypothesisgeneration,notconfirmation⚫Superioritytrialvs.Non-inferioritytrial⚫Implica

tionsforthechoiceofcomparisongroup⚫Multiplecomparison(no-no!)October2009Hangzhou58Subgroupanalysis⚫HortonR.Fromstarsign

stotrialguidelines.Lancet2000;355:1033-34⚫ISIS-2Collaborationgroup.Randomisedtrialofintravenousstreptokinase,oralaspirin,both,orneitheramon

g17,187casesofsuspectedmyocardialinfarction.Lancet1988;ii:39-60⚫“Theanalysisshowedthataspirinwasbenefic

ialinallpatientsexceptthosewiththestarsignsofLibraandGemini.”October2009Hangzhou59Differencebetweenpharmacoepidemi

olgyandothertopicsinepidemiology⚫Focus⚫Exposurevs.Outcome⚫Confounders⚫Bias⚫Agreementwithclinicaltrials⚫Regulatoryimp

licationsOctober2009Hangzhou60Whatiftheclinicaltrialsresultsdifferfromtheobservationalfindings?⚫Women’sHealthInitia

tive,hormonereplacementtherapy,andcardiovascularoutcomes⚫http://jama.ama-assn.org/cgi/content/abstra

ct/288/3/321⚫http://jama.ama-assn.org/cgi/content/abstract/297/13/1465⚫http://content.nejm.org/cgi/content/abstract/356/25/2591

October2009Hangzhou61Clinicaltrialsandobservationalstudies⚫“Rethinkingthehierarchyofevidence”–Vandenbroucke⚫Objectivesofstudy⚫I

ntendedeffectoftherapy(confirmation)⚫Unintendedeffectoftherapy(discovery)October2009Hangzhou62Aspecialmethodinpha

rmacoepidemiology:Registrieshttp://effectivehealthcare.ahrq.gov./reports/topic.cfm?topic=0&sid=2&rTyp

e=11&sType=3Aregistryisbasicallyaprospectivelyidentifiedcohort,definedby⚫Disease⚫Exposure⚫OutcomeOctober2009Hangzhou63Registriesinp

harmacoepidemiology⚫Diseaseregistry⚫e.g.cancer,diabetes,rheumatoidarthritis,multiplesclerosis,myocardialinfarction(Natio

nalRegistryofMyocardialInfarction)…⚫Exposure(medicalproductsandprocedures)⚫Coronaryrevascularization⚫Specialpopulation⚫Pregnancyregistry⚫Adve

rseoutcomes⚫AcuteliverfailureOctober2009Hangzhou64Lancet2002;359:1173–77October2009Hangzhou65SomeregistryexamplesOctober2009Hangzhou66Antiepilepti

cdrugpregnancyregistry⚫http://www.aedpregnancyregistry.org/⚫WyszynksiD.F.,NambisanM.,SurveT.,AlsdorfR.M.,SmithC.R.,HolmesL.B.Increasedrat

eofmajormalformationsinoffspringexposedtovalproateduringpregnancy.Neurology2005;64:961-965.⚫HolmesL.B.,Wys

zynskiD.F.NorthAmericanAntiepilepticDrugPregnancyRegistry.Epilepsia2004;45(11):1465.⚫HolmesL.B.,WyszynskiD.F.,

LiebermanE.S.,TheAED(AntiepilepticDrug)PregnancyRegistry:A6-YearExperience.ArchNeurol.2004;61:673-678.Octobe

r2009Hangzhou67Registry,surveillance,andsafetyassessment⚫Registryofdisease⚫Internalcomparisongroups⚫Seculartre

ndintermsofclinicalepidemiologyandtreatment⚫Treatmentregistry⚫Limitedbyavailabilityofexternalcomparisongroups⚫Adverseoutcome

registry⚫Well-suitedforcasecontrolstudyOctober2009Hangzhou68Casecontrolstudiesinpharmacoepidemiology⚫Identif

yingthecases⚫Completecaseascertainment?⚫Selectionofcontrols⚫Nestedcase-controlstudies(fromadefinedstudypopulation)⚫Non-nestedcase-controlst

udies⚫Hospitalbased⚫Communitybased⚫Ascertainmentofexposure⚫AscertainmentofpotentialconfoundersOctober20

