a renaissance in signal management
TRANSCRIPT
RenaissanceinSignalManagement
WorldDrugSafetyCongress
September14,2016
Copyright2016,CommonwealthInformaCcs,Inc.
Allrightsreserved
vRenaissanceinSignalManagement
§ SignalManagement§ AcleardescripConoftheprocess(CIOMS-VIII)§ Allowsustocollectprocessmetrics§ MakeobjecCvechoicestoopCmizetheprocess
§ VirtuouscycleofprocessopCmizaCon§ beOerprocess§ beOerdata§ beOermethods
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vKeypoints§ Welldefinedprocessallowsustomeasureperformance,
experimentwithchanges,andchoosethosethatopCmizetheprocess
§ WearestarCngtohaveinformaCononthestrengthsofeachdatasourceandmethod§ Movedpastthesearchforthe"one"methodand"one"datasource
§ SpontaneousreporCngsystemsconCnuetoprovidethebestsignaldetecConperformanceforrareadversereacCons
§ Electronichealthrecords(EHR)arenopanacea,buthavearolethatcomplementsspontaneousreportsinbothsignaldetecConandinsignalrefinement
§ OverallsignalmanagementperformanceisaffectedbytheefficiencyofiniCalreviewandsignalrefinement
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vOntheshouldersofgiants
§ CollecCvelywebenefitfromtheintellectuallyrigorousandtransparentpublishedworkofmanyteams§ CIOMS§ EuropeanMedicinesAgency(EMA)§ InnovaCveMedicinesIniCaCve(IMI)
§ PROTECT,Web-RADR,...§ UppsalaMonitoringCentre(UMC)
§ vigiRank,vigiPoint,...§ USFDA
§ mini-SenCnel,SenCnel,...§ Andothers
§ EU-ADR,OMOP,OHDSI,iMEDS,...
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vCIOMS-VIIISignalManagementProcess
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Impactassessment
andprioriCzaCon
NEEDFURTHER
INVESTIGATION?
MonitorviarouCnepharmacovigilance
(ifsignalisindeterminate)OR
Closeout(ifsignalisrefuted)
INDIVIDUALCASEADVERSEEVENTREPORTS• Clinicaltrials(seriousadverseevents)• Post-markeCngsources(seriousandnon-seriousadverseevents)
• Literaturereport
SIGNALDETECTIONINADVERSEEVENTREPORTINGSYSTEM• Healthauthority/monitoringcentersystems
• Companydatabases
TRADITIONALPHARMACOVIGILANCEMETHODS• Reviewofindividualcases• Aggregateanalysesofcasereportdata,usingcasecounts,crudeoradjustedreporCngrates,etc.
DATAMININGALGORITHMS• ProporConalReporCngRaCo(PRR)• MulC-itemGamma-PoissonShrinker(MGPS)
• BayesianConfidencePropagaConNeuralNetwork(BCPNN)
TRIAGEOFOUTPUTS• Interpretwithinthecontextofallotherrelevantsourcesofsafetydata,diseaseknowledge,biologicalplausibility,alternaCveeCologiesforsuspectedadversedrugreacCons,etc.
SIGNALEVALUATION• Caseseriesanalysis• AnalysisofexisCngclinicaltrialdata• Literaturesearchandreview• Pharmacoepidemiologicstudies• MechanisCcstudies• AddiConalclinicaltrials• Othertypesofstudies
OTHERSAFETYDATATOBEMONITORED• Non-clinical/pharmacologystudies• Non-intervenConalstudies• Publishedliterature(studyreports,mechanismofacCon,etc.)
• Periodicsafetyreports• InformaConondrugsinthesameclass• OtherrelevantinformaCon
FromFigure1,page22,ReportofCIOMSWorkingGroupVIII
vICSRs–EMASignalingStudy§ StudyperiodSep-2003toMar-2007usingEudravigilancedata§ 191chemicallydisCnctproducts§ 532adversereacConsaddedtotheSPCintheperiod§ SearchedEMArecordstoseewhentheagencyfirstbecameawareofeachoftheadversereacCons
§ LookedretrospecCvelytofindtheearliestpointwhenthesignalofdisproporConatereporCng(SDR)criteriawouldhaveoccurred
§ ComparedCmeofSDRwithCmeofEMAawareness
Reference:Alvarez,Y.,Hidalgo,A.,Maignen,F.,&SlaOery,J.(2010).ValidaConofstaCsCcalsignaldetecConproceduresinEudraVigilancepost-authorizaCondata.Drugsafety,33(6),475-487.
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vICSRs–EMASignalingStudy§ UsedPRR025>1todefineasignalofdisproporConatereporCng(SDR)§ 6356SDRs§ 1561SDRssurvivedfirsttriageandrequiredfurtherinvesCgaCon
§ 217SDRsrepresentedrealissuesfoundearlierbySDRthatwereeventuallyaddedtoSPC
§ 1561/217=7.2invesCgaConspersignal§ 405IMEADRsaddedtotheSPCs
§ 217(54%)foundearlierbySDRthanexisCngmethods§ 79foundlaterbySDR§ 109notsignalledbySDRinthestudyperiod
Reference:Alvarez,Y.,Hidalgo,A.,Maignen,F.,&SlaOery,J.(2010).ValidaConofstaCsCcalsignaldetecConproceduresinEudraVigilancepost-authorizaCondata.Drugsafety,33(6),475-487.
