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Drug Safety Challenges: Considerations for Sources of Data

Drug Safety Challenges: Considerations for Sources of Data. Gerald J. Dal Pan, MD, MHS Director Office of Drug Safety Center for Drug Evaluation and Research FDA. Known Side Effects. Avoidable. Unavoidable. Preventable Adverse Events. Injury or Death.

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Drug Safety Challenges: Considerations for Sources of Data

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  1. Drug Safety Challenges:Considerations for Sources of Data Gerald J. Dal Pan, MD, MHS Director Office of Drug Safety Center for Drug Evaluation and Research FDA

  2. Known Side Effects Avoidable Unavoidable Preventable Adverse Events Injury or Death Sources of Risk From Medical Products Medication and Device Errors Product Defects • Remaining • Uncertainties: • Unexpected side effects • Unstudied uses • Unstudied populations

  3. Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events • A fundamental goal of post-marketing drug safety programs • Must account for many different types of risk • Must account for many potentially confounding factors • Must account for time course of events

  4. Product Label Post-marketing Drug Safety Risk Assessment:What Pre-marketing Safety Data Tell Us Pre-clinical Pharmacology And Toxicology Clinical Pharmacology Pre-Marketing Safety Data Clinical Safety Data Controlled Studies Clinical Safety Data Open-label Studies

  5. Market Introduction Post-marketing Period Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events Pre-marketing Safety Data

  6. voluntary voluntary Manufacturer FDA MedWatch FDA FDA’s Adverse Event Reporting System (AERS) database How post-marketing adverse event reports get to FDA Patients, consumer, and healthcare professionals regulatory requirements

  7. Market Introduction Pre-marketing Safety Data Post-marketing Period Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events ? ? ?

  8. Market Introduction Pre-marketing Safety Data Post-marketing Period Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events Rare but serious adverse event • Aplastic anemia • Drug-induced liver injury

  9. Market Introduction Pre-marketing Safety Data Post-marketing Period Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events Also common in the population • Myocardial infarction

  10. Market Introduction Pre-marketing Safety Data Post-marketing Period Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events Also a manifestation of the underlying disease • Myocardial infarction

  11. Market Introduction Pre-marketing Safety Data Post-marketing Period Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events How do we separate a potential signal from the background?

  12. Rare but serious adverse event Market Introduction Intensive case evaluation Pre-marketing Safety Data Post-marketing Period Look back at pre-marketing safety database Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

  13. Common in the population OR Manifestation of the underlying disease Market Introduction Intensive case evaluation Pre-marketing Safety Data Post-marketing Period Look back at pre-marketing safety database Still hard to establish and quantify risk Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

  14. Treatment of Interest Random Allocation Control Treatment Follow-up Period Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk Clinical Trial

  15. Treatment of Interest Random Allocation Control Treatment Follow-up Period Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk Clinical Trial

  16. Excess Risk Treatment of Interest Random Allocation Risk Ratio Control Treatment Follow-up Period Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk Clinical Trial

  17. Alternative Sources of Information • Large health care utilization databases • Electronic medical record systems • Registries • Can be used for active surveillance or to answer specific drug safety questions

  18. Heath Care Utilization Databases • Large, population-based, integrated pharmacy and medical claims databases • filled prescriptions • professional services • hospitalizations • Can capture real-world practice patterns, in the context of the system that gives rise to the data (in US, generally within a given health insurance plan or set of plans)

  19. Heath Care Utilization Databases • Strengths • size • based on actual care • data already collected • Limitations • specific clinical data not present • lack of some important health-related information (eg, smoking status) • only captures what is billed for • frequent patient turnover as insurance changes

  20. Relative risk or hazard ratio Start observation Time Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk Epidemiological Study - Cohort Study

  21. Example of a cohort study:Statins and hospitalized rhabdomyolysis Cohort: Drug-specific inception cohorts of statin and fibrate users, based on data from 11 US health plans using automated claims covering prescription drugs, outpatient care, hospitalizations, and medical procedures Exposure: Algorithm developed to calculate person-time on drug for each patient based on prescription claims. Separate classifications for monotherapy and statin-fibrate combination therapy Outcome: Medical record review of all patients based on hospitalization claims with at least one ICD-9-CM code suggestive of severe muscle injury, followed by a blinded review to determine cases of rhabdomyolysis. Source: Graham D et al. JAMA 2004;292:25885-2590

  22. Example of a cohort study:Statins and hospitalized rhabdomyolysis Analysis: Relative risk estimates of rhabdomyolysis, adjusted for age, sex, and diabetes mellitus were calculated using Poisson regression. Incidence rates per 10,000 person-years of treatment, with 95% CIs, were calculated. Source: Graham D et al. JAMA 2004;292:25885-2590

  23. Electronic Medical Records • Contain more information than claims databases: • medications prescribed • detail clinical information (eg, symptoms and signs) • physical examination results • results of diagnostic tests • Example: General Practitioner Research Database (GPRD)

  24. Persons with disease of interest Case-control studies Study natural history or survival Estimate magnitude of problem Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk Registry

  25. Persons with exposure of interest Risk factors for exposure Outcome of exposure Estimate magnitude of exposure Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk Registry

  26. Enrollment 7 months Postpartum Birth Outcome ascertainment Use of a Postmarketing Registry:Antiepileptic Drugs and Teratogenicity Pregnant women with epilepsy on valproic acid 149 VPA-exposed, 16 with major malformations (10.7%, 95% CI: 6.3-16.9) Internal comparator rate: 2.9% (95% CI: 2.0-4.1) External comparator rate: 1.62% Source: Wyszynski DF et al. Neurology 2005;64:961-965

  27. New Database Acquisitions • Four organizations with linked pharmacy-medical claims databases • Contracts signed September 2005 • Allows for collaborations between FDA epidemiologists and experts at these organizations • Four organizations: • HMO Research Network/Harvard Pilgrim Health • Kaiser Family Foundation • Vanderbilt University • Ingenix (i3Drug Safety)

  28. New Database Acquisitions • Four organizations: • Harvard Pilgrim Health/HMO Research Network • Eight geographically diverse health plans with 3.2 million members • Electronic medical records available for 6 of 8 sites • Kaiser Family Foundation • 6.1 current members in northern and southern California • Fully integrated databases, linked to vital statistics and cancer registries • Unique formulary limited to selected drugs and indications • Vanderbilt University • Two state Medicaid populations (Tennessee and Washington) • 2.2 millions members, some at high medical risk (eg, the poor, nursing home residents) • Ingenix • Geographically diverse insured population of 12 million members • Some laboratory data also available

  29. Active Surveillance • Request for Information issued April 2005 • Responses received June 2005 • Responses currently under review • Agency will decide on next steps

  30. CMS Interactions • ODS epidemiogists are working with CMS and AHRQ staff to understand better the nature of CMS data • Current efforts focused on using Part B data for a pilot drug safety study • Still in learning/exploratory stages

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