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Population-Based Epidemiologic Safety Studies: Overview and Challenges

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. Center for Drug Evaluation and Research. Why Postmarketing Safety Studies ?.

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Population-Based Epidemiologic Safety Studies: Overview and Challenges

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  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 Center for Drug Evaluation and Research

  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

  3. Mechanisms for Performing Postmarketing Drug Safety Studies • Phase 4 • Ad hoc postmarketing studies • 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. 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

  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

  6. Basic Database Features • Population-based • “Large” • Longitudinal • Automated claims • Pharmacy • Provider-encounters • Procedures • Record-linkage capacity

  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 • Medicare Could be $$$

  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

  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

  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

  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

  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

  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

  14. Types of Studies • Patterns of drug use • Persistency • Co-prescribing • Case series • Prevalence cohort • Inception cohort • Case-control • Nested case-control • Patient surveys

  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

  16. 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 Potential Limitations of Databases Specific to some Common to most or all

  17. Challenges (1) • Budgetary • Databases • Operation • Infrastructure • Personnel • Training Hardware/software • Methodologic • Study design • Proper covariates • Power

  18. Challenges (2) • Topic identification & selection • Matching question & data resource • Prioritization • Use for regulatory purposes

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