1 Postmarketing Drug Safety and Risk Intervention Studies Evelyn M Rodriguez MD, MPH Director, DDREII, OPDRA

2 Topics for Today’s Discussion Postmarketing Drug Safety Two Risk Intervention Case Studies –Review of the Labeling History –Study Objective, Methods, Results and Conclusions Summary / Considerations Future Directions

3 Why Post-Marketing Surveillance? Limitations of Phase 3 Trials –Too few, too simple, too median aged, too narrow, too brief Population of Users Expands After Drug Approval –Age, Sex, Race/Ethnicity, Use in pregnancy Rare Events

4 Postmarketing Safety Surveillance Database reporting system: Adverse Event Reporting System (AERS) Cost effective Signal generation Receives > 250,000 reports per year

5 Postmarketing Causality Assessment Temporal Relationship Biological Plausibility Known Class Effect Previous Pre-marketing Findings Dose-related Effect

6 Postmarketing Causality Assessment Onset Time and Progression Confirmed Diagnosis Dechallenge - discontinue drug Rechallenge - restart drug Underlying Disease Concomitant Drugs

7 Use of Cases Identified in AERS Case definition - reporter’s clinical diagnosis or one from the literature Develop Case Series –Causality Assessment –Conditions of exposure –Risk Factors and Confounders

8 Underreporting: Barriers to Reporting Voluntary System Recognize, Attribute, and Establish Adverse Event to Drug Labeled adverse events less likely reported Constraints, Litigation Fear, Desire to Publish Findings, Privacy Concerns

9 Underreporting of Adverse Drug Reactions From the Literature

10 Lotronex Pre-marketing cases of ischemic colitis and constipation Postmarketing reports of serious cases –Ischemic colitis –Serious complications of Constipation Early in marketing (3 months)

11 Possible Next Steps Incidence Study for Serious Outcomes –Ischemic Colitis and Constipation difficult to ascertain in automated databases (ICD-9 codes and underreporting)

12 Possible Next Steps Risk Factor Study –Risk factor identification may be feasible for Ischemic Colitis IF complete ascertainment is assured –Constipation as a risk factor for serious GI outcomes hard to evaluate because it is associated with IBS, the indication for the drug

13 Possible Next Steps Implement Risk Interventions (e.g. Education, Labeling change) Evaluate whether the Risk Interventions are achieving desired goals

14 First Drug History Risk Intervention Study

15 First Case History Approved in January 1997 Marketed in March 1997 Seven months after marketing, first Acute Liver Failure death Several Re-labelings and Dear Healthcare Practitioner letters including recommendations for Liver Transaminase (LT) testing

16 Risk Intervention Study Objective To assess the impact of the labeling changes regarding LT monitoring in a large managed care organization automated claims database using ICD-9 and CPT codes

17 Risk Intervention Study Objective Recommended LT monitoring varied slightly with each labeling change Last labeling change recommended a baseline test with monthly monitoring for first 8 months, data presented to AC 3/99

18 Overview of Study in the United HealthGroup Database Cohort 1 n = 2307 Cohort 2 n = 2823 Cohort 3 n = Oct 971 Dec 9730 Jun 981 Aug 9831 Dec 9825 Oct 971 Dec 9730 Jun 981 Aug 98 Cohort 3 n = Dec 98Mar 9725 Oct 97*1 Dec 97*30 Jun 981 Aug 98*

19 LT Monitoring at Baseline after the First Prescription by Cohort

20 Full Compliance with Monthly LT Monitoring by Cohort among Drug Users *Data Shown as Percentage of Eligible Subjects at Each Time Period

21 Conclusion Poor compliance with full LT monitoring scheme recommended by labeling Better compliance with baseline LT testing that improved with each labeling change to a maximum of 45%

22 Investigators FDA Dave Graham MD, MPH Evelyn M Rodriguez MD, MPH FDA Cooperative Agreement Program UHG Carol Drinkard, PhD Deborah Shatin, PhD

23 Second Drug History Risk Intervention Study

24 Second Drug 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

25 Second Drug History Black Box Warning with Contraindication for QT interval prolonging drugs and Cardiovascular and Medical Conditions, 2nd line indication & DHPL 6/98

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

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

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

29 Cohorts Before and After Labeling Changes through 6/98

30 Results: Contraindicated Drug or Disease

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

32 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)

33 Summary / Considerations Risk Intervention studies are useful to assess the effect of labeling and DHPL These two studies suggest labeling fatigue phenomenon Other strategies, such as Education targeting Prescribers and Patients, may be useful to encourage the implementation of recommended risk management efforts

34 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 materials, CME courses

35 Future Directions Determine –How information, contraindications, and monitoring recommendations are used Feasibility of constipation as contraindication

36 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

37 Back Up Slides

38 Sample Size of Study Population, UHG Ever received drug9,369 Total person-years4,873  90 day prior enrollment 7,568 Included in LT monitoring study6,541

39 Criteria for Inclusion in the Study Cohort for LT Monitoring Enrollment Date  90 days prior to 1 st troglitazone prescription

40 Study Method for Measuring Liver Transaminase Monitoring in UHG BaselineMonth 1 …….. Last Rx. -30d30d1st Rx.60d -30d - + 7d+/- 7d Month 2

41 Cohorts

42 Age Distribution (%) of Cisapride Users, Pre Year % Female: Site A: 60.3 Site B: 67.2 Site C: 62.8 %

43 Contraindicated Drugs (At least 1 day of use concurrent with cisapride use) Antiarrhythmics: procainamide, quinadine, sotalol, amiodarone, disopyramide Antipsychotics: chlorpromazine, mesoridazine, thioridazine, trifluoperazine, thiothixene, haloperidol, fluphenazine, triflupromazine, pimozide, risperidone, perphenazine Cyclic antidepressants: amitriptyline, clomipramine, imipramine, doxepin, trimiprramine, amoxapine, desipramine, nortriptyline, protiptyline, maprotiline

44 Contra- indicated Drugs

45 Contraindicated Comorbidity Heart Failure Other Ischemic Heart Disease Electrolyte Disorder Ventricular Arrhythmia Renal Failure Respiratory Failure Any diagnosis in the 180 days preceding t 0. Restricted to cohort members with 180+ days prior enrollment

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

47 Contraindicated Drug or Comorbidity, By Age Site B only

48 Future Directions Conduct studies among prescribers to identify the “best communication practices” that will enhance timely and useful communication by industry and FDA Assess the impact of the health care services delivery system on prescribing and medical practice in the context of safer drug use

49 Future Directions Form industry-government partnerships & interagency collaborations to conduct further studies to identify effective risk intervention strategies Using the results from these studies, implement strategies and evaluate success