1. AA-3-1 Carola P. Friedman, MD, FACC Executive Medical Director Worldwide Consumer Medicines 7asdf

2. AA-3-2 Pravachol 10 OTC Program 7asdf

3. AA-3-3 The OTC Population Men  35 years, women  45 years Told by physician to lower cholesterol Not at desirable cholesterol level despite diet and exercise but are not taking Rx therapy: –TC: 200 - 240 mg/dl, LDL-C > 130 mg/dl –Generally healthy: no CHD or DM –Likely to reach NCEP goal with a moderate reduction in LDL-C

4. AA-3-4 Points to Consider with OTC Availability of a Lipid Lowering Medication Appropriate use in an OTC setting –The product will be used by a population who will receive benefit –Physician involvement will be maintained –Compliance with the OTC product will result in a similar profile of biologic activity –Use in a less supervised environment will result in a similar safety profile

5. AA-3-5 Consumer Use Program Label Comprehension (n=612) Pravachol Experience Documented In a Consumer Trial (PREDICT) (n=3,872) OTC Pravachol Trial In an Observed Naturalistic Setting (OPTIONS) (n=782)

6. AA-3-6 Consumer Use Trials: Objectives Develop Label Consumers can understand and test with attention to low literacy Consumer Use –Allow everyone to participate, including those who are inappropriate –Assess behavior by creating natural environments –Generate data that is:  Generalizable  Reliable –Confirm results by utilizing protocols of different designs in diverse populations  PREDICT:Create OTC and Rx environments to assess comparability  OPTIONS:Capture real-world OTC setting

7. AA-3-7 Label Comprehension: People Understood the Label 612 people surveyed; 27% read  9th grade No a priori cholesterol concern required People understood key messages  9th Grade  9th Grade LiteracyLiteracy –“See MD / Get level checked”95%95% –Do not use if CHD present94%92% –Do not use if diabetic79%83% –“Follow up with MD for unusual muscle pain”93%93%

8. AA-3-8 Comparison of Label Tested and Proposed OTC Label Changes primarily reflect Drug Facts Format requirements Number of “See a doctor” messages remain constant Additional information added to usage section: –LDL-C  130mg/dl –Cholesterol level graphic Other changes –Age for women changed to  45 years –Erythromycin warning eliminated

9. AA-3-9 PREDICT Objectives Allow diverse populations to participate Randomize participants to OTC vs Rx environments prior to any knowledge of medical history (no screening); Rx population served as control group Observe behavior for 6 months Assess physician consultation for OTC purchasers Compare OTC vs Rx participants who qualified for Pravachol 10 for –Physician follow-up –LDL-C reduction –Safety

10. AA-3-10 PREDICT Advertising Designed to Capture Broad Spectrum of the Population 20 geographically diverse areas Demographics of radio, print media mirror community Augmented by –Hispanic and Gospel stations –Minority magazines Key communication message of advertisement –Non prescription medicine to lower cholesterol –For generally healthy people with TC 200-240 mg/dl –No mention of age or specific medical conditions

11. AA-3-11 Randomized to OTC or Rx Environments n=3,872 Information provided by Call Center Directions to site Hours of operation No screening conducted (women of childbearing potential excluded; 5% of calls) PREDICT Participant Disposition 80% responded to advertising 20% walk-thru Visited Retail Sites n=3,888 n=3,888 Responded to Advertisement through Call Center n=11,065 n=11,065

12. AA-3-12 Generalizable Neighborhoods accessible to –Public transportation –Minority populations –Low literacy populations Randomization to OTC or Rx environments prior to knowledge of medical conditions PREDICT Retail Site Characteristics No contact for 6 months Natural No medical personnel Dissociated from clinics No screening performed Minimal exclusion criteria OTC participants could purchase  18 years No research study participation  30 days Women of childbearing potential / breastfeeding

