Enhancing Post-Marketing Surveillance: Lessons from the Veterans Health Administration

1. Enhancing Post-Marketing Surveillance: Lessons from the Veterans Health Administration Fran Cunningham, PharmDDirector Center for Medication Safety PSCI and Pharmacoepidemiologic/ Outcomes Assessment VHA National Pharmacy Benefits Management Strategic Healthcare Group Robert Campbell, JD, MPH, PhDAssistant Director for Evaluation, VISN 8 Patient Safety Center of InquiryTampa, FLDustin French, PhDHealth Economist, VISN 8 Patient Safety CenterTampa, FL

2. Drug Safety and Pharmacovigilance in the Department of Veterans Affairs: National Overview Fran Cunningham, Pharm.D. Director Center for Medication Safety PSCI and Pharmacoepidemiologic/ Outcomes Assessment VHA National Pharmacy Benefits Management Strategic Healthcare Group

3. Pharmacovigilance in the Department of Veterans Affairs: Overview • National program initiated - FY 1999 • Optimizing National Rx database for quality and research initiatives • FY 2000/2001 • Pilot drug safety program • National medication safety and DUE initiated focusing on ADEs • Rx database used for pharmacovigilance efforts • Sildenafil-NTG interactions • Protease Inhibitors - CYP 3A 4 inhibitors

4. Pharmacovigilance in VA • FY 2002/2003 • Integrated databases merged and used as primary source for tracking ADEs by national PBM • First National Pharmacovigilance Projects • Integrated databases used to assist in formulary decisions regarding drug safety • National pharmacoepidemiolgic studies conducted • Hines • Bedford • New Haven • Seattle • Durham • Houston

5. Pharmacovigilance in VA • FY 2004–2006 • Center for Medication Safety PSCI – Grant co-funded by VACO PBM/SHG and National Center for Patient Safety • Infrastructure for enhanced pharmacovigilance in VA developed • Risk Reduction Program • Pilot completed program operationalized • Field investigators conduct pharmacoepidemiologic studies • as a follow-up to pharmacovigilance/drug surveillance rapid cycle analysis results • IOM Presentation

6. Pharmacovigilance in VA • FY 2006-2007 • Programs continued and enhanced • Active Surveillance Program pilot • Sentinel Event Network • FDA/VA MOU developed and signed • FDA/VA Charter initiated

7. GOAL of VA PHARMACOVIGILANCE PROGRAM • Track and evaluate high risk and high volume agents in veteran population • Formalize the national drug safety program with emphasis on: • Utilizing integrated databases as the foundation of the VA national pharmacovigilance program • Modernizing and enhancing spontaneous ADE reporting

8. GOAL of PHARMACOVIGILANCE PROGRAM • Track inappropriate use of therapy as part of the national pharmacovigilance program • Polypharmacy • High Doses • Altered End Organ Function • NMEs • Conduct risk reduction efforts • Develop Active Surveillance Program • Initiate and encourage drug safety research using national databases

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

10. Adverse Drug Events in VAReporting, Tracking, Monitoring • Adverse Drug Event Database • Spontaneous Reporting • FDA MedWatch Form 3500 • Allergy Reaction Tracking Package (ART Package) • CPRS – Electronic Medical Record • Every VA Facility • Adverse Drug Event Tracking and Evaluation Using VA Integrated Databases • Prescription Databases • Inpatient/Outpatient Files • Mortality Database

11. INTEGRATED DATABASES

12. VA National Prescription Database • Includes data from October 1998 to present • Provides every individual Rx filled in the VA • Provides prescription days supply • Data is specific to outpatient divisions • Patient identifier is included for every Rx • Provides cost per unit for every prescription • Provides dosing instructions for each prescription

13. VA Integrated Databases Linkages with Pharmacy Data VA National Health Surveys Mortality data VA National Patient Care Databases Pharmacy Databases DEpiC Diabetes Epidemiology Cohort CMS Medicare data Other Potential Data - VA Rehab - VA Dz Registries

14. VA Databases as a Tool • VA databases provide the mechanism for • Medication safety projects and initiatives • Clinical decisions • Research • An effective tool in VA • Monitoring exposure rate and ADEs • High risk agents • New agents • Agents with newly identified safety information • An effective tool for evaluation of appropriate use • Safety • Central Office and Field queries • Other Government Agencies

