Mevacor Daily ® Merck NDA Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Advisory Committee Meeting Silver Spring, Maryland December 13, 2007 Linda Hu, M.D. Division of Nonprescription Clinical Evaluation Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Advisory Committee Meeting Silver Spring, Maryland December 13, 2007 Linda Hu, M.D. Division of Nonprescription Clinical Evaluation Center for Drug Evaluation and Research

NDAC December 13, 2007 Self Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT)

NDAC December 13, OverviewOverview Regulatory Background SELECT Labeling Paradigms SELECT Study Design SELECT Results –Analyses of Mitigations –Analysis Of Eligibility Criteria Subsets (Hierarchies) –Analysis Of User Population Summary Regulatory Background SELECT Labeling Paradigms SELECT Study Design SELECT Results –Analyses of Mitigations –Analysis Of Eligibility Criteria Subsets (Hierarchies) –Analysis Of User Population Summary

NDAC December 13, Regulatory Background Initial submission 1999 Response to October 2000 non-approval letter, which included –CUSTOM actual use study, “A Consumer Use Study of Over-The-Counter MEVACOR” –Label comprehension study –Other efficacy data and safety data Led to non-approval letter in February, 2005 Initial submission 1999 Response to October 2000 non-approval letter, which included –CUSTOM actual use study, “A Consumer Use Study of Over-The-Counter MEVACOR” –Label comprehension study –Other efficacy data and safety data Led to non-approval letter in February, 2005

NDAC December 13, CUSTOM Actual-Use Study 10% of CUSTOM users correctly self-selected –Required criteria age, LDL-C, CHD risk factors, absence of certain conditions (conditions = liver disease, high triglycerides, history of statin-induced muscle pain) 54% (571/1059) of CUSTOM users considered appropriate by sponsor –416 said they talked to their doctor 10% of CUSTOM users correctly self-selected –Required criteria age, LDL-C, CHD risk factors, absence of certain conditions (conditions = liver disease, high triglycerides, history of statin-induced muscle pain) 54% (571/1059) of CUSTOM users considered appropriate by sponsor –416 said they talked to their doctor

NDAC December 13, Deficiencies in Feb 2005 Non Approval Letter Concern about inability of consumers, on their own, to make decisions on the appropriateness of statin therapy for their own personal use Remaining safety concerns –Use by pregnant women and women of childbearing potential –Compliance with muscle pain warning –Use by patients with asymptomatic liver disease Concern about inability of consumers, on their own, to make decisions on the appropriateness of statin therapy for their own personal use Remaining safety concerns –Use by pregnant women and women of childbearing potential –Compliance with muscle pain warning –Use by patients with asymptomatic liver disease

NDAC December 13, Recommendations from Feb 2005 Non Approval Letter A self-selection/use study or studies Label comprehension studies Address the risk in subjects with asymptomatic liver disease A self-selection/use study or studies Label comprehension studies Address the risk in subjects with asymptomatic liver disease

NDAC December 13, 2007 SELECT Study Label Paradigms LDL-C Label Total-C Label Total-C Label LDL-C Label Total-C Label Total-C Label

NDAC December 13, LDL-C Label Target Population Males ≥ 45 years; females ≥ 55 years LDL in range mg/dL One or more additional cardiac risk factors Males ≥ 45 years; females ≥ 55 years LDL in range mg/dL One or more additional cardiac risk factors

NDAC December 13, Cardiac Risk Factors Cigarette smoking Hypertension or on BP medication Family history of premature CHD (below age of 55 years in a male parent or sibling or below 65 in female relative) HDL-C < 40 mg/dL Age (men > 45 years, women > 55 years). Cigarette smoking Hypertension or on BP medication Family history of premature CHD (below age of 55 years in a male parent or sibling or below 65 in female relative) HDL-C < 40 mg/dL Age (men > 45 years, women > 55 years).