13. AA-3-13 Fill Prescription n=352 Fill Prescription n=352 Participant Behavior Choices Throughout the Course of PREDICT OTCRx n=1,306n=1,160 n=352n=285 Qualified and Treated Consult TolerabilitySafetySafety n=405n=315Qualified Primary Objective OTC Treated n=499 OTC Treated n=499 OTC Purchasers n=720 OTC Purchasers n=720 n=1,948n=1,924 Randomized to Environments Characterize People Interested

14. AA-3-14 PREDICT Results: Baseline Characteristics of Participants Responding to Advertisement

15. AA-3-15 PREDICT Participants Responding to Advertisement Demographics PREDICT Participants Responding to Advertisement Demographics (Randomized Population n=3,872) Mean Age (yr.  SD)56  12  75 6 Other3 Age Group  35 4 35-5442 55-7448 Gender Race Black8 Hispanic5 Caucasian84 Male62 Female38 (%)  9th Grade Literacy 8

16. AA-3-16 PREDICT Participants Responding to Advertisement Health Care Status / Cholesterol Action PREDICT Participants Responding to Advertisement Health Care Status / Cholesterol Action (Randomized Population n=3,872) Have a Doctor85 (%) Following AHA Diet (MEDFICTS)81 Taking Non-Rx Therapies18 Have Prescription Coverage72 Taking Rx Therapy 9 See MD Yearly83 Saw MD Specifically for Cholesterol25 Cholesterol Elevated  5 Years 24 Health Care Status Cholesterol Action

17. AA-3-17 PREDICT Subsequent Evaluations Follow-up Week 8 Initial physician consultation l Physicians saw both OTC and Rx participants l Mimic typical practice l Lipid evaluation l Therapy recommendation according to study guidelines Week 0 (Participant Decision) 6 month extension (Optional) Week 48 Week 24 Completion of Study l Cholesterol questionnaire l Lipid profile l Diet assessment (MEDFICTS) (All Participants)

18. AA-3-18 PREDICT Results: OTC Consumer Behavior

19. AA-3-19 PREDICT Disposition of OTC Participants Wanted to consult MD47% Recognized label warning18% Cost15% Need more information9% Not interested / other9% Randomized to OTC n=1,924 n=1,924 PurchasePurchase Yesn=720Yesn=720Non=1,204Non=1,204

20. AA-3-20 PREDICT Characteristics of the OTC Purchase Population 80 (%)Characteristics Had been told of high cholesterol 87 Total cholesterol  200 mg/dl * 91 LDL-C above desirable levels *74 Knew healthy total-C was  200mg/dl 98Free of diabetes mellitus 96Free of CHD * Based on purchasers with evaluable data

21. AA-3-21 PREDICT Behavior to Consult a Physician (OTC Purchase Population n=720) 0 10 20 30 40 50 60 70 80 90 100 % of Subjects Consulted  2 Months of Product Use 77 Took and Never Consulted 10 Did Not Consult and Did Not Take 8 Consulted  2 Months of Product Use 5 90%

22. AA-3-22 PREDICT Profile of Participants Who Took Without Consulting PREDICT Profile of Participants Who Took Without Consulting (n=72) Health Care Status / Risk Factor Profile – Discussed cholesterol with MD within 6 months88% – Free of CHD94% – Free of diabetes94% 2 people reported adverse events of myalgia and prostate surgery 90% did not repurchase

23. AA-3-23 OTC n=315 Rx n=405 PREDICT OTC Availability Did Not Distract from Physician Involvement (Qualified Population) p=NS OTC vs Rx Follow-up after Initial Consultation

24. AA-3-24 PREDICT Utilization of Health Care System Maintained Minimal distraction from Rx therapy 183 participants randomized to OTC environment were taking prescription therapy at baseline –Only 2% “shifted” to OTC therapy

25. AA-3-25 PREDICT Pravachol 10 Did Not Distract From Dietary Therapy: AHA Diet Status at 6 Months (Qualified Population)

26. AA-3-26 PREDICT Dialogue Served as Gateway into Healthcare System At entry, 321 people qualified for higher dose prescription therapy because of high risk. At 6 months: –46% (n=147) saw their personal physician –29% (n=93) were taking Rx lipid lowering medicine New medical conditions diagnosed included hypertension, diabetes and thyroid disease