09Hangzhou69Case-controlstudies⚫Confounding⚫Confoundingbyindication/severity⚫Bias⚫Selectionbias⚫Informationbias(recallbias)October2009Hangzhou70Ast

hmadeaths⚫http://www.nytimes.com/1995/05/10/obituaries/teresa-teng-singer-40-dies-famed-in-asia-for-love-songs.html⚫P

earce&Hensley.Epidemiologicstudiesofbetaagonistsandasthmadeaths.EpidemiolRev1998;20:173-86October2009Hang

zhou71Outcomeregistryandcase-controlstudyNEnglJMed1995;333:1600-7October2009Hangzhou72NEnglJMed1996;335:609-16October2009Hangzhou73Case-controls

tudiesofcongenitalanomaly⚫NEnglJMed2003;349:2556-59October2009Hangzhou74NEnglJMed2000;343:1608-14.October20

09Hangzhou75SloneEpidemiologyCenter“Since1976,theSloneEpidemiologyUnitBirthDefectsStudyhasinterviewedmothersoflive-borninfantswithmalf

ormationsin80maternityortertiarycarehospitalsinthegreatermetropolitanareasofBoston,Philadelphia,andToronto,and,between1983and1985,inpartofIowa

.Since1988,womenwhohadstillborninfantsandthosewhosefetuseswereabortedbecauseofamalformationhavealsobeenincluded.Studysubje

ctsareidentifiedthroughthereviewofadmissionsanddischargesatmajorreferralhospitalsandclinicsandthroughregularc

ontactwithnew-bornnurseriesincommunityhospitals(toidentifyinfantswithmalformationswhosemothersmaynothavebeenreferredtomajorcenters).”Octobe

r2009Hangzhou76Case-crossoverdesign⚫Similartoacrossovertrial⚫Evaluationofshortterm/‘triggering’effect⚫Mittlemaneta

l.TriggeringofAcuteMyocardialInfarctionbyHeavyPhysicalExertion--ProtectionagainstTriggeringbyRegularExertion.NE

nglJMed1993;329:1677-83⚫Hunteretal.Recentdiureticuseandtheriskofrecurrentgoutattacks:theonlinecase-crossovergoutstudy.JRheu

matology2006;33:1341-5October2009Hangzhou77October2009Hangzhou78JRheumatol2006;33:1341–5October2009Hangzhou79Datapoolingandmeta-an

alysisJAMA2001;286:954-9October2009Hangzhou80Datapoolingandmeta-analysis⚫JAMA2005;294:2581-6.October2009Hangzhou81Post

ingofclinicaltrialdatainthepublicdomainOctober2009Hangzhou82www.gsk-clinicalstudyregister.com/files/p

df/3104.pdf⚫Rationale:AspartofGSK’songoingpharmacovigilanceprogram,anevaluationoftheassociation(ifany)betweenrosiglitazone(RSG)andcardiovas

culareventswasundertakenforeventsofcongestiveheartfailure(CHF)andforeventsrelatedtomyocardialischemia.Twodistinctapproacheshavebe

enusedinthisevaluation.⚫OneapproachexaminedeventsofCHFaswellaseventsrelatedtomyocardialischemiautilizingaretrospectivestatistical

analysisofintegratedclinicaltrials.ThemajorityofpatientsinthisanalysiswererandomizedtoafixeddoseofRSGadd

edtobackgroundtherapyvsmaintenanceofthebackgroundtherapyalone.⚫Thesecondapproachexaminedeventsrelatedtomyocardialischemia(hospitalizationsformyocard

ialinfarctionand/orcoronaryrevascularization)utilizingalarge,well-balancedretrospectiveobservationalstudy.Comparisonsweremad

ebetweenmatchedcohortsofpatientsinitiatingantidiabetictherapyasoralmonotherapyororaldualtherapyorcombinationswithinsulinin

whichpatientsweretreatedinaUSclinicalpracticeenvironment.October2009Hangzhou83Lancet2009;373:2125-35.⚫321peopleintherosiglitaz

onegroupand323intheactivecontrolgroupexperiencedtheprimaryoutcomeduringamean5.5-yearfollow-up,…⚫HRwas0.84(0.59-1

