1. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 1 Overview of Drug Safety Challenges Gerald J. Dal Pan, MD, MHS Director Division of Surveillance, Research & Communication Support Office of Drug Safety FDA

2. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 2 Post-marketing Drug Safety Risk Assessment: Multifaceted Challenges Identification of new adverse events Investigation of risk Characterization of context

3. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 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. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 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

5. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 5 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period

6. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 6 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period ???

7. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 7 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

8. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 8 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

9. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 9 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

10. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 10 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?

11. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 11 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period Long latency between drug exposure and event

12. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 12 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period Multiple Effect Modifiers Drug-drug, drug-disease, drug-herbal, drug-food interactions

13. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 13 Post-marketing Drug Safety Risk Assessment: Identification of New Adverse Events Pre-marketing Safety Data Market Introduction Post-marketing Period Proper Identification of Medication Errors Medication Errors

14. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 14 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

15. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 15 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

16. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 16 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Clinical Trial Random Allocation Treatment of Interest Control TreatmentFollow-up Period

17. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 17 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Clinical Trial Random Allocation Treatment of Interest Control TreatmentFollow-up Period

18. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 18 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

19. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 19 Post-marketing Drug Safety Risk Assessment: Investigation of New Adverse Event Risk Epidemiological Study - Case-Control Case Ascertainment Control Ascertainment Exposure Ascertainment TreatmentNo Treatment Case Control Odds Ratio

20. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 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. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 21 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

22. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 22 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

23. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 23 Post-marketing Drug Safety Risk Assessment: Understanding Context - Duration of Exposure Duration of Exposure Risk Initial Exposure Critical period to study

24. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 24 Post-marketing Drug Safety Risk Assessment: Understanding Context - Population Exposure Duration of Exposure Number of Persons Exposed

25. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 25 Post-marketing Drug Safety Risk Assessment: Understanding Context - Population Exposure Duration of Exposure Number of Persons Exposed

26. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 26 Post-marketing Drug Safety Risk Assessment: Understanding Context - Population Exposure Duration of Exposure Number of Persons Exposed

27. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 27 Post-marketing Drug Safety Risk Assessment: Understanding Context Duration of Exposure Number of Persons Exposed Duration of Exposure Risk Potential for many adverse events

28. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 28 Post-marketing Drug Safety Risk Assessment: Understanding Context: Concomitant Use No concomitant use AB Population database studies can help us understand where risk exists in the population Prevalence of Concomitant Use Prevalence of Adverse Events High level concomitant use AB Low level concomitant use AB

29. Drug Safety and Risk Management Advisory Committee May 18-19, 2005 29 Post-marketing Drug Safety Risk Assessment: Summary Multifaceted challenges Many ways to explore risk Context can be important