DRAFT SLIDES FOR NDA 21-213 ADVISORY COMMITTEE PRESENTATION

1. DRAFT SLIDES FOR NDA 21-213 ADVISORY COMMITTEE PRESENTATION

2. Joint Advisory Committee Meeting on OTC Availability of Lovastatin 10 mg Actual Use Trials Andrea Leonard-Segal, M.D. Division of OTC Drug Products

3. Outline • 3 Actual Use Trials • Self-Selection and Compliance issues (trial 076) • Compliance issues (trial 079) • Self-selection and safety (trial 081)

4. Actual Use Studies Background • Simulate OTC Use of a Product • Exclusion criteria: The fewer the better! • Self-selection: Are people choosing product properly based on indications and contraindications? • Compliance: Are dosing and duration of use according to directions? • Safety: What are the adverse experiences? • Efficacy information often limited by open-label, uncontrolled design

5. Actual Use Issues for Lovastatin • Cholesterol: • Do people know their values? • Do they understand TC, LDL-C, and HDL-C? • Do they understand when to treat? • What is the treatment goal and do consumers understand it?

6. Actual Use Issues (Continued) • Cholesterol Measurement: • Can OTC desktop cholesterol screening offer accurate cholesterol measurement? • What is the appropriate duration of fast prior to measurement? • How many measurements should be performed to obtain an accurate value? • If averaging multiple cholesterol values is recommended, can consumers do the math?

7. Actual Use Issues (Continued) • Self-Selection: • Can consumers understand what underlying conditions and concomitant medications put them at safety risk if they take lovastatin? • Do consumers know when they are taking contraindicated drugs? • Do consumers understand when to seek the counsel of a physician?

8. Actual Use Issues (Continued) • Compliance: • Are consumers sufficiently compliant in the OTC setting to derive clinical benefits of lovastatin treatment over the long-term? • Benefit and Risk • Is monitoring needed to determine if there has been a benefit of use as well as no adverse safety events? • Can consumers identify symptoms associated with adverse events?

9. Actual Use Issues (Cont’d) • Label: • Can a label adequately convey all necessary information about lovastatin so it can be used properly?

10. Inclusion Criteria Common to Trials 076, 079, 081 • TC = 200-240 mg/dl • LDL-C  130 mg/dl • HDL-C was not an inclusion criterion

11. Exclusion Criteria Common to Trials 076, 077, 081 • Current or recent (< 2 months) participation in drug study • Allergy to lovastatin • Current or Hx liver disease • Contraindicated drugs • Other cholesterol medication

12. Exclusion Criteria Common to 076, 079, 081 (Cont’d) • Hx heart disease • FHx MI before age 55 (parents, siblings) • Pregnant, breast-feeding, childbearing potential • Inability to read English • HDL-C was not an exclusion criterion

13. Sponsor’s Definitions • Persistence = # (%) of subjects who returned for a follow-up visit having taken any of the study tablets • Compliance was calculated in persistent subjects and was defined as: • # tablets taken/# days drug taken during specified time period • Expressed as a percentage

14. Open-label Uncontrolled Multicenter (pharmacies) 24-week (4 visits) “Extension trial” option To Evaluate: LDL-C Self-selection Compliance Adverse experiences Study Design - 076

15. Criteria - 076 • Inclusion (as described) plus: • Age: • Men  45; women  55 • General good health; no disabling disease • Low-fat diet during previous year • Exclusion (as described) plus: • Corticosteroid use • Peripheral vascular disease •  3 alcoholic beverages/day most days

16. Label - 076 • “Pharmacy” Label: • Lists Inclusion-Exclusion criteria • Did not list all interactive medications • 1 tablet qhs • Retest cholesterol after 8 weeks and contact study doctor if level did not decrease

17. Recruitment via ads Review “Pharmacy” label and make self-selection decision Complete Hx form Pharmacist triage: potentially qualified or not Cholesterol test ( 2-hr fast) Qualified received study drug Study Design - 076

