Enhancing PostEnhancing Post--Marketing Marketing Surveillance: Lessons from Surveillance: Lessons from the Veterans Health the Veterans Health AdministrationAdministration

Fran Cunningham, PharmDFran Cunningham, PharmD Director Center for Medication Safety PSCI andDirector Center for Medication Safety PSCI and

Pharmacoepidemiologic/ Outcomes Assessment

VHA National Pharmacy Benefits ManagementVHA National Pharmacy Benefits ManagementStrategic Healthcare GroupStrategic Healthcare Group

Robert Campbell, JD, MPH, PhDRobert Campbell, JD, MPH, PhD Assistant Director for Evaluation, VISN 8 Patient Safety Center Assistant Director for Evaluation, VISN 8 Patient Safety Center of Inquiryof Inquiry

Tampa, FLTampa, FL

Dustin French, PhDDustin French, PhD Health Economist, VISN 8 Patient Safety CenterHealth Economist, VISN 8 Patient Safety Center

Tampa, FLTampa, FL

Drug Safety and Drug Safety and Pharmacovigilance in the Pharmacovigilance in the Department of Veterans Department of Veterans Affairs: National OverviewAffairs: National Overview

Fran Cunningham, Pharm.D.Fran Cunningham, Pharm.D.Director Center for Medication Safety PSCI andDirector Center for Medication Safety PSCI andPharmacoepidemiologic/ Outcomes Assessment

VHA National Pharmacy Benefits ManagementVHA National Pharmacy Benefits ManagementStrategic Healthcare GroupStrategic Healthcare Group

Pharmacovigilance in the Department of Pharmacovigilance in the Department of Veterans Affairs: OverviewVeterans Affairs: Overview

National program initiated National program initiated -- FY 1999FY 1999–– Optimizing National Rx database for quality and research Optimizing National Rx database for quality and research

initiativesinitiativesFY 2000/2001FY 2000/2001–– Pilot drug safety program Pilot drug safety program

National medication safety and DUE initiated focusing on National medication safety and DUE initiated focusing on ADEsADEs

–– Rx database used for pharmacovigilance effortsRx database used for pharmacovigilance effortsSildenafilSildenafil--NTG interactionsNTG interactionsProtease Inhibitors Protease Inhibitors -- CYP 3A 4 inhibitorsCYP 3A 4 inhibitors

Pharmacovigilance in VAPharmacovigilance in VA

FY 2002/2003FY 2002/2003–– Integrated databases merged and used as primary source Integrated databases merged and used as primary source

for tracking ADEs by national PBMfor tracking ADEs by national PBM–– First National Pharmacovigilance ProjectsFirst National Pharmacovigilance Projects

Integrated databases used to assist in formulary Integrated databases used to assist in formulary decisions regarding drug safetydecisions regarding drug safety

–– National pharmacoepidemiolgic studies National pharmacoepidemiolgic studies conductedconducted

HinesHinesBedfordBedfordNew HavenNew HavenSeattleSeattleDurhamDurhamHoustonHouston

Pharmacovigilance in VAPharmacovigilance in VA

FY 2004FY 2004––2006 2006 –– Center for Medication Safety PSCI Center for Medication Safety PSCI –– Grant coGrant co--

funded by VACO PBM/SHG and National Center funded by VACO PBM/SHG and National Center for Patient Safetyfor Patient Safety

Infrastructure for enhanced pharmacovigilance Infrastructure for enhanced pharmacovigilance in VA developedin VA developedRisk Reduction Program Risk Reduction Program

–– Pilot completed program operationalizedPilot completed program operationalized–– Field investigators conduct Field investigators conduct

pharmacoepidemiologic studiespharmacoepidemiologic studies–– as a followas a follow--up to pharmacovigilance/drug up to pharmacovigilance/drug

surveillance rapid cycle analysis results surveillance rapid cycle analysis results –– IOM PresentationIOM Presentation

Pharmacovigilance in VAPharmacovigilance in VA

FY 2006FY 2006--20072007–– Programs continued and enhancedPrograms continued and enhanced–– Active Surveillance Program pilotActive Surveillance Program pilot–– Sentinel Event NetworkSentinel Event Network–– FDA/VA MOU developed and signedFDA/VA MOU developed and signed–– FDA/VA Charter initiatedFDA/VA Charter initiated