.18)forcardiovasculardeath⚫1.14(0.80-1.63)formyocardialinfarction⚫0.72(0.49-1.06)forstrokeOctober2009Hangzhou8

4http://www.fda.gov/bbs/topics/NEWS/2007/NEW01597.htmlThroughoutFebruaryandMarch2007,NovartisreportedtoFDAtheresultsofanewanalysisof29short-te

rm(1-3months)randomized,controlledclinicaltrialsofZelnorm.FDAhasconcluded,basedonthesedatathatformostpatientsthebenefitsofthisdrugnolongeroutwei

ghtherisks.Theanalysisincludedmorethan11,600patientstreatedwithZelnormandover7000patientstreatedwithplacebo.Thedatashowedthattheriskofseriou

scardiovascularadverseevents(e.g.,angina,heartattacks,andstrokes)associatedwithuseofZelnormishigherthanwithplacebotreatment.ThirteenZelnorm-trea

tedpatients(or0.1%)hadconfirmedcardiovascularischemicevents,andonly1placebo-treatedpatient(or0.01%)withanevent.October2

009Hangzhou85DatapoolingconductedbydrugcompaniesOctober2009Hangzhou86Tegaserodwww.fda.gov/bbs/topics/NEWS/2007/NEW01597.html⚫"

ThisdecisionreflectstheFDA'scommitmenttocontinuouslymonitorapproveddrugsthroughouttheirmarketinglife,

andtakeactionwhenwebelievetherisksexceedthebenefits,"saidDr.DouglasThrockmorton,DeputyDirectorfortheCenterforDrugEvaluationandResea

rch."Here,apotentialriskofveryseriousharmtopatientswhohavethisnon-life-threateningconditionwasrecentl

yidentified,makingthisactionnecessary."October2009Hangzhou87Risk-benefitcalculus⚫Alternatives⚫Naturalhistor

yofdisease⚫Characterizeandquantifythebenefit⚫EfficacyANDEffectiveness⚫Characterizeandquantifytherisks⚫Utility/Valueassessment⚫Populationlevelvs.indi

viduallevelOctober2009Hangzhou88Anotherdatapoolingexercise:TiotropiumandstrokeOctober2009Hangzhou89http://www.fda.gov/cder/drug/early_comm/tiotropiu

m.htmBoehringerIngelheimreportedtotheFDAthatithasconductedananalysisofthesafetydatafrom29placebocontrolledclinicalstudies(“pool

edanalysis”).In25oftheclinicalstudies,patientsweretreatedwithSpirivaHandiHaler.Intheother4clinicalstudiespatientsweret

reatedwithanotherformulationoftiotropiumapprovedinEurope,SpirivaRespimat.The29clinicalstudiesincludedapproximately13,500patientswith

COPD.Basedondatafromthesestudies,thepreliminaryestimatesoftheriskofstrokeare8patientsper1000patientstreatedfo

roneyearwithSpiriva,and6patientsper1000patientstreatedforoneyearwithplacebo.Thismeansthattheestimatedexcessr

iskofanytypeofstrokeduetoSpirivais2patientsforeach1000patientsusingSpirivaoveraoneyearperiod.October2009Hangzhou90http://www.fda.gov/cder/drug/early