27. AA-3-27 PREDICT Safety Profile Maintained No deaths 19 serious adverse events unrelated to Pravachol Overall incidence of AEs similar to Rx experience Most common reason for discontinuation was myalgia (1%) and headache (1%); no difference OTC vs Rx

28. AA-3-28 PREDICT Tolerability of Pravachol 10 mg Is Similar in OTC and Rx Environments (Qualified and Treated Population) *A subject could have more than 1 reason for discontinuing study medication OTC (n=285) Rx (n=352) 4(1) 3(1)MD Discontinued Treatment 7(2) 5(2)Unknown 14(5) 10(3)Other 22(8) 16(5)Adverse Events 13(5) 12(3)Withdrew Consent13(5) 16(5)Protocol Violation 10(4) 7(2)Lost to follow-up 79(28) 66(19)Total Number of Subjects p=NS OTC vs Rx n(%) Reasons for Discontinuing Medication*

29. AA-3-29 50% 40% 30% 20% 10% 0%18% 10 Protocol 27201-2 n=61 (12 weeks) 22% 13 Protocol 27201-42 n=18 (8 weeks) 18% 26 Protocol 27201-89 n=64 (8 weeks) Dose Response Studies OTC Pravachol 10 mg: Percent Reduction in LDL-C (mg/dl) ± SE Maintained in OTC Environment 17% 18% 14 16 Consumer Use Studies 8 weeks 24 weeks PREDICT OTC Subjects (n=253) 83% of OTC subjects reach NCEP goal p  0.001 vs placebo

30. AA-3-30 PREDICT Extension: OTC Compliance Maintained at 1 Year OTCRx Qualifiedn=315Qualifiedn=315 On Drug at Week 48 52% 52% Qualifiedn=405Qualifiedn=405 53% 53%

31. AA-3-31 PREDICT Extension Reduction in LDL-C Maintained at 1 Year (Extension Population) OTC n=186 Rx n=244 Week 8Week 24Week 48 0% 10% 20% 30%

32. AA-3-32 PREDICT Behavior to Follow-Up with a Physician at One Year (Extension Population) OTC n=186 Rx n=244 Consulted Prior to D/C Did Not Consult at 1 Year or Prior to D/C Discontinued and Consulted at 1 Year Completed 48 ± 6 Weeks and Consulted at 1 Year 85 86 2 1

33. AA-3-33 Summary of PREDICT OTC Behavior In the OTC Environment 1,925 people exposed to OTC Pravachol 10 499 (25%) bought and took drug 414 (83%) consulted with MD and adjusted behavior correctly For people whose doctor recommended OTC Pravachol 10 –52% still on drug at 48 weeks and received meaningful LDL-C reduction; similar compliance to Rx group

34. AA-3-34 OTC Pravachol Trial In an Observed Naturalistic Setting (OPTIONS)

35. AA-3-35 OPTIONS Study Design and Objectives Conducted in 20 communities in 6 states Participants able to purchase Pravachol 10 in their own pharmacies Observe behavior for 3 months HMO populations allowed access to patient charts for verification of data in a real world setting Assess: –Physician consultation within 2 months of product use –Appropriate self-selection:  No CHD, DM, liver disease or pregnancy  Not currently taking Rx lipid lowering medication –Safety

36. AA-3-36 OPTIONS Advertising and Pharmacy Site Characteristics Generalizable –Site placement accessible to diverse populations –Advertisement mailed to non-targeted sample Natural –Posters and floor stands placed to attract walk-thru –Commercial looking advertising –Participants could purchase –No contact for 3 months

37. AA-3-37 OPTIONS Exclusion Criteria < 18 years Research study participation  30 days HMO member  6 months Pregnant or breastfeeding

