1. Department of Health and Human Services Center for Drug Evaluation and Research 1 Issues in Projecting Increased Risk of Cardiovascular Events to the Exposed Population Robert T. O’Neill, Ph.D. Director, Office of Biostatistics February 18, 2005

2. Department of Health and Human Services Center for Drug Evaluation and Research 2 Issues for Discussion The approach we used (one of several) and why? Rofecoxib as an example - data sets available What do we know from the rofecoxib randomized controlled trials (RCTs) Data sources for projections of events to the exposed population Model assumptions A range of estimates for different scenarios Uncertainties in the projection strategies Concluding remarks

3. Department of Health and Human Services Center for Drug Evaluation and Research 3 Approach to estimation of excess events associated with exposure Estimate the absolute difference in cumulative incidence rates of events from the VIGOR and APPROVE studies (event definitions) at monthly intervals for 1 to 36 months of exposure - control and dose groups assumed Estimate from IMS data the total prescriptions (usage) for 25mg and 50 mg between years 1999 thru 2004 Define episodes of exposure from the Caremark database and estimate approximate patient numbers with different durations of successive episodes Use a ratio multiplier to project up from Caremark database to IMS data base - provides U.S. estimate of number of patients with various successive episodes

4. Department of Health and Human Services Center for Drug Evaluation and Research 4 Approach to estimation of excess events associated with exposure (cont.) Multiply this estimate of numbers of patients with exposure episodes by the estimate of increased risk (incidence) to obtain number of excess events Add estimates from all mutually exclusive episode groups to get total excess events over the control background risk (rate) Discuss statistical variability of estimate (confidence interval) Repeat for different sets of assumptions about control rates, relative risk by duration, and risk factors

5. Department of Health and Human Services Center for Drug Evaluation and Research 5 For chronically used drugs, the duration of person exposure and the calculated risk at that time matter As does the appropriate estimate of risk and increased risk at defined intervals of time or durations of exposure

6. Department of Health and Human Services Center for Drug Evaluation and Research 6 What did we learn from two Rofecoxib clinical trials? (Studies were not prospectively designed for CV events) Study VIGORAPPROVe EndpointPUBsRecurrent CA IndicationRheumatoid ArthritisPolyp prevention Duration1 year3 year Dose50 mg25 mg Mean Age58 years59 years Subjects79% Female48% Female ComparatorNaproxenPlacebo

7. Department of Health and Human Services Center for Drug Evaluation and Research 7 Replication Do we believe there is an effect to project? Is there consistency of effects in different studies on same endpoints? – Alzheimer’s Disease – Mild Cognitive Impairment

8. Department of Health and Human Services Center for Drug Evaluation and Research 8 Event Definitions Matter ! Event rates are a function of event definitions and how many different subtypes are included in the definition Blindly adjudicated vs. investigator reported events will (can) make a difference risk estimates and risk ratios

9. Department of Health and Human Services Center for Drug Evaluation and Research 9 Event definitions in VIGOR & APPROVe We will examine two of them: Confirmed thrombotic events within 14 days of last dose of study drug: Myocardial infarction (fatal and non-fatal), or sudden cardiac death APTC events within 14 days of last dose of study drug

10. Department of Health and Human Services Center for Drug Evaluation and Research 10 VIGOR Patients withdraw from exposure (trial) early ! Impact on event rates and comparisons Completed: rofecoxib: 2862 / 4047 ( 70.7% ) naproxen: 2880 / 4029 ( 71.5% ) Discontinued (Reasons): Clinical AE’s: rofecoxib: 563 (13. 9%); naproxen: 492 (12.2%) Lack of efficacy: rofexocib: 256 ( 6.3%); naproxen: 263 (6.5%) Other: laboratory AE’s, moved, lost, withdrew consent

11. Department of Health and Human Services Center for Drug Evaluation and Research 11

12. Department of Health and Human Services Center for Drug Evaluation and Research 12 RR = 2.28, P =0.0035 (1.31,3.97 )

13. Department of Health and Human Services Center for Drug Evaluation and Research 13 Myocardial infarction contributes most to the composite endpoint in the VIGOR Study

14. Department of Health and Human Services Center for Drug Evaluation and Research 14 (Huque)

15. Department of Health and Human Services Center for Drug Evaluation and Research 15 Data support risk and increased risk, increases with longer duration of exposure