15. Safety Evaluations • Rx databases, electronic medical record (inpatient and outpatient files), and mortality database are linked at patient level to monitor agents • Patients characterized by demographic, medical hx, medication and tx variables • Patients followed for 12-24 months or greater • NME’s – tracking initiated from inception in system and formally evaluated every 6 months • Control agent chosen • Rates of exposure and adverse outcomes assessed

16. Galantamine Pegylated Interferons Bisphosphanates PDE V Inhibitors ARB’s Antipsychotics Ezetimibe Varenacline Deferasirox DMARDS Vitamin E LABAs Select Example of VA Pharmacovigilance/Drug Surveillance Projects - FY 2005-2007 • Fluoroquinolones • High Dose Statins • Rosuvastatin • Statin-Fibrates • Cox II Inhibitors • Etodolac • Accutane • Cilostazol • Leflunamide • Bevacizumab

17. VA Sites Conducting Pharmacoepidemilogic Projects • St. Louis HSR&D (Washington University) • Bedford HSR&D (Boston University) • Pittsburgh HSR&D (Univ of Pittsburgh and Univ of Pennsylvania) • Ann Arbor VAMC HSR&D (Univ of Michigan) • Hines HSR&D (Northwestern University and UIC) • VISN 1 Co-op Studies Program (Harvard) • New Haven VAMC and Center of Excellence (Yale) • Durham VAMC and HSR&D (Duke University) • Minneapolis HSR&D • Dallas VAMC • Birmingham VAMC and HSR&D (Univ of Alabama) • Nashville VAMC and CSP • Houston VAMC and HSR&D • Seattle HSR&D (University of Washington) • San Antonio HSR&D (University of Texas) • VISN 8 PSCI and HSR&D

18. Post-marketing Medication Safety: Paradigm Shifts Robert Campbell, JD, MPH, PhDAssistant Director for Evaluation, VISN 8 Patient Safety Center of InquiryTampa, FL

19. Post Marketing SurveillanceParadigm Shifts • Adverse Drug Reactions (ADRs) • Adverse Drug Events (ADEs) • Other Outcomes and Problems (OOPs)

20. Non-FDA Drug Safety Initiatives Impacting Post Marketing Surveillance Activities Risk Management Reporting Systems Accreditation Programs Performance Measurement Systems

21. Proactive Surveillance Research: VISN 8 Patient Safety Center of Inquiry Medication Safety Team Falls and medications in the elderly Drugs as risk factors for adverse outcomes

22. Drug Safety and Pharmacovigilance in the Department of Veterans Affairs: Methodological Issues Dustin D. French, PhD Health Economist Patient Safety Center of Inquiry. Tampa, FL.

23. Drug Safety: Lost under the street light? A cop walking his beat one night finds a drunk on his knees, searching for something on the street. The cop asks the drunk, “What are you doing?” “Looking for my car keys,” says the drunk. The cop asks, “Where did you lose your keys?” “I don’t know,” the man answers. The cop, a bit perplexed, asks, “Then, why are you looking here if you don’t know where you lost your keys?” Responds the drunk, “Because the light is better here, under the streetlight.” e.g. COX-2 and GI Bleeds

24. Where to look? • Healthcare system that is fragmented (e.g. Medicare, Medicaid, HMOs, PPOs). • EU – Nationally financed healthcare systems • US – VHA – Integrated healthcare system with (inpatient, outpatient, pharmacy, lab, etc.)

25. Joining Data Silos for Drug Safety

26. What to Look For? E.G. COX-2 GI Bleeds or Strokes and MIs • From Case Reports • Systems with Biological mechanisms • Systems without Biological Mechanisms • Proactive VS Reactive Surveillance for not just harms but potential benefits

27. How to Look? • Incidence of adverse outcomes temporally associated with medication use (signal detection) • More sophisticated multivariate modeling (e.g. logistic regression, GEE, case cross-over designs) of Medications related outcomes (drug-drug and drug-disease interactions, comorbidities etc.) • Expert panel review of the national Electronic Medical Record (VISTA) of drug related cases from signal detection phase

28. VHA Drug Safety Studies • PDE-5 and NION (AJO 2007) • Amantadine and CE (Cornea forthcoming) • Medication profiling (CVS, CNS, MSS) and fractures, syncope, MI, etc. (Drugs and Aging 2005, Br J Clin Pharm 2006, Am J Clin Pharm 2007). • Risk Adjusted Models (Pharmacoepidemiology and Drug Safety 2005)

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