Risk Intervention Study Cisapride Evelyn M Rodriguez MD

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

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

Cisapride’s Regulatory History Risk Intervention Study 3

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 4

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

Study Objective • To describe the impact of the cumulative labeling changes through 6/98 – CYP P 450 3 A 4 Enzyme Inhibitor Drugs – QT Prolonging Drugs – Contraindicated Comorbidities 6

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

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

Cohorts Before and After Labeling Changes through 6/98 9

Results: Contraindicated Drug or Disease 10

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

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, 12 Ph. D. (Health. Partners)

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 13

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 14

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

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 16

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 17

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

Back Up Slides 19

Contraindicated Drugs 20

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