16. Department of Health and Human Services Center for Drug Evaluation and Research 16 RR = 1.92, p = 0.008) (1.19, 3.11)

17. Department of Health and Human Services Center for Drug Evaluation and Research 17

18. Department of Health and Human Services Center for Drug Evaluation and Research 18 (Merck, 2005 ) Risk and increased risk, increases with exposure duration and time

19. Department of Health and Human Services Center for Drug Evaluation and Research 19 (Merck, 2005 )

20. Department of Health and Human Services Center for Drug Evaluation and Research 20 25 mg Tablet strength - Increased Risk (Difference in rates)

21. Department of Health and Human Services Center for Drug Evaluation and Research 21 50 mg Tablet strength - Increased Risk (Difference in rates)

22. Department of Health and Human Services Center for Drug Evaluation and Research 22 Assumptions for increased risk beyond 12 months

23. Department of Health and Human Services Center for Drug Evaluation and Research 23 Assumptions for increased risk beyond 12 months: Using APPROVe estimates for 12 to 36 months

24. Department of Health and Human Services Center for Drug Evaluation and Research 24 Projections to the Population Projections to the population involve: Estimating how many persons are exposed For how long To what increased risk, and Against what background rate We will rely on drug use prescription data – many assumptions are made

25. Department of Health and Human Services Center for Drug Evaluation and Research 25 National Prescription Data Sources IMS Health, National Prescription Audit Plus  – Total number of prescriptions dispensed from U.S. retail pharmacies – Does not provide patient demographic information IMS Health, National Disease and Therapeutic Index  – Survey of 2000 - 3000 office-based physicians – Projections may be unstable given small sample size

26. Department of Health and Human Services Center for Drug Evaluation and Research 26 Total number of prescriptions dispensed for Vioxx from 1999 - 2004 in outpatient settings IMS Health, National Prescription Audit Plus™, Years 1999 – 2004, Extracted January 2005, Original File: 0501viox.dvr

27. Department of Health and Human Services Center for Drug Evaluation and Research 27 Indications for Use of Vioxx: 1999-2003 Average use of Vioxx for 1999 - 2003 OA: 18% RA : 3% Highest use was in 1999 OA: 23% RA: 5% Use in 2003 OA: 16% RA: 3%

28. Department of Health and Human Services Center for Drug Evaluation and Research 28 Estimating Patient Level Duration of Rofecoxib Exposure The Caremark Data An attempt to estimate how many persons are exposed for how long a duration to different tablet strengths

29. Department of Health and Human Services Center for Drug Evaluation and Research 29 Source of Data for Defining Episodes of Vioxx Use Dataset obtained through Caremark™ – Large pharmacy benefits manager – Covers 70+ million patient lives and ~25% of total U.S. prescriptions Dataset included all Vioxx claims (n=1,969,285) from 1 January 2002 through 31 December 2004 – Patients must have been in Caremark™ for entire study time period (~25% of all claims)

30. Department of Health and Human Services Center for Drug Evaluation and Research 30 Analytical Caremark™ Dataset We excluded prescriptions claims where: – Strength = 12.5 mg – Patients who were younger than 18 years – Suspension formulation We also removed nonsensical data – Days supply dispensed equal to zero – Patients aging more than 2 years between subsequent prescriptions – Patients whose gender changed between prescriptions Final dataset included 1,736,639 claims and 403,293 patients

31. Department of Health and Human Services Center for Drug Evaluation and Research 31 Limitations of Caremark™ Data Not nationally representative Limited to insured persons with prescription drug coverage – Under-representation of elderly persons (due to Medicare coverage) – Poor, indigent persons underrepresented Quality of prescription claims data – Data not collected for research purposes

32. Department of Health and Human Services Center for Drug Evaluation and Research 32 Definition of exposure episode One exposure-episode Two exposure-episodes Caremark 36-month window) 6/1/2002 Exposure-episode included in analysis (≥ 3 months observed) Exposure-episode excluded (< 3 months observed) 1/1/2002 12/31/2004

33. Department of Health and Human Services Center for Drug Evaluation and Research 33 Definition of Continuous Episode of Vioxx Use Days supply (initial Rx) Time between prescriptions < = 15 days15 days 16 – 60 days30 days 61+ days60 days

