1. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 2 Sources of Risk From Medical Products Known Side Effects Unavoidable Avoidable Medication and Device Errors Product Defects Preventable Adverse Events Remaining Uncertainties: Unexpected side effects Unstudied uses Unstudied populations Injury or Death

3. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 4 Post-marketing Drug Safety Risk Assessment: What Pre-marketing Safety Data Tell Us Pre-clinical Pharmacology And Toxicology Clinical Pharmacology Clinical Safety Data Open-label Studies Clinical Safety Data Controlled Studies Pre-Marketing Safety Data Product Label

5. National Health Policy Conference, Washington, DC February 6, 2006 5 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period

6. National Health Policy Conference, Washington, DC February 6, 2006 6 How post-marketing adverse event reports get to FDA Patients, consumer, and healthcare professionals FDA MedWatch Manufacturer FDA FDAs Adverse Event Reporting System (AERS) database voluntary regulatory requirements

7. National Health Policy Conference, Washington, DC February 6, 2006 7 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period ???

8. National Health Policy Conference, Washington, DC February 6, 2006 8 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period Rare but serious adverse event Aplastic anemia Drug-induced liver injury

9. National Health Policy Conference, Washington, DC February 6, 2006 9 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period Also common in the population Myocardial infarction

10. National Health Policy Conference, Washington, DC February 6, 2006 10 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period Also a manifestation of the underlying disease Myocardial infarction

11. National Health Policy Conference, Washington, DC February 6, 2006 11 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period How do we separate a potential signal from the background?

12. National Health Policy Conference, Washington, DC February 6, 2006 12 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Pre-marketing Safety Data Market Introduction Post-marketing Period Rare but serious adverse event Intensive case evaluation Look back at pre-marketing safety database

13. National Health Policy Conference, Washington, DC February 6, 2006 13 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Pre-marketing Safety Data Market Introduction Post-marketing Period Common in the population OR Manifestation of the underlying disease Intensive case evaluation Look back at pre-marketing safety database Still hard to establish and quantify risk

14. National Health Policy Conference, Washington, DC February 6, 2006 14 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Clinical Trial Random Allocation Treatment of Interest Control TreatmentFollow-up Period

15. National Health Policy Conference, Washington, DC February 6, 2006 15 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Clinical Trial Random Allocation Treatment of Interest Control TreatmentFollow-up Period

16. National Health Policy Conference, Washington, DC February 6, 2006 16 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Clinical Trial Random Allocation Treatment of Interest Control TreatmentFollow-up Period Excess Risk Risk Ratio

17. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 20 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Epidemiological Study - Cohort Study Start observation Time Relative risk or hazard ratio

21. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 24 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Registry Case-control studies Estimate magnitude of problem Study natural history or survival Persons with disease of interest

25. National Health Policy Conference, Washington, DC February 6, 2006 25 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Registry Risk factors for exposure Estimate magnitude of exposure Outcome of exposure Persons with exposure of interest

26. National Health Policy Conference, Washington, DC February 6, 2006 26 Use of a Postmarketing Registry: Antiepileptic Drugs and Teratogenicity Pregnant women with epilepsy on valproic acid Enrollment7 months Birth Postpartum Outcome ascertainment 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. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 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. National Health Policy Conference, Washington, DC February 6, 2006 29 Active Surveillance Request for Information issued April 2005 Responses received June 2005 Responses currently under review Agency will decide on next steps

30. National Health Policy Conference, Washington, DC February 6, 2006 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