1. Population-Based Epidemiologic Safety Studies: Overview and Challenges Drug Safety and Risk Management Advisory Committee Silver Spring, Maryland June 19, 2005 David J. Graham, MD, MPH Office of Drug Safety Drug Safety and Risk Management Advisory Committee Silver Spring, Maryland June 19, 2005 David J. Graham, MD, MPH Office of Drug Safety Center for Drug Evaluation and Research

2. Drug Safety and Risk Management Advisory Committee May 19, 2005 2 Why Postmarketing Safety Studies ? Residual uncertainty at approval New safety signal post-approval Beyond case reports Serious Potentially large exposure Potentially large excess risk Potentially “safer” alternatives “Less serious” indication Inappropriate off-label use Residual uncertainty at approval New safety signal post-approval Beyond case reports Serious Potentially large exposure Potentially large excess risk Potentially “safer” alternatives “Less serious” indication Inappropriate off-label use

3. Drug Safety and Risk Management Advisory Committee May 19, 2005 3 Mechanisms for Performing Postmarketing Drug Safety Studies Phase 4 Ad hoc postmarketing studies Existing national data Cooperative Agreement Program GPRD Special projects: Kaiser Permanente, California Veterans’ Administration database Phase 4 Ad hoc postmarketing studies Existing national data Cooperative Agreement Program GPRD Special projects: Kaiser Permanente, California Veterans’ Administration database Performed by Companies Performed by ODS

4. Drug Safety and Risk Management Advisory Committee May 19, 2005 4 National Data Resources NHANES QT prolongation in general population NHDS Pancreatitis in children AMI in children NAMCS Prevalence of drug therapy Prevalence of diagnosed diseases NCHS statistics Age-specific denominators Cause of death NHANES QT prolongation in general population NHDS Pancreatitis in children AMI in children NAMCS Prevalence of drug therapy Prevalence of diagnosed diseases NCHS statistics Age-specific denominators Cause of death

5. Drug Safety and Risk Management Advisory Committee May 19, 2005 5 FDA Population-Based Data Resources Cooperative Agreements HMO network: ~1.8M, >5 yrs TN Medicaid: ~1.5M, >15 yrs UnitedHealth: ~2M, >5 yrs GPRD: ~3M, >5 yrs Special projects: Kaiser California: ~6M, >5 yrs VA Medical System: ~3.4M, >5 yrs ? Medicare: ~36M Cooperative Agreements HMO network: ~1.8M, >5 yrs TN Medicaid: ~1.5M, >15 yrs UnitedHealth: ~2M, >5 yrs GPRD: ~3M, >5 yrs Special projects: Kaiser California: ~6M, >5 yrs VA Medical System: ~3.4M, >5 yrs ? Medicare: ~36M

6. Drug Safety and Risk Management Advisory Committee May 19, 2005 6 Basic Database Features Population-based “Large” Longitudinal Automated claims Pharmacy Provider-encounters Procedures Record-linkage capacity Population-based “Large” Longitudinal Automated claims Pharmacy Provider-encounters Procedures Record-linkage capacity

7. Drug Safety and Risk Management Advisory Committee May 19, 2005 7 FDA Funding Costs of Resources National resources$0 Cooperative Agreements$900 K per yr GPRD$500 K per yr Special projects VA medical system$10 K Kaiser Permanente$60 K MedicareCould be $$$ National resources$0 Cooperative Agreements$900 K per yr GPRD$500 K per yr Special projects VA medical system$10 K Kaiser Permanente$60 K MedicareCould be $$$

8. Drug Safety and Risk Management Advisory Committee May 19, 2005 8 Cooperative Agreement Program Access to 3 population-based data resources with research expertise Longitudinal Outpatient prescriptions Diagnosis & procedure claims Medical record linkage No routine death ascertainment Ability to study Patterns of use w/in database Exposure-outcome Effects of regulatory interventions Access to 3 population-based data resources with research expertise Longitudinal Outpatient prescriptions Diagnosis & procedure claims Medical record linkage No routine death ascertainment Ability to study Patterns of use w/in database Exposure-outcome Effects of regulatory interventions