GOAL of VA PHARMACOVIGILANCE GOAL of VA PHARMACOVIGILANCE PROGRAMPROGRAM

Track and evaluate high risk and high volume agents Track and evaluate high risk and high volume agents in veteran populationin veteran populationFormalize the national drug safety program with Formalize the national drug safety program with emphasis on:emphasis on:–– Utilizing integrated databases as the foundation Utilizing integrated databases as the foundation

of the VA national pharmacovigilance programof the VA national pharmacovigilance program–– Modernizing and enhancing spontaneous ADE Modernizing and enhancing spontaneous ADE

reportingreporting

GOAL of PHARMACOVIGILANCE GOAL of PHARMACOVIGILANCE PROGRAMPROGRAM

Track inappropriate use of therapy as part of Track inappropriate use of therapy as part of the national pharmacovigilance programthe national pharmacovigilance program–– PolypharmacyPolypharmacy–– High DosesHigh Doses–– Altered End Organ FunctionAltered End Organ Function–– NMEsNMEs

Conduct risk reduction effortsConduct risk reduction effortsDevelop Active Surveillance Program Develop Active Surveillance Program Initiate and encourage drug safety research Initiate and encourage drug safety research using national databasesusing national databases

VA for Pharmacovigilance/Drug VA for Pharmacovigilance/Drug SurveillanceSurveillance

The VA as a resource for surveillance The VA as a resource for surveillance and adverse event evaluation and adverse event evaluation –– Older/Sicker patientsOlder/Sicker patients–– High medication use High medication use –– Penetration of new agents is fairly rapidPenetration of new agents is fairly rapid–– Good Information Systems Good Information Systems –– Ongoing monitoring of outcomes in place Ongoing monitoring of outcomes in place

Adverse Drug Events in VAAdverse Drug Events in VA Reporting, Tracking, MonitoringReporting, Tracking, Monitoring

Adverse Drug Event DatabaseAdverse Drug Event Database–– Spontaneous ReportingSpontaneous Reporting–– FDA MedWatch Form 3500FDA MedWatch Form 3500

Allergy Reaction Tracking Package (ART Package)Allergy Reaction Tracking Package (ART Package)–– CPRS CPRS –– Electronic Medical RecordElectronic Medical Record–– Every VA FacilityEvery VA Facility

Adverse Drug Event Tracking and Evaluation Using Adverse Drug Event Tracking and Evaluation Using VA Integrated DatabasesVA Integrated Databases–– Prescription DatabasesPrescription Databases–– Inpatient/Outpatient FilesInpatient/Outpatient Files–– Mortality DatabaseMortality Database

INTEGRATED DATABASESINTEGRATED DATABASES

VA National Prescription VA National Prescription DatabaseDatabase

Includes data from October 1998 to presentIncludes data from October 1998 to presentProvides every individual Rx filled in the VAProvides every individual Rx filled in the VAProvides prescription days supplyProvides prescription days supplyData is specific to outpatient divisionsData is specific to outpatient divisionsPatient identifier is included for every RxPatient identifier is included for every RxProvides cost per unit for every prescriptionProvides cost per unit for every prescriptionProvides dosing instructions for each Provides dosing instructions for each prescriptionprescription

Mortality data

Pharmacy Databases

VA National Patient Care

Databases

VA National Health Surveys

CMSMedicare data

DEpiCDiabetes Epidemiology

CohortOther Potential Data- VA Rehab- VA Dz Registries

VA Integrated DatabasesLinkages with Pharmacy Data

VA Databases as a ToolVA Databases as a ToolVA databases provide the mechanism forVA databases provide the mechanism for–– Medication safety projects and initiativesMedication safety projects and initiatives–– Clinical decisionsClinical decisions–– ResearchResearch

An effective tool in VAAn effective tool in VA–– Monitoring exposure rate and ADEs Monitoring exposure rate and ADEs

High risk agents High risk agents New agentsNew agentsAgents with newly identified safety informationAgents with newly identified safety information

An effective tool for evaluation of appropriate useAn effective tool for evaluation of appropriate use–– SafetySafety–– Central Office and Field queriesCentral Office and Field queries–– Other Government AgenciesOther Government Agencies

Safety EvaluationsSafety EvaluationsRx databases, electronic medical record (inpatient Rx databases, electronic medical record (inpatient and outpatient files), and mortality database are and outpatient files), and mortality database are linked at patient level to monitor agentslinked at patient level to monitor agents

Patients characterized by demographic, medical hx, Patients characterized by demographic, medical hx, medication and tx variablesmedication and tx variables