NDAC December 13, Total-C Label Target Population Total-C in range mg/dL Males –> 45 years Females –HDL < 60 mg/dL –> 55 years –One or more additional cardiac risk factors Total-C in range mg/dL Males –> 45 years Females –HDL < 60 mg/dL –> 55 years –One or more additional cardiac risk factors

NDAC December 13, SELECT Label Paradigms Label should be consistent with NCEP ATP III guidelines LDL-C label conforms better to ATP III than Total-C label Focus on results from LDL-C label arm Label should be consistent with NCEP ATP III guidelines LDL-C label conforms better to ATP III than Total-C label Focus on results from LDL-C label arm

NDAC December 13, NCEP ATP III Guidelines <

NDAC December 13, 2007 (SELECT)(SELECT) Self Evaluation of Lovastatin to Enhance Cholesterol Treatment Study Design and Study Population

NDAC December 13, SELECT Self-Selection Study How many consumers will decide correctly that Mevacor is OK for them to use (“self- selection”)? Study should be naturalistic How many consumers will decide correctly that Mevacor is OK for them to use (“self- selection”)? Study should be naturalistic Self-selection: A decision by a consumer whether or not to choose a product for use based on two things: (1) his or her unique medical history and (2) the product labeling.

NDAC December 13, SELECT Self-Selection Study Consumers were asked –Self-assessment (SA) question –Purchase decision (PD) question –Reasons why, if incorrect Subjects randomized to two labels –LDL-C –Total-C Consumers were asked –Self-assessment (SA) question –Purchase decision (PD) question –Reasons why, if incorrect Subjects randomized to two labels –LDL-C –Total-C Focus on LDL-C

NDAC December 13, Focus on Self-Assessment Purchase Decision is influenced by potentially confounding economic and marketing issues –cost –consumer appeal of product Our interest is in whether the consumer understands –who should use –why should one use –how to use Purchase Decision is influenced by potentially confounding economic and marketing issues –cost –consumer appeal of product Our interest is in whether the consumer understands –who should use –why should one use –how to use

NDAC December 13, Directions Prior to Self-Assessment Question Participants were told –The product is not appropriate for everyone –You will be asked whether the product was appropriate for you –You will be asked whether you wish to purchase –Concentrate and to take as much time as needed Participants were told –The product is not appropriate for everyone –You will be asked whether the product was appropriate for you –You will be asked whether you wish to purchase –Concentrate and to take as much time as needed

NDAC December 13, Self-Assessment (SA) “Based on this label, is this product appropriate for you to use right now or not?” –Yes –No –Other (unsure or wanted to ask a doctor) “Based on this label, is this product appropriate for you to use right now or not?” –Yes –No –Other (unsure or wanted to ask a doctor)

NDAC December 13, Purchase Decision (PD) “Would you like to pay for this right now for your own use or put it back in the display?” If the participant wants to purchase, then ask, “Is there anything you plan to do before you start using it?” “Would you like to pay for this right now for your own use or put it back in the display?” If the participant wants to purchase, then ask, “Is there anything you plan to do before you start using it?”

NDAC December 13, RecruitmentRecruitment Recruitment by mass media advertising Ads told subjects to know: –total cholesterol, LDL, HDL, and triglycerides Advertising may have recruited more informed subjects who were better prepared for self-selection Recruitment by mass media advertising Ads told subjects to know: –total cholesterol, LDL, HDL, and triglycerides Advertising may have recruited more informed subjects who were better prepared for self-selection

NDAC December 13, SELECT: Self-Assessment Population Number of Calls N=5107 LDL-C Paradigm N=767 Number Randomized N=1520 Total-C Paradigm N=753 LDL-C Paradigm after exclusions N=662 Total-C Paradigm after exclusions N=664

NDAC December 13, SELECT Study Population 1520 subjects randomized – typically well educated, middle-class –90% high school graduates and 60% had some college –70% had insurance –14% low literate 1520 subjects randomized – typically well educated, middle-class –90% high school graduates and 60% had some college –70% had insurance –14% low literate

NDAC December 13, Areas Targeted For Improvement in SELECT Decrease the proportion of women <55 Decrease the proportion of women of childbearing potential Decrease the proportion of low CHD risk (<5% risk of CHD in 10 years) Decrease the proportion of women <55 Decrease the proportion of women of childbearing potential Decrease the proportion of low CHD risk (<5% risk of CHD in 10 years)