_comm/tiotropium.htmItisimportanttointerpretthesepreliminaryresultswithcaution.FDAhasnotconfirmedtheseanalyses.Pooledanalysescanprov

ideearlyinformationaboutpotentialsafetyissues.However,theseanalyseshaveinherentlimitationsanduncertaintythatrequirefurtherinvestiga

tionusingotherdatasources.ThisearlycommunicationisinkeepingwithFDA’scommitmenttoinformthepublicaboutitsongoingsafetyreviews

ofdrugs.October2009Hangzhou91EarlyCommunicationaboutanOngoingSafetyReviewofTiotropium(marketedasSpirivaHandiHaler)⚫Upda

te10/07/2008:FDA’sEarlyCommunicationAboutanOngoingSafetyReviewissuedonMarch18,2008statedthatBoehringerI

ngelheim,themakerofSpirivaHandiHaler(tiotropiumbromide),hadconductedapooledanalysisof29trialsthatsuggestedasmallexcessriskofstr

oke(2casesper1000)withtiotropiumbromideoverplacebo.FDAhasnowreceivedpreliminarydatafromUPLIFT(UnderstandingthePotentialLong-TermImpactsonFu

nctionwithTiotropium),alarge,4-year,placebocontrolledclinicaltrialwithSpirivaHandiHalerinapproximately6000patientswithchronicobstructivepulmonarydis

ease(COPD).ThepreliminaryresultsofUPLIFTreportedbyBoehringerIngelheimtotheFDAshowedthattherewasnoincreasedriskofstrokewithtiotropi

umbromide(SpirivaHandiHaler)comparedtoplacebo.October2009Hangzhou92Potentialissueswithdatapoolingandmeta-analysis⚫Publicationbias

⚫Whetherthestudywaspublished⚫Whetherthesafetyend-pointwasreported⚫Studypopulationofthetrials⚫Exclusion/exclusioncriteria⚫Highrisk

patients?⚫Real-lifepractice?⚫Durationoffollow-up?⚫Methodstocombinedata⚫Fixedeffectassumption⚫Randomeffectmodel⚫Z

erocellsOctober2009Hangzhou93Regulatoryoptionswhenthereisasafetyconcern⚫Delayedapprovalandwithdrawal

⚫Tremendoussocietalcosts⚫Conditionalapprovaland(Therapeutic)RiskManagement⚫Productlife-cycleassessment⚫Ri

skidentification(signaldetection)⚫Riskassessment(incidenceandriskfactors)⚫Riskcommunication⚫RiskManagementPlan

s(RMP)/RiskEvaluation&MitigationStrategy(REMS)October2009Hangzhou94InresponsetotherofecoxibeventandInstituteofMedicinereportFDAinitiativesincludedeve

lopingnewscientificapproachestodetecting,understanding,predicting,andpreventingadverseevents,developingand

incorporatingnewquantitativetoolsintheassessmentofbenefitandrisk,andconductingapilotprogramtoreviewthesafetyprofilesofcertainne

wlyapproveddrugsonaregularlyscheduledbasis.http://www.fda.gov/bbs/topics/NEWS/2007/NEW01551.htmlOctober2009Hangzhou95S

omeexamples⚫Isotretinoinandpregnancy⚫Clozapineandagranulocytosis⚫Thalidomideformultiplemyeloma⚫Alosetronforirritablebowelsyndr

ome⚫…⚫http://www.fda.gov/cber/genadmin/rems.htm⚫NeedobjectiveevidencetoevaluatetheeffectivenessofRMPsOctober2009Hangzhou96Restrictedaccess

:treatmentINDOctober2009Hangzhou97Arethereeffectivetoolstoidentifyhighriskpatients?October2009Hangzhou98ATRMtool:blackboxwarning

⚫BlackBoxWarningand“DearDoctorLetter”⚫Howeffectivearethey?⚫Smalleyetal.ContraindicatedUseofCisapride:ImpactofFoodandDrugAd

ministrationRegulatoryActionJAMA2000;284:3036-9.⚫Woosley.DrugLabelingRevisions—GuaranteedtoFail?JAMA2000;284:3047-9.October2009Hangzhou99October2009H

angzhou100Smalleyetal.JAMA2000;284:3036-9.