Patients followed for 12Patients followed for 12--24 months or greater24 months or greater

NMENME’’s s –– tracking initiated from inception in system tracking initiated from inception in system and formally evaluated every 6 monthsand formally evaluated every 6 months

Control agent chosenControl agent chosen

Rates of exposure and adverse outcomes assessedRates of exposure and adverse outcomes assessed

Select Example of VA Select Example of VA Pharmacovigilance/Drug Surveillance Pharmacovigilance/Drug Surveillance

Projects Projects -- FY 2005FY 2005--20072007FluoroquinolonesFluoroquinolonesHigh Dose StatinsHigh Dose StatinsRosuvastatinRosuvastatinStatinStatin--FibratesFibratesCox II InhibitorsCox II InhibitorsEtodolacEtodolacAccutaneAccutaneCilostazolCilostazolLeflunamideLeflunamideBevacizumabBevacizumab

GalantamineGalantaminePegylated InterferonsPegylated InterferonsBisphosphanatesBisphosphanatesPDE V InhibitorsPDE V InhibitorsARBARB’’ssAntipsychoticsAntipsychoticsEzetimibeEzetimibeVarenaclineVarenaclineDeferasiroxDeferasiroxDMARDSDMARDSVitamin EVitamin ELABAsLABAs

VA Sites Conducting VA Sites Conducting Pharmacoepidemilogic ProjectsPharmacoepidemilogic Projects

St. Louis HSR&D (Washington University)St. Louis HSR&D (Washington University)Bedford HSR&D (Boston University) Bedford HSR&D (Boston University) Pittsburgh HSR&D (Univ of Pittsburgh and Univ of Pennsylvania)Pittsburgh HSR&D (Univ of Pittsburgh and Univ of Pennsylvania)Ann Arbor VAMC HSR&D (Univ of Michigan)Ann Arbor VAMC HSR&D (Univ of Michigan)Hines HSR&D (Northwestern University and UIC)Hines HSR&D (Northwestern University and UIC)VISN 1 CoVISN 1 Co--op Studies Program (Harvard)op Studies Program (Harvard)New Haven VAMC and Center of Excellence (Yale)New Haven VAMC and Center of Excellence (Yale)Durham VAMC and HSR&D (Duke University)Durham VAMC and HSR&D (Duke University)Minneapolis HSR&DMinneapolis HSR&DDallas VAMC Dallas VAMC Birmingham VAMC and HSR&D (Univ of Alabama)Birmingham VAMC and HSR&D (Univ of Alabama)Nashville VAMC and CSPNashville VAMC and CSPHouston VAMC and HSR&DHouston VAMC and HSR&DSeattle HSR&D (University of Washington)Seattle HSR&D (University of Washington)San Antonio HSR&D (University of Texas)San Antonio HSR&D (University of Texas)VISN 8 PSCI and HSR&DVISN 8 PSCI and HSR&D

PostPost--marketing marketing Medication Safety: Medication Safety: Paradigm ShiftsParadigm Shifts

Robert Campbell, JD, MPH, PhDRobert Campbell, JD, MPH, PhD Assistant Director for Evaluation, Assistant Director for Evaluation, VISN 8 Patient Safety Center of InquiryVISN 8 Patient Safety Center of Inquiry Tampa, FLTampa, FL

Post Marketing SurveillancePost Marketing Surveillance Paradigm ShiftsParadigm Shifts

Adverse Drug Reactions (ADRs)Adverse Drug Reactions (ADRs)

Adverse Drug Events (ADEs)Adverse Drug Events (ADEs)

Other Outcomes and Problems (OOPs)Other Outcomes and Problems (OOPs)

NonNon--FDA Drug Safety Initiatives FDA Drug Safety Initiatives Impacting Post Marketing Impacting Post Marketing

Surveillance ActivitiesSurveillance Activities

Risk Management Reporting Systems

Accreditation Programs

Performance Measurement Systems

Proactive Surveillance Research: Proactive Surveillance Research: VISN 8 Patient Safety Center of VISN 8 Patient Safety Center of

InquiryInquiry

Medication Safety TeamMedication Safety Team

Falls and medications in the elderlyFalls and medications in the elderly

Drugs as risk factors for adverse Drugs as risk factors for adverse outcomesoutcomes

Drug Safety and Drug Safety and Pharmacovigilance in the Pharmacovigilance in the Department of Veterans Department of Veterans Affairs: Methodological Affairs: Methodological IssuesIssues

Dustin D. French, PhDDustin D. French, PhDHealth EconomistHealth EconomistPatient Safety Center of Inquiry. Tampa, FL.Patient Safety Center of Inquiry. Tampa, FL.