34. Department of Health and Human Services Center for Drug Evaluation and Research 34

35. Department of Health and Human Services Center for Drug Evaluation and Research 35

36. Department of Health and Human Services Center for Drug Evaluation and Research 36 Projection Ratio R IMS Rx relative increase over Caremark™ Rx : A ssume constant multiplier R = (Total IMS Rx’s in 1999-2004) /(Total Rx’s in Caremark) Caremark (2002-2004) IMS Rx's (in 1,000) R # Exposure /episodes# Rx's 25 mg48990014372318420558.59 50 mg78748190914960150.29 Total568648162814593806

37. Department of Health and Human Services Center for Drug Evaluation and Research 37 What is the increased risk in exposure sub-populations? By dose By duration of exposure No other factors possible to examine: – Age – Gender – Indication, or – Other risk factors

38. Department of Health and Human Services Center for Drug Evaluation and Research 38 Calculation Average Increased Number (Events) Attributable to Vioxx For each dose strength and length of exposure- episode L N L = (# of exposures) x (Increased Incidence) x R To obtain the increased events for each dose strength Sum over all exposure lengths Sum over both dose strengths to obtain total

39. Department of Health and Human Services Center for Drug Evaluation and Research 39 Estimates of Population Increased Events: MI & Sudden Cardiovascular Deaths (Events) 25 mg = 28,686 (95% CI upper limit = 100,159) 50 mg = 3,732 (9,256) – constant projection = 4,407 (w / APPROVe Projection ) Both 25mg and 50mg strengths combined 32,418 (109,415) events (w/constant projection) 33,093 (w/APPROVe Projection)

40. Department of Health and Human Services Center for Drug Evaluation and Research 40 Estimates of Population Increased Events: Confirmed thrombotic events within 14 days of last study dose 25 mg = 41,406 (95% CI upper limit 145,046) 50 mg = 6304 (15,380) for constant projection = 8034 for APPROVe projection Both 25mg and 50mg strengths combined 47,710 (160,426) events for constant projection 49,440 events for APPROVe Projection

41. Department of Health and Human Services Center for Drug Evaluation and Research 41 Sensitivity of the Estimate Estimates of t he number of increased events are influenced by: – Validity of the assumption to use clinical trial incidence for population incidence and comparability of populations (cross trial data) – Relevance of observational data odds ratio to short term use, hazard rate – The Caremark inclusion criteria for left censored exposure-episode and the cutoff time of the first prescription – The variability of the ratio projected from Caremark to US population (nationwide) and its validity – Variability of the estimates of increased incidence – Assumption of projection from 13-month trial exposure data to 36-month of exposure

42. Department of Health and Human Services Center for Drug Evaluation and Research 42 Where do some of the differences in estimates come from? Assumption of constant hazard rate calculated as events per 100 person years - can overestimate early 1 - 2 month hazard, underestimates later ( > 8 months, 1.5 year ) hazard Assumption of constant (proportional hazard ratio over exposure time) Estimate of very large number of people exposed for short (1-2 months) episodes - RCT vs. Caremark vs. Actual US pop

43. Department of Health and Human Services Center for Drug Evaluation and Research 43 Exposure Length Distribution Difference

44. Department of Health and Human Services Center for Drug Evaluation and Research 44

45. Department of Health and Human Services Center for Drug Evaluation and Research 45

46. Department of Health and Human Services Center for Drug Evaluation and Research 46 Increased Incidence of MI & Sudden Cardiovascular Death by Kaplan-Meier Diff and Average Patient-Month Diff 25 mg – By Kaplan-Meier diff 28,686 – By Patient-Month diff 39,187 50 mg – By Kaplan-Meier diff 7,542 (w/APPROVe Projection) – By Patient-Month diff5,843 25 mg & 50 mg Combined – By Kaplan-Meier diff 36,228 – By Patient-Month diff 45,030

47. Department of Health and Human Services Center for Drug Evaluation and Research 47 Summary Goal of the projection effort : – Provide a framework for considering estimates – Provide a range of estimates to show how assumption dependent each is - not to emphasize any one estimate – To describe the logic, process, assumptions and uncertainties in the estimates – To focus attention on duration of exposure and time related risk – Given the data limitations and uncertainties, argue that there is no best approach nor estimate and it is difficult to choose an estimate without qualifying its relevance

48. Department of Health and Human Services Center for Drug Evaluation and Research 48 Acknowledgements ODS Team – Laura Governale – Gerald Dal Pan – Aaron Mendelsohn – Judy Staffa OB Team – Joanne Zhang – Yi Tsong – Mohammad Huque