9. Drug Safety and Risk Management Advisory Committee May 19, 2005 9 Claims Data Quality Pharmacy claims High validity  95% complete within 2 mos Diagnosis claims Outpatient: low validity Inpatient: it depends  95% complete within 6 mos Procedure claims High validity  95% complete within 6 mos Pharmacy claims High validity  95% complete within 2 mos Diagnosis claims Outpatient: low validity Inpatient: it depends  95% complete within 6 mos Procedure claims High validity  95% complete within 6 mos

10. Drug Safety and Risk Management Advisory Committee May 19, 2005 10 Proposed Changes in Cooperative Agreement Shift from grant to contract Growing pains Intention to fund multiple databases Focus on safety-related issues important to FDA Retain collaborative relationship Shift from grant to contract Growing pains Intention to fund multiple databases Focus on safety-related issues important to FDA Retain collaborative relationship

11. Drug Safety and Risk Management Advisory Committee May 19, 2005 11 General Practice Research Database UK-based electronic medical record GP-centered, longitudinal Low turnover GP visits, health measures Consultant referrals and hospitalizations Labs, procedures ± results Computer-generated outpatient prescriptions Death ascertainment Complex relational file structure In-house access via Internet UK-based electronic medical record GP-centered, longitudinal Low turnover GP visits, health measures Consultant referrals and hospitalizations Labs, procedures ± results Computer-generated outpatient prescriptions Death ascertainment Complex relational file structure In-house access via Internet

12. Drug Safety and Risk Management Advisory Committee May 19, 2005 12 Unique Limitations UK population - not US National formulary - cost containment Different health care standards and practice Different prescribing patterns Very large data files In-house resource requirements UK population - not US National formulary - cost containment Different health care standards and practice Different prescribing patterns Very large data files In-house resource requirements

13. Drug Safety and Risk Management Advisory Committee May 19, 2005 13 Other Population-Based Resources VA medical system Moving to EMR Males, older, sicker Some acute hospitalizations missed Some lab data Kaiser Permanente Large HMO Closed system, integrated Some formulary restrictions Computerized lab data Death ascertainment VA medical system Moving to EMR Males, older, sicker Some acute hospitalizations missed Some lab data Kaiser Permanente Large HMO Closed system, integrated Some formulary restrictions Computerized lab data Death ascertainment

14. Drug Safety and Risk Management Advisory Committee May 19, 2005 14 Types of Studies Patterns of drug use Persistency Co-prescribing Case series Prevalence cohort Inception cohort Case-control Nested case-control Patient surveys Patterns of drug use Persistency Co-prescribing Case series Prevalence cohort Inception cohort Case-control Nested case-control Patient surveys

15. Drug Safety and Risk Management Advisory Committee May 19, 2005 15 Study Examples Factors associated with QTc prolongation Predictors of COX-2 inhibitor use Birth defect incidence with an antibiotic Incidence of severe liver injury with a diabetes drug Chronic use of corticosteroids in children Incidence of rhabdomyolysis with lipid-lowering drugs Compliance with contraindicated use labeling Compliance with liver enzyme monitoring recommendations Factors associated with QTc prolongation Predictors of COX-2 inhibitor use Birth defect incidence with an antibiotic Incidence of severe liver injury with a diabetes drug Chronic use of corticosteroids in children Incidence of rhabdomyolysis with lipid-lowering drugs Compliance with contraindicated use labeling Compliance with liver enzyme monitoring recommendations

16. Drug Safety and Risk Management Advisory Committee May 19, 2005 16 Potential Limitations of Databases Outpatient Rxs only Market penetration Sample size No OTC, herbal, alternative Data time-lag Special populations Completion time Privacy issues Outpatient Rxs only Market penetration Sample size No OTC, herbal, alternative Data time-lag Special populations Completion time Privacy issues Employee-insurance based Formulary issues Co-pays Patient turnover Lab results Death ascertainment Common to most or all Specific to some

17. Drug Safety and Risk Management Advisory Committee May 19, 2005 17 Challenges (1) Budgetary Databases Operation Infrastructure Personnel Training Hardware/software Methodologic Study design Proper covariates Power Budgetary Databases Operation Infrastructure Personnel Training Hardware/software Methodologic Study design Proper covariates Power

18. Drug Safety and Risk Management Advisory Committee May 19, 2005 18 Challenges (2) Topic identification & selection Matching question & data resource Prioritization Use for regulatory purposes Topic identification & selection Matching question & data resource Prioritization Use for regulatory purposes