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vLowagreementbetweenassessors
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Reference:Alvarez,Y.,Hidalgo,A.,Maignen,F.,&SlaOery,J.(2010).ValidaConofstaCsCcalsignaldetecConproceduresinEudraVigilancepost-authorizaCondata.Drugsafety,33(6),475-487.
vElectronicHealthRecords(EHR)§ IMI-PROTECT
§ WorkPackage3Sub-package10,"SignaldetecConinElectronicHealthRecords"
§ Keypoints§ DevelopedandtestedaquesConnaireforstructuredassessmentoftemporallyassociateddrug-eventcombinaCons
§ DemonstratedthatexploratoryanalysisofelectronicmedicalrecordscandetectimportantpotenCalsafetysignals
§ AnexperttriagestepisrequiredtoachieveanacceptablefalseposiCverate(aswithsignaldetecConfromICSRs)
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Reference:Cederholm,S.,Hill,G.,Asiimwe,A.,Bate,A.,Bhayat,F.,Brobert,G.P.,...&Norén,G.N.(2014).StructuredAssessmentforProspecCveIdenCficaConofSafetySignalsinElectronicMedicalRecords:EvaluaConintheHealthImprovementNetwork.Drugsafety,38(1),87-100.
vSignaldetecConfromEHR-Methods§ 42drugsrandomlyselected§ Upto20eventsperdrugselectedfromthosewithatemporalassociaCon
§ AssociaCondeterminedbycalibratedself-controlledcohortanalysis
§ DatafromUKprimarycareelectronicmedicalrecords§ TheHealthImprovementNetwork(THIN)
§ 6assessorsevaluated7drugseach§ upto20medicaleventsperdrug§ usingapre-specifiedquesConnaire
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Reference:Cederholm,S.,Hill,G.,Asiimwe,A.,Bate,A.,Bhayat,F.,Brobert,G.P.,...&Norén,G.N.(2014).StructuredAssessmentforProspecCveIdenCficaConofSafetySignalsinElectronicMedicalRecords:EvaluaConintheHealthImprovementNetwork.Drugsafety,38(1),87-100.
vSignaldetecConfromEHR-Results
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Reference:Cederholm,S.,Hill,G.,Asiimwe,A.,Bate,A.,Bhayat,F.,Brobert,G.P.,...&Norén,G.N.(2014).StructuredAssessmentforProspecCveIdenCficaConofSafetySignalsinElectronicMedicalRecords:EvaluaConintheHealthImprovementNetwork.Drugsafety,38(1),87-100.
vChronograph
Copyright2016CommonwealthInformaCcsInc. Slide12Reference:HaubenM.,LiuQ.,HungE.,BlackwellW.,FramD.,BateA.SignalDetecConUsingTemporalPaOernDiscovery(TPD)inElectronicHealthRecords(EHRs).Posterpresentedat:32ndICPE,2016,Dublin
vCIOMS-VIIISignalManagementProcess
Copyright2016CommonwealthInformaCcsInc. Slide13
Impactassessment
andprioriCzaCon
NEEDFURTHER
INVESTIGATION?
MonitorviarouCnepharmacovigilance
(ifsignalisindeterminate)OR
Closeout(ifsignalisrefuted)
INDIVIDUALCASEADVERSEEVENTREPORTS• Clinicaltrials(seriousadverseevents)• Post-markeCngsources(seriousandnon-seriousadverseevents)
• Literaturereport
SIGNALDETECTIONINADVERSEEVENTREPORTINGSYSTEM• Healthauthority/monitoringcentersystems
• Companydatabases
TRADITIONALPHARMACOVIGILANCEMETHODS• Reviewofindividualcases• Aggregateanalysesofcasereportdata,usingcasecounts,crudeoradjustedreporCngrates,etc.
DATAMININGALGORITHMS• ProporConalReporCngRaCo(PRR)• MulC-itemGamma-PoissonShrinker(MGPS)
• BayesianConfidencePropagaConNeuralNetwork(BCPNN)
TRIAGEOFOUTPUTS• Interpretwithinthecontextofallotherrelevantsourcesofsafetydata,diseaseknowledge,biologicalplausibility,alternaCveeCologiesforsuspectedadversedrugreacCons,etc.
SIGNALEVALUATION• Caseseriesanalysis• AnalysisofexisCngclinicaltrialdata• Literaturesearchandreview• Pharmacoepidemiologicstudies• MechanisCcstudies• AddiConalclinicaltrials• Othertypesofstudies
OTHERSAFETYDATATOBEMONITORED• Non-clinical/pharmacologystudies• Non-intervenConalstudies• Publishedliterature(studyreports,mechanismofacCon,etc.)
• Periodicsafetyreports• InformaConondrugsinthesameclass• OtherrelevantinformaCon
FromFigure1,page22,ReportofCIOMSWorkingGroupVIII
vPosterpresentedatthe32ndInternaConalConferenceonPharmacoepidemiology&TherapeuCcRiskManagementAugust25-28,2016Dublin,Ireland
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Chronograph
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vConcludingpoints§ Metricsfromthesignalmanagementprocessprovidedataforprocessimprovement
§ WehavetheresearchresultstoguideintegraConofdatasourcesandappropriatemethodsleveragingtheircomplementarystrengths§ SpontaneousreporCngsystemsconCnuetoprovidethebestsignaldetecConperformanceforrareadversereacCons
§ Electronichealthrecords(EHR)arenopanacea,buthavearolethatcomplementsspontaneousreportsinbothsignaldetecConandinsignalrefinement
§ TheexpertdecisionmakingduringiniCalreviewandsignalrefinementisakeyareaforaOenCon
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v
QuesCons/Comments
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End
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