NDAC December 13, SELECT RESULTS

NDAC December 13, Eligibility Assessment Criteria Age Pregnant or breastfeeding May become pregnant Heart disease Stroke Diabetes Liver disease Listed risk factors Age Pregnant or breastfeeding May become pregnant Heart disease Stroke Diabetes Liver disease Listed risk factors Allergy to drug Lipid-lowering medications Interacting drugs LDL-C HDL-C Grapefruit juice Fasting lipid profile

NDAC December 13, Self-Assessment Results LDL-C Is it appropriate for you? SA population N=662 Not appropriate for me (SA =No) N=448 (68%) N=448 (68%) Appropriate for me (SA =Yes) N=214 (32%) N=214 (32%) Correct 439 (98%) Incorrect 9 (2%) Incorrect 180 (84%) Correct 34 (16%) Correct 473 (71.5%) Incorrect 189 (28.5%)

NDAC December 13, Self-Assessment Results Total-C Is it appropriate for you? SA population N=664 Not appropriate for me (SA =No) N=422 (64%) N=422 (64%) Appropriate for me (SA =Yes) N=242 (36%) N=242 (36%) Correct 414 (98%) Incorrect 176 (73%) Correct 66 (27%) Incorrect 8 (2%) Correct 480 (72%) Incorrect 184 (28%)

NDAC December 13, Mitigations for Incorrect Self-Assessment Some subjects who incorrectly self-selected to use gave open-ended responses that were acceptable and could be “mitigated” –Would talk to doctor –Gave reasonable rationale for treatment –Gave evidence of not understanding the self- assessment question Some subjects who incorrectly self-selected to use gave open-ended responses that were acceptable and could be “mitigated” –Would talk to doctor –Gave reasonable rationale for treatment –Gave evidence of not understanding the self- assessment question

NDAC December 13, MitigationsMitigations Label (# Incorrect) Talk to Doctor Did Not Understand SA Other Mitigations Total Mitigated LDL (n=180)461623*85 Total-C (n=176)301132*73 Almost half of incorrect subjects were mitigated –Talk to doctor was most common reason for mitigation –Cannot verify whether subjects would actually talk to a doctor Other Mitigations –*Reviewers did not agree with 9 mitigations for LDL and 11 mitigations for Total-C

NDAC December 13, Examples of Other Mitigations Made by Sponsor Substitution of Mevacor for current lipid medication without talking to doctor High risk subject who self-selected to use without talking to doctor Self-selected yes when had prior side effects on statins Substitution of Mevacor for current lipid medication without talking to doctor High risk subject who self-selected to use without talking to doctor Self-selected yes when had prior side effects on statins

NDAC December 13, Self-Selection Percent Completely Correct, and Correct After Mitigations Label Self Assessment % Completely Correct % Correct After Mitigations LDL Yes16%~50% Total-CYes27%~50%

NDAC December 13, SELECT RESULTS: ANALYSIS OF ELIGIBILITY CRITERIA SUBSETS HIERARCHIES

NDAC December 13, HierarchiesHierarchies Many eligibility criteria –Difficult to get all eligibility criteria correct –Some criteria of more clinical importance then others New analyses where % correct was calculated for subsets of eligibility criteria (“hierarchies”) Self-assessment hierarchies will be presented Many eligibility criteria –Difficult to get all eligibility criteria correct –Some criteria of more clinical importance then others New analyses where % correct was calculated for subsets of eligibility criteria (“hierarchies”) Self-assessment hierarchies will be presented

NDAC December 13, Hierarchies for LDL-C Arm Self-Selection Results Using ALL Label Criteria –% entirely correct (16%) –% correct after mitigation (~50%) Using “hierarchies” or subsets of label criteria –% correct before mitigation –% correct after mitigation % correct depends on which criteria are used in hierarchy Self-Selection Results Using ALL Label Criteria –% entirely correct (16%) –% correct after mitigation (~50%) Using “hierarchies” or subsets of label criteria –% correct before mitigation –% correct after mitigation % correct depends on which criteria are used in hierarchy

