1. 1 Risk Intervention Study: Cisapride Evelyn M Rodriguez MD, MPH Director, DDREII, OPDRA

2. 2 Topics for Today’s Discussion Cisapride: Risk Intervention Case Study Summary / Considerations Future Directions

3. 3 Cisapride’s Regulatory History Risk Intervention Study

4. 4 Cisapride’s Regulatory History Approved in July 1993 First reports of Ventricular Arrhythmia with an antifungal drug 12/94 Multiple Dear Healthcare Practitioner letters that described new contraindications and warnings for specific drugs and conditions

5. 5 Cisapride’s Regulatory History Black Box Warning with Contraindication for QT interval prolonging drugs and Cardiovascular and Medical Conditions, 2nd line indication & DHPL 6/98

6. 6 Study Objective To describe the impact of the cumulative labeling changes through 6/98 –CYP P450 3A4 Enzyme Inhibitor Drugs –QT Prolonging Drugs –Contraindicated Comorbidities

7. 7 Methods Automated Databases: –Sites A, B, and C Time Periods –Before DHPL: 7/97 - 6/98 –After DHPL: 7/98 - 6/99

8. 8 Study Sites N based on calendar 1998; no material change for any of databases in 1999.

9. 9 Cohorts Before and After Labeling Changes through 6/98

10. 10 Results: Contraindicated Drug or Disease

11. 11 Conclusion No reduction in contraindicated use was found following labeling changes and DHPL of 6/98

12. 12 Study Group FDA Investigators Diane Wysowski Ph.D., Evelyn M. Rodriguez, Dave Graham M.D., M.P.H. United Health Group (Site A) Deborah Shatin, Ph.D., Stephanie D. Schech, Ph.D. Tennessee Medicaid (Site B) Walter Smalley, M.D., M.P.H., Jim Daugherty, M.S., Wayne Ray, Ph.D. Harvard Consortium (Site C) Jerry Gurwitz, M.D, Susan Andrade, D.Sc., Jackie Cernieux, M.P.H. (Meyers Primary Care Institute, Fallon Healthcare System); Richard Platt, M.D., M.S., Arnold Chan, M.D., Dr.P.H. (Harvard Pilgrim Healthcare, Michael Goodman, Ph.D. (HealthPartners)

13. 13 Summary / Considerations Risk Intervention studies are useful to assess the effect of labeling and DHPL This study suggests labeling fatigue Other strategies, such as Education targeting Prescribers and Patients, may be useful to encourage the implementation of recommended risk management efforts

14. 14 Future Directions Determine –How prescribers interpret information from DHPL & other educational materials –Best format to inform prescribers and patients of drug safety concerns -- PPI, Med Guide, company sales force materials, CME course

15. 15 Future Directions Determine –How information, contraindications, and monitoring recommendations are used

16. 16 Future Directions Conduct risk intervention studies in multiple databases that reflect the range of health care services delivery systems Validate the findings in databases with medical record review

17. 17 Possible Next Steps Incidence Study for Serious Outcomes –QT Prolongation and Torsades de Pointe difficult to assess (non-specific ICD-9 codes and underreporting) –Sudden Death possible; use unexposed comparator group

18. 18 Possible Next Steps Implement Risk Interventions: EKG monitoring, other Evaluate whether the Risk Interventions (e.g. Education, Labeling) is achieving desired goals

19. 19 Back Up Slides

20. 20 Contra- indicated Drugs

21. 21 Contraindicated Comorbidity Based on (pre/post) persons with 180+ days of enrollment: Site A: 13613/12418; B: 4379/4229; C: 6848/5812