18. Study Design - 076 • Return visits: • count returned pills • record adverse events • lipid profile • new drug at visits 2, 3

19. Results - 076 (Self-Selection) • 722 (12%) of all 6095 study participants qualified to receive drug • 981 (16%) of study participants self-selected to obtain and use the drug • Only 119 (12%) of this self-selection group actually received drug

20. Results - 076 (Self-Selection) • 6081 completed self-selection process • 82% needed more than “Pharmacy” label to decide whether to obtain drug • 53% thought they met criteria for TC level, but did not • No information about how well consumers understood the meaning of the components of the lipid profile

21. Results - 076 (Self-Selection) • 5% who were likely to buy lovastatin were in “safety risk” group • Liver disease (72) • Prohibited medications as per label (44) • Pregnancy risk (3) • Allergic to lovastatin (8)

22. Results - 076 (Compliance) • Completion, Persistence and Compliance: • 523/722 (72%) completed the study • 504/722 (69%) were persistent at last visit (Visit 4) • 441/722 (61%) were taking  75% of medicine at Visit 4 • No diary, so precise information about how people actually dosed is unavailable.

23. Multicenter Open-Label Uncontrolled Storefront 8 weeks “Extension trial” option To test: Mean change in LDL at 8 weeks Ability of consumers to remain on lovastatin Tolerability of lovastatin as measured by AE incidence Study Design - 079

24. Study Design - 079 • Recruitment via ads • Telephone history screening

25. Criteria • Inclusion (as described) plus: • men  40; women  55 • Exclusion (as described) plus: •  3 alcoholic beverages most days; diabetes; angina; peripheral vascular disease; TIA; stroke; invasive procedures (PTCA, CABG); taking >1 BP drug; diastolic BP  100 or systolic BP  180 mm/Hg; subjects who knew their TC was < 190 mg/dl or > 250 mg/dl; corticosteroids

26. Study Label - 079 • “Restricted Access” Label • Designed to reinforce appropriate post-purchase behavior, not to guide self-selection • Contained trial inclusion and exclusion criteria • More expansive list of contraindicated medications than “Pharmacy” label • Recommended seeing doctor at least yearly to discuss cholesterol treatment plan

27. Study Design - 079 • Storefront appointment for potentially eligible (Visit 1) • Lipid profile (6-hour fast) • BP • Weight, Height • Eligible received drug with “Restricted Access” label and study information card

28. Study Design - 079 • Visit 2 (approximately week 8) • Lipid profile (6-hour fast) • Collect remaining drug tablets • Adverse experience information collected

29. Results - 079 • 4878 called telephone number • 1312 (27%) potentially eligible and visited storefront • 60% of these were not qualified (cholesterol) • 460 (9%) received study drug

30. Results - 079 • Persistence and Compliance • 363 people took some drug (were persistent) • 265 were compliant at least 75% of the time over the 8-week study • No diary, so precise information about how people actually dosed is unavailable. • Trial did not test the ability of consumers to properly self-select

31. Study Design - 081 • Open-label • Uncontrolled • Multicenter • Storefront clinical sites • 4 Weeks • “Extension trial” option

32. Study Design - 081Objectives • To test: • Effectiveness of an enhanced “Red Arrow” label & reinforcement tools (videotape, pamphlet, insert) • Effectiveness of these in 3 risk subsets: • drug risk • 1° prevention subjects (cholesterol > 240 mg/dl) • high cardiovascular risk group • Tolerability of lovastation 10 mg as measured by incidence of adverse events.