NDAC December 13, Sponsor Safety Hierarchy Pregnant/breast feeding May become pregnant Allergy to lovastatin On interacting medications On lipid-lowering medications Liver problem Pregnant/breast feeding May become pregnant Allergy to lovastatin On interacting medications On lipid-lowering medications Liver problem

NDAC December 13, SAFETY Hierarchy SA=Yes (LDL arm) N=214 Of 2 Pregnant/breastfeeding Correct No N=0 N=214 Of 12 may become pregnant Correct No N=1 N=213 Of 4 allergy to lovastatin Correct No N=0 N=213 Of 12 on interacting medicine Correct No N=3 N=210

NDAC December 13, SAFETY Hierarchy SA=Yes N=210 Of 140 on lipid lowering medicine Correct No N=36 N=174 Of 23 liver problem Correct No N=0 N=174 Percent Correct 81.3%

NDAC December 13, Sponsor Safety Hierarchy Hierarchy LDL (N=214)Total-C (N=242) % Correct Before Mitigation % Correct After Mitigation % Correct Before Mitigation % Correct After Mitigation Sponsor Safety * 81.3%89.3%83.1%90.1% For all eligibility criteria 16% correct Sponsor Safety: Pregnant/breast-feeding, may become pregnant, allergy to lovastatin, interacting medications, lipid lowering medications, and liver problems

NDAC December 13, Eligibility Assessment Criteria Age Pregnant or breastfeeding May become pregnant Heart disease Stroke Diabetes Liver disease Listed risk factors Age Pregnant or breastfeeding May become pregnant Heart disease Stroke Diabetes Liver disease Listed risk factors Allergy to drug Lipid-lowering medications Interacting drugs LDL-C HDL-C Grapefruit juice Fasting lipid profile

NDAC December 13, Sponsor Hierarchies Hierarchy LDL (N=214)Total-C (N=242) % Correct Before Mitigation % Correct After Mitigation % Correct Before Mitigation % Correct After Mitigation Safety * 81.3%89.3%83.1%90.1% Benefit ** 25.7%57.0%41.7%62.4% Safety & Benefit 21.0%52.8% 35.1%58.3% * Pregnant/breast-feeding, may become pregnant, allergy to lovastatin, interacting medications, lipid lowering medications, liver problems ** Age, lipid values (LDL-C or Total-C), and risk factors

NDAC December 13, Other Sponsor Hierarchies Hierarchy LDL (N=214)Total-C (N=242) % Correct Before Mitigation % Correct After Mitigation % Correct Before Mitigation % Correct After Mitigation Benefits w/o Lipid * 65.4%77.1%77.3%88.4% Expanded Benefit ** 40.7%65.9%57.4%77.3% * Age and risk factors ** Age, risk factors, heart disease, stroke, and diabetes, lipid lowering medications

NDAC December 13, FDA Review Team Hierarchies Hierarchy LDL (N=214)Total-C (N=242) % Correct Before Mitigation % Correct After Mitigation % Correct Before Mitigation % Correct After Mitigation #1 * 21.0%52.8%35.1%58.3% #2 ** 17.8%50.9%31.4%57.0% * Age, lipid lowering medications, lipid values, interacting medications, risk factors ** Age, lipid lowering medications, lipid values, interacting medications, heart disease, stroke, diabetes, risk factors

NDAC December 13, HierarchiesHierarchies None of the hierarchies was defined a priori in the study protocol Depending on which criteria are included, the percent correct in the hierarchies before mitigations ranged from 20-80% None of the hierarchies was defined a priori in the study protocol Depending on which criteria are included, the percent correct in the hierarchies before mitigations ranged from 20-80%

NDAC December 13, SELECT RESULTS: Profiles of User Population

NDAC December 13, CHD Risk Profiles SA=Yes LDL-C 10-Year CHD Risk MenWomen Total Men + Women n%n%n% unknown43.2%11.1%52.4% <5%1310.5%4246.7%5525.7% 5-20%5141.1%2224.4%7334.1% >20%1310.4%11.1%146.6% CHD/DM/Stroke1612.9%1213.3%2813.1% Rx Chol. Med %1213.3%3918.2%

