1. DRAFT SLIDES FOR NDA 21-198 ADVISORY COMMITTEE PRESENATIONS

2. Pravachol  10 mg Tablets Rx to OTC Switch Daiva Shetty, M.D. Division of Over-the-Counter Drug Products (HFD-560) Food and Drug Administration Friday, July 14, 2000

3. Actual Use Studies Background  Simulate OTC Use  Have few exclusion criteria  Objectives depend on the specific product and concerns related to that product such as:  compliance, dosing, duration of use  off-label use  safety and efficacy in OTC population

4. Actual Use Issues for Pravachol   Are consumers able to:  self-diagnose  know their own cholesterol values  understand serum cholesterol values  self-select  identify risk factors for CHD

5. Actual Use Issues for Pravachol   Are consumers able to:  self-treat hypercholesterolemia  when to start treatment  are they able to follow label directions for dosing and duration of use  do they understand the treatment goal

6. Review of Pravachol  Actual Use Trials  PREDICT, Protocol # 800-01-97  OPTIONS, Protocol # 800-03-97

7. Actual Use Trials PREDICT The Pravachol Experience Documented In a Consumer Trial

8. Study PREDICT  Study design:  multi-center  randomized  parallel  open-label  6 months duration  To test:  behavior  efficacy  tolerability

9. Study PREDICT  Study design (cont.)  recruitment done via advertising (newspapers, radio, pharmacies)  the call center directed interested subjects to the enrollment site  the call center also served as a screening site for premenopausal or childbearing potential women

10. Study PREDICT  Study design (cont.)  Inclusion criteria:  > 18 years

11. Study PREDICT  Study design (cont.)  Exclusion criteria:  less than 18 years old  females of childbearing potential  breast feeding females  participation in a research study within the last 30 days

12. Study PREDICT  Criteria for treatment on the label:  Total cholesterol 200-240 mg/dl  LDL cholesterol > 130 mg/dl

13. Study PREDICT  Primary Objective:  Proportion of OTC randomized subjects, who having purchased OTC Pravachol 10 mg, consult a physician within two months of using medication

14. PREDICTResults

15.  119 subjects were ineligible to participate  61 (2%) women of childbearing age  Of the 11,065 who called, unknown how many were women of childbearing potential

16. Behavior of OTC Population (n=1,924)

17. Treatment Guidelines Initiate Treatment/LDL-CGoal/LDL-C No CHD or diabetes & 2 risk factors >130 mg/dl, < 190 mg/dl< 130 mg/dl No CHD or diabetes, <1 risk factor >160 mg/dl, < 190 mg/dl< 160 mg/dl

18. PREDICTResults Lipid Profile at Baseline in Qualified and Treated Population LDL-C: Mean 162 mg/dl + 17 Median 163 mg/dl TC: Mean 245 mg/dl + 21 Median 245 mg/dl

19. Behavior of OTC Treated Population  290 (58%) withdrew from the study  123 were withdrawn from the study by a physician  Discontinuation due to adverse events  8% OTC vs. 5% Rx  53 subjects were titrated to a higher dose

20. PREDICTResults  Compliance  Assessed by pill count and self-report, and defined by 80-120%:  54% OTC vs. 65% RxCI -19%,-3.7%  Mean duration of treatment:  109.4 days OTC vs. 152.5 days RX

21. Are consumers able to self-diagnose hypercholesterolemia?

22. Knowledge about Cholesterol values Randomized Population (n=3,872) Healthy level TC: < 20074% Unknown21% Healthy level LDL-C: < 13012% Unknown80% Knowledge of HDL-C was not tested

23. Actual Use Trials OPTIONS OTC Pravachol Trial In an Observed Naturalistic Setting

24. Study OPTIONS  Study design:  multi-center  open-label  pharmacy based  3 months duration  To assess:  behavior  compliance  safety

25. Study OPTIONS  Study design (cont.)  Inclusion criteria:  > 18 years  member of a participating HMO for at least 6 months

26. Study OPTIONS  Study design (cont.)  Exclusion criteria:  pregnancy or lactation  participation in a research study within the last 30 days  less than 18 years old

27. Study OPTIONS  Study design (cont.)  Recruitment was done via:  mailing the study brochure to the HMO members  walk through traffic in the participating pharmacies  radio  newspaper

28. Study OPTIONS  Population was not representative of overall U.S. OTC population:  restricted to certain geographical areas  all participants had health care insurance and prescription drug coverage

29. Study OPTIONS  Study design (cont.)  Criteria for treatment on the label  Total serum cholesterol 200-240 mg/dl  > 35 years for men  > 55 years for women

30. Study OPTIONS  Primary Objective  To determine the proportion of subjects, who having purchased Pravachol 10 mg, contact their health care provider within 2 months of using the medication

31. OPTIONSResults

34.  95 (24%) purchase population were not recommended Pravachol by their health care provider  Median total-C level 235 mg/dl  Median LDL-C level 151 mg/dl  59.8% women were <55 years old

35. Proposed Label Total cholesterol 200-240 mg/dl “Bad” cholesterol (LDL) > 130 mg/dl Do not use if you are under 18 years if you have liver disease or drink >3 alcoholic beverages daily if you are allergic to pravastatin

36. Latest Proposed Label Total cholesterol 200-240 mg/dl “Bad” cholesterol (LDL) > 130 mg/dl For men over 35 years of age For women over 45 years of age

37. Overall Conclusions  Low consumer understanding of specific serum cholesterol values  Substantial number of self-selection errors  High withdrawal rate  Poor adherence

38. Overall Conclusions  Behavior of childbearing age women was not addressed in these 2 trials  Consumer understanding was not assessed about:  the goal (to lower cholesterol)  the length of the therapy  titration to a higher dose  Targeted OTC population on the current proposed label has not been studied