33. Criteria • Inclusion • Men  40; women  1 year post-menopausal • Express interest in purchasing lovastatin • Exclusion • Employed in healthcare • Diabetes • Stroke • Taking > 1 anti-hypertension drug • Participated in cholesterol lowering study < 2 years

34. Label - 081 • “Red Arrow” label • Flip-up back panel design • Warnings emphasized with red arrows and stop signs • Examples of muscle pain, tenderness or weakness added to drug interaction warnings • “Warnings” precede “who should use” • Boxed warning to “carefully read package before self-selecting and call a product specialist for help understanding the label”

35. Study Design - 081 • Recruitment via ads • Visit 1 - Storefront site: • Participants read product concept & label; then made self-selection decision • If “yes” paid $15 for lovastatin 10 mg and answered specific safety risk questions • Contraindicated meds • Current liver disease • Childbearing potential • Allergy to lovastatin

36. Study Design - 081 • If participant self-selected, “yes,” but was excluded for safety risk: • 2nd chance to review label and reinforcements and to make self-selection decision • No drug was provided

37. Study Design - 081 • Cholesterol test offered to those who needed before could self-select, then: • Repeat self-selection decision • Answered safety risk questions • Medical Hx performed on all who left storefront site without drug: • Self-selected “no” • Failed safety risk exclusion questions • Did not want to purchase

38. Study Design - 081 • Eligible Participants • Received 4-week supply of open-label lovastatin 10 mg • Were told to take drug according to label

39. Study Design - 081 • Were given incentive to call toll-free # • Those who did were asked medical Hx using screening script (incl-excl criteria) • If deemed inappropriate for drug, were told to: • D/C • return remaining drug and packaging

40. Study Design - 081 • Visit 2 (Week 4) • Returned packaging and unused drug • For those who had not called toll-free #, nurse administered medical Hx and determined appropriateness of Rx • Lipid testing for those interested in extension

41. Results - 081 • 2416 subjects screened overall • 1230 (51%) self-selected, “yes” • 1144 (47%) received drug; 86 did not (safety risk)

42. Results - 081Completed vs Discontinued • 74% completed the 4-week study • Reasons the rest discontinued: • 10% not appropriate (as per medical Hx) • 6% adverse experience • 4% lost to follow-up • 3% returned drug by mail • 2% withdrew consent

43. Results - 081 • Self-selection errors among the 1144: • Heart disease - 22 • Stroke/TIA - 14 • Other cholesterol treatment - 45 • Hypertension 211 (147 on medication) • Hx hepatitis or liver disease - 35 • Alcohol  3/day - 26 • Diabetes - 23

44. Results - 081 (Self-Selection) • 1112/2264 consumers with known medical history said they would purchase • 39% self-selected erroneously after seeing label • Decreased to 22% erroneous self-selection after seeing label + reinforcements • 61% of subjects with known medical eligibility status did not call toll-free # • 36% were ineligible to take lovastatin

45. Results - 081: Safety Group Self-Selection Errors After Label • Safety risk group = 120 participants • 83 took interacting medication • 30% self-selected incorrectly to take lovastatin • 16 < 1 year postmenopausal • 50% self-selected incorrectly • 14 - current liver disease • 36% self-selected incorrectly • 8 - allergic • 13% self-selected incorrectly

46. Results - 081: Cardiovascular Self-Selection Error After Label) • 381 subjects with cholesterol > 240 mg/dl as only contraindication • 46% self-selected incorrectly • 262 participants were in high cardiovascular risk categories • 32% self-selected incorrectly to take lovastatin

47. Results - 081 (Safety) • 15% people who received drug had an adverse experience (AE) likely related to lovastatin • 4% discontinued due to drug-related AE • None of 6 serious AE likely to have been study-drug related • Incomplete information because LFTs and CPKs were not done & short duration Rx

48. Conclusions (Overall) • Cholesterol: • Many lack accurate knowledge of their cholesterol values • Trials do not assess if consumers understand LDL-C and HDL-C levels • NCEP guidelines were not used to determine cholesterol values. • Not known if OTC consumers would comply with standard fasting recommendations & >1 blood test prior to use

49. Conclusions • Treatment goal was a lower cholesterol value (not a clinical endpoint) • Appropriateness of that goal and whether consumers understood it was not addressed

50. Conclusions • Self-Selection: • Self-selection errors were common • It was not demonstrated that subjects know when to involve their physicians • Compliance in the OTC setting is less than desired over the short-term