Drug Safety: Lost under the street light?Drug Safety: Lost under the street light?

A cop walking his beat one night finds a drunk on his A cop walking his beat one night finds a drunk on his knees, searching for something on the street. The cop knees, searching for something on the street. The cop asks the drunk, asks the drunk, ““What are you doing?What are you doing?”” ““Looking for my Looking for my car keys,car keys,”” says the drunk. The cop asks, says the drunk. The cop asks, ““Where did you Where did you lose your keys?lose your keys?”” ““I donI don’’t know,t know,”” the man answers. The the man answers. The cop, a bit perplexed, asks, cop, a bit perplexed, asks, ““Then, why are you looking Then, why are you looking here if you donhere if you don’’t know where you lost your keys?t know where you lost your keys?”” Responds the drunk, Responds the drunk, ““Because the light is better here, Because the light is better here, under the streetlight.under the streetlight.””

e.g. COXe.g. COX--2 and GI Bleeds2 and GI Bleeds

Where to look?Where to look?

Healthcare system that is fragmented (e.g. Healthcare system that is fragmented (e.g. Medicare, Medicaid, HMOs, PPOs).Medicare, Medicaid, HMOs, PPOs).EU EU –– Nationally financed healthcare Nationally financed healthcare systemssystemsUS US –– VHA VHA –– Integrated healthcare system Integrated healthcare system with (inpatient, outpatient, pharmacy, lab, with (inpatient, outpatient, pharmacy, lab, etc.)etc.)

Joining Data Silos for Drug SafetyJoining Data Silos for Drug Safety

What to Look For?What to Look For?

E.G. COXE.G. COX--2 GI Bleeds or Strokes and MIs2 GI Bleeds or Strokes and MIs–– From Case ReportsFrom Case Reports–– Systems Systems withwith Biological mechanismsBiological mechanisms–– Systems Systems withoutwithout Biological Mechanisms Biological Mechanisms –– Proactive VS Reactive Surveillance for not Proactive VS Reactive Surveillance for not

just harms but potential benefitsjust harms but potential benefits

How to Look?How to Look?

–– Incidence of adverse outcomes Incidence of adverse outcomes temporally temporally associated with medication use (signal detection)associated with medication use (signal detection)

–– More sophisticated multivariate modeling (e.g. More sophisticated multivariate modeling (e.g. logistic regression, GEE, case crosslogistic regression, GEE, case cross--over over designs) of Medications related outcomes (drugdesigns) of Medications related outcomes (drug-- drug and drugdrug and drug--disease interactions, comorbidities disease interactions, comorbidities etc.)etc.)

–– Expert panel review of the national Electronic Expert panel review of the national Electronic Medical Record (VISTA) of drug related cases Medical Record (VISTA) of drug related cases from signal detection phasefrom signal detection phase

VHA Drug Safety StudiesVHA Drug Safety Studies

PDEPDE--5 and NION (5 and NION (AJO AJO 2007)2007)Amantadine and CE (Amantadine and CE (CorneaCornea forthcoming)forthcoming)Medication profiling (CVS, CNS, MSS) and Medication profiling (CVS, CNS, MSS) and fractures, syncope, MI, etc. (fractures, syncope, MI, etc. (Drugs and Drugs and AgingAging 2005, 2005, Br J Clin PharmBr J Clin Pharm 2006, 2006, Am J Am J Clin PharmClin Pharm 2007).2007).Risk Adjusted Models Risk Adjusted Models ((Pharmacoepidemiology and Drug SafetyPharmacoepidemiology and Drug Safety 2005)2005)

When to Look? Time Frame?When to Look? Time Frame?

IBM 3390 IBM 3390 -- 5.7 million patients, 120 million 5.7 million patients, 120 million outpatient prescriptions and outpatient care, outpatient prescriptions and outpatient care, and perform signal detection study, short and perform signal detection study, short turn around (e.g. <1 week). turn around (e.g. <1 week). Real Time Transaction Data BasesReal Time Transaction Data BasesData Cubes and Dash Boards (SQL)Data Cubes and Dash Boards (SQL)Banking Industry, Airline, etc.Banking Industry, Airline, etc.Real ID ACTReal ID ACT-- The Future of Patient The Future of Patient Identification?Identification?