NDAC December 13, Women Too Young (<55 yo) LDL arm 391 women were asked the self-assessment question in the LDL arm, 220 (56.3%) were too young. – 13.2% (29/220) self-selected to use Of 391 women asked the SA question, 101 women of all ages self-selected to use –Of these 101 women, ~ 29% were < 55 years old Reasons for their decision were: age is close, lower my cholesterol, family history 391 women were asked the self-assessment question in the LDL arm, 220 (56.3%) were too young. – 13.2% (29/220) self-selected to use Of 391 women asked the SA question, 101 women of all ages self-selected to use –Of these 101 women, ~ 29% were < 55 years old Reasons for their decision were: age is close, lower my cholesterol, family history

NDAC December 13, Pregnant/May Become Pregnant Pregnant (n=4) –1 out of 4: SA=Yes, –sponsor mitigated –reviewers agreed May become pregnant (n=22) –9% (2/22) chose SA=Yes, –sponsor mitigated –reviewers did not agree Pregnant (n=4) –1 out of 4: SA=Yes, –sponsor mitigated –reviewers agreed May become pregnant (n=22) –9% (2/22) chose SA=Yes, –sponsor mitigated –reviewers did not agree

NDAC December 13, Heart Disease (LDL Arm) 48.5% (33/68) with heart disease self-selected yes Subjects at high CHD risk might be undertreated by 20 mg of lovastatin 48.5% (33/68) with heart disease self-selected yes Subjects at high CHD risk might be undertreated by 20 mg of lovastatin

NDAC December 13, Already on Lipid Medications (LDL arm) 140/750 (18.7%) in the self-selection population were already taking lipid- lowering medication 44/140 (31.4%) of these participants self-selected yes 140/750 (18.7%) in the self-selection population were already taking lipid- lowering medication 44/140 (31.4%) of these participants self-selected yes

NDAC December 13, Reasons Why Subjects on Rx Selected Incorrectly The most frequent reasons for choosing to use or purchasing, when the subject was already taking lipid-lowering medication – to replace the prescription medication –specifically to replace it because of lower cost The most frequent reasons for choosing to use or purchasing, when the subject was already taking lipid-lowering medication – to replace the prescription medication –specifically to replace it because of lower cost

NDAC December 13, Substitution Rate of OTC for Rx Medications CHD Reported Action LDL-C (N=27) N(%) Take along with it8 (29.6%) Take in place14 (51.9%) Don’t know1 (3.7%) Other3 (11.1%) Missing1 (3.7%)

NDAC December 13, Reasons for Preferring OTC Med Rather than Rx Med for Cholesterol The most frequent reasons for preferring OTC medications, for those who self-selected yes : –less expensive (50%) –convenience (29%) –don’t have to see the doctor (15%) –feels safer/less side effects (11.3%) The most frequent reasons for preferring OTC medications, for those who self-selected yes : –less expensive (50%) –convenience (29%) –don’t have to see the doctor (15%) –feels safer/less side effects (11.3%)

NDAC December 13, High Risk, CHD, Diabetes, Stroke: LDL-C arm On average, ~30% of subjects with CHD, DM or stroke wanted to buy 2/3 of these subjects were not on any lipid- lowering medications On average, ~30% of subjects with CHD, DM or stroke wanted to buy 2/3 of these subjects were not on any lipid- lowering medications

NDAC December 13, What Medications Would Be Substituted: LDL arm

NDAC December 13, Knowing LDL-C versus Total-C In the LDL-C arm, 37.5% (268/714) did not know their LDL-C, whereas in the Total-C arm, 21% (149/708) did not know their Total-C. Of those who did not know their cholesterol numbers –LDL-C: 22.4% ( 60/268) self-selected yes –Total-C: 17.4% (26/149) self- selected yes In the LDL-C arm, 37.5% (268/714) did not know their LDL-C, whereas in the Total-C arm, 21% (149/708) did not know their Total-C. Of those who did not know their cholesterol numbers –LDL-C: 22.4% ( 60/268) self-selected yes –Total-C: 17.4% (26/149) self- selected yes