38. AA-3-38 OPTIONS Results: Baseline Characteristics of Participants Responding to Advertisement

39. AA-3-39 OPTIONS Participant Disposition Walk-thru(n=414) Mailer(n=355) Other(n=13) Walk-thru(n=414) Mailer(n=355) Other(n=13) Enrolledn=782Enrolledn=782 Received Recruitment Mailer n=161,322 n=161,322 Came to Pharmacies n=2,207 n=2,207

40. AA-3-40 OPTIONS Participants Responding to Advertisement Demographics OPTIONS Participants Responding to Advertisement Demographics (Enrolled Population n=782) (%) Mean age (yr.  SD) 51  10  75 1 Age group  35 5 35-5458 55-7435 Gender 46Male Female54 Race Black21 Hispanic5 Other5 68Caucasian  9th Grade Literacy 12

41. AA-3-41 Visit MD at least yearly96 OPTIONS Participants Responding to Advertisement Health Care Status / Cholesterol Action OPTIONS Participants Responding to Advertisement Health Care Status / Cholesterol Action (Enrolled Population n=782) (%) See MD specifically for cholesterol31 Discussed cholesterol with MD within last 6 months Taking Rx medication Taking non-prescription therapies Cholesterol Action 16 26 70 Cholesterol elevated  5 years 23 Health Care Status

42. AA-3-42 OPTIONS Physician Office Activities Participant decision to make appointment Participants saw their own primary care physicians HMO setting enabled physician verification of: –CHD risk factors –Consultation

43. AA-3-43 OPTIONS Results: Consumer Behavior

44. AA-3-44 OPTIONS Purchase Population was Appropriate Of 782 enrolled participants, 404 purchased Reasons for non-purchase: –47% wanted to consult MD –20% recognized label warnings Of those who purchased: –95% free of CHD, 90% free of diabetes –Of subjects with lab values in chart:  89% had total cholesterol  200 mg/dl  79% had LDL-C  130 mg/dl

45. AA-3-45 0 10 20 30 40 50 60 70 % of Subjects OPTIONS Behaviors of Purchase Population (n=404) Consulted Within 2 Months 44 Did Not Consult / Did Not Appropriately Self-select 7 Consulted After 2 Months 5 12 Did Not Consult / Did Not Take Did Not Consult / Appropriately Self-selected 93% No CHD, DM or liver disease Not pregnant or on Rx medication 32%

46. AA-3-46 OPTIONS Profile of Participants Who Took Without Consulting OPTIONS Profile of Participants Who Took Without Consulting (n=157) 157 participants took without consulting –82% were not at high risk –75% discussed cholesterol with physician within prior 6 months –90% had Total-C  200 mg/dl Incidence of adverse events similar to those who consulted

47. AA-3-47 OPTIONS Safety Safety Profile Maintained –No deaths reported –No serious adverse events related to Pravachol –No transaminase abnormalities –Most common reason for discontinuation was nausea and dizziness in 1% of participants Safety of OTC environment demonstrated –99 participants enrolled were taking prescription therapy at baseline: 11% “shifted” to OTC

48. AA-3-48 Summary of the Pravachol Consumer Use Program Comprehension of the OTC label was evaluated with special attention to the low literacy population Identification of the OTC consumer and evaluation of OTC behavior has been assessed in large and varied populations by different study designs that allowed real world behavior Monitoring will continue after approval

49. AA-3-49 Characteristics of OTC Purchase Population Are Consistent Across Studies 74 PREDICT (n=720) (%) 79 OPTIONS (n=404) (%) Taking Non-Prescription Therapies 712Taking Prescription Therapy 2325 See MD Yearly8297 LDL-C  130 mg/dl * 8789 Total-C  200 mg/dl * *Based on purchasers with available laboratory data. 9190Told of High Cholesterol

50. AA-3-50 Summary of Results Pravachol 10 mg can be used appropriately in an OTC environment Consumers understand label communications The physician remains involved initially and over time The profile of safety and biologic activity is maintained OTC availability does not significantly shift people from prescription therapy OTC availability can serve as a gateway for increased utilization of appropriate therapy