NDAC December 13, Ineligible Subjects for Lipid Values Many of the subjects who had LDL outside the eligible range nevertheless selected yes in the LDL-C arm –43% (52/122) of subjects w/ LDL-C too high (above 170) self-selected yes –17% (26/153) of subject whose LDL-C too low (below 130) self-selected yes Many of the subjects who had LDL outside the eligible range nevertheless selected yes in the LDL-C arm –43% (52/122) of subjects w/ LDL-C too high (above 170) self-selected yes –17% (26/153) of subject whose LDL-C too low (below 130) self-selected yes

NDAC December 13, SELECT Summary ~20% self-selected yes entirely correctly –With mitigations, % correct ~ 50% Only 4 pregnant women in the study Of those who may become pregnant –2/22 (9%) were incorrect (SA=Yes) ~ 30% of participants with CHD, diabetes mellitus, or stroke wanted to buy –2/3 were not on cholesterol medications ~20% self-selected yes entirely correctly –With mitigations, % correct ~ 50% Only 4 pregnant women in the study Of those who may become pregnant –2/22 (9%) were incorrect (SA=Yes) ~ 30% of participants with CHD, diabetes mellitus, or stroke wanted to buy –2/3 were not on cholesterol medications

NDAC December 13, SELECT Summary (LDL paradigm) ~ 30% of subjects on lipid-lowering medication self- selected to use Of those who would purchase and were on lipid-lowering medication –50% would take Mevacor “in place of” Rx med –30% would take Mevacor along with their Rx Med –The most commonly taken lipid-lowering medications were atorvastatin, simvastatin, rosuvastatin, and lovastatin ~ 30% of subjects on lipid-lowering medication self- selected to use Of those who would purchase and were on lipid-lowering medication –50% would take Mevacor “in place of” Rx med –30% would take Mevacor along with their Rx Med –The most commonly taken lipid-lowering medications were atorvastatin, simvastatin, rosuvastatin, and lovastatin

NDAC December 13, SELECT Summary (LDL paradigm) Those who self-selected to use in the LDL arm included: 101 of 391 women who were asked the SA question – 29% were < 55 years old 13.2% of women < 55 years old 22% of the participants who did not know their LDL-C value 43% of subjects who had LDL too high (above 170) 17% of subject whose LDL was too low (below 130) Those who self-selected to use in the LDL arm included: 101 of 391 women who were asked the SA question – 29% were < 55 years old 13.2% of women < 55 years old 22% of the participants who did not know their LDL-C value 43% of subjects who had LDL too high (above 170) 17% of subject whose LDL was too low (below 130)

NDAC December 13, SELECT Summary 10 -Year CHD risk: LDL-C Label (SA=Yes) 41.1% men were in the targeted CHD risk range –Most men outside the target range were of high risk, CHD equivalent or on lipid lowering meds 24.4% of women were in the targeted range –Most women outside this range were low risk ~11% of men and over 45% of women were of low CHD risk (<5% risk of CHD in 10 years) 10 -Year CHD risk: LDL-C Label (SA=Yes) 41.1% men were in the targeted CHD risk range –Most men outside the target range were of high risk, CHD equivalent or on lipid lowering meds 24.4% of women were in the targeted range –Most women outside this range were low risk ~11% of men and over 45% of women were of low CHD risk (<5% risk of CHD in 10 years)

NDAC December 13, AcknowledgementsAcknowledgements Division of Nonprescription Clinical Evaluation Review Team –Daiva Shetty, M.D. –Joel Schiffenbauer, M.D. –Andrea Leonard Segal, M.D. –Laura Shay, CNP –Stan Lin, Ph.D. –Michael Koenig, Ph.D. –Matthew Holman, Ph.D. –Mary Lewis, PM Division of Nonprescription Clinical Evaluation Review Team –Daiva Shetty, M.D. –Joel Schiffenbauer, M.D. –Andrea Leonard Segal, M.D. –Laura Shay, CNP –Stan Lin, Ph.D. –Michael Koenig, Ph.D. –Matthew Holman, Ph.D. –Mary Lewis, PM