1. Mevacor 20 mg Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees December 13, 2007 Andrea Leonard-Segal, M.D. Director Division of Nonprescription Clinical Evaluation Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees December 13, 2007 Andrea Leonard-Segal, M.D. Director Division of Nonprescription Clinical Evaluation Center for Drug Evaluation and Research

2. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 2 Introduction History of Development Program for Nonprescription Mevacor 2006 NDAC Meeting on Consumer Study Design Issues –Changes in study design approach Regulatory requirements for nonprescription marketing Agenda History of Development Program for Nonprescription Mevacor 2006 NDAC Meeting on Consumer Study Design Issues –Changes in study design approach Regulatory requirements for nonprescription marketing Agenda

3. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 History of Development Program for Nonprescription Mevacor 20 mg

4. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 4 Lovastatin (10 mg – 80 mg/day) Marketed by prescription in U.S. since 1987 Indications: –Adjunct to diet to reduce elevated total cholesterol (Total-C) and low-density lipoprotein cholesterol (LDL-C) adults with 1º hypercholesterolemia adolescents with heterozygous familial hypercholesterolemia –Slow progression of coronary atherosclerosis in patients with coronary heart disease (CHD) Marketed by prescription in U.S. since 1987 Indications: –Adjunct to diet to reduce elevated total cholesterol (Total-C) and low-density lipoprotein cholesterol (LDL-C) adults with 1º hypercholesterolemia adolescents with heterozygous familial hypercholesterolemia –Slow progression of coronary atherosclerosis in patients with coronary heart disease (CHD)

5. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 5 Rx to OTC Switch Application Today is the 3 rd Joint NDAC/EMDAC meeting on this switch application –Original Submission 1999 – AC 2000 –Re-submission 2004 – AC 2005 –Re-submission 2007 Proposed labeling for over-the-counter (OTC) Mevacor has changed substantially from one submission to the next, much data has been submitted and reviewed, and progress has been made along the way Today is the 3 rd Joint NDAC/EMDAC meeting on this switch application –Original Submission 1999 – AC 2000 –Re-submission 2004 – AC 2005 –Re-submission 2007 Proposed labeling for over-the-counter (OTC) Mevacor has changed substantially from one submission to the next, much data has been submitted and reviewed, and progress has been made along the way

6. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 6 Mevacor Switch History: 2000 Application for Mevacor 10 mg product for OTC switch based on a Total-C label paradigm was deficient –Did not establish Consumer use in accordance with National Cholesterol Education Program (NCEP) guidelines Clinical benefit of 10 mg in proposed OTC population That consumers could treat to cholesterol goal –Consumer comprehension and behavior inadequacies –Safety concerns not adequately addressed (e.g., liver, muscle, pregnancy) Application for Mevacor 10 mg product for OTC switch based on a Total-C label paradigm was deficient –Did not establish Consumer use in accordance with National Cholesterol Education Program (NCEP) guidelines Clinical benefit of 10 mg in proposed OTC population That consumers could treat to cholesterol goal –Consumer comprehension and behavior inadequacies –Safety concerns not adequately addressed (e.g., liver, muscle, pregnancy)

7. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 7 Mevacor Switch History: 2005 Mevacor 20 mg product with a new label LDL-C Label Paradigm Target Population –Males ≥ 45 years / Females ≥ 55 years –LDC-C 130 – 170 mg/dL –At least one of these risk factors: Smoking HDL-C 1 – 39 mg/dL Family Hx in father/brother < 55 or in mother/sister < 65 Hypertension Mevacor 20 mg product with a new label LDL-C Label Paradigm Target Population –Males ≥ 45 years / Females ≥ 55 years –LDC-C 130 – 170 mg/dL –At least one of these risk factors: Smoking HDL-C 1 – 39 mg/dL Family Hx in father/brother < 55 or in mother/sister < 65 Hypertension

8. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 8 Mevacor Switch History: 2005 Advisory Committee Agreed: –Proposed nonprescription LDL-C paradigm target population merits statin treatment to lower cholesterol along with an improved diet –Adequate rationale for use of fixed dose lovastatin 20 mg to ↓ cholesterol and heart disease risk in the target population assuming adherence to label Advisory Committee Agreed: –Proposed nonprescription LDL-C paradigm target population merits statin treatment to lower cholesterol along with an improved diet –Adequate rationale for use of fixed dose lovastatin 20 mg to ↓ cholesterol and heart disease risk in the target population assuming adherence to label

9. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 9 Mevacor Switch History: 2005 The Mevacor 20 mg label was tested: –Label Comprehension Study Determined if potential consumers could understand the label information –Consumer Use Study of OTC Mevacor (CUSTOM) Determined if consumers could properly self-select to use the product and then use it according to the labeling Deficiencies in label comprehension, self- selection, and use led to submission of new data that we will consider today The Mevacor 20 mg label was tested: –Label Comprehension Study Determined if potential consumers could understand the label information –Consumer Use Study of OTC Mevacor (CUSTOM) Determined if consumers could properly self-select to use the product and then use it according to the labeling Deficiencies in label comprehension, self- selection, and use led to submission of new data that we will consider today

10. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 10 20072007 Merck modified the 2005 label to address deficiencies Two new label comprehension studies –Pivotal and Muscle Warning –Using two label paradigms LDL-C (same population as in 2005) and a new Total-C paradigm New Self-Selection Study: Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT) using both label paradigms Merck modified the 2005 label to address deficiencies Two new label comprehension studies –Pivotal and Muscle Warning –Using two label paradigms LDL-C (same population as in 2005) and a new Total-C paradigm New Self-Selection Study: Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT) using both label paradigms

11. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 11 What We Will and Will Not Address Today There are issues that have been previously addressed by the committee and subsequently by the Agency that we will not revisit today The purpose of today’s meeting is to consider data in the 2007 resubmission that Merck provided to address issues that remained after the 2005 AC meeting There are issues that have been previously addressed by the committee and subsequently by the Agency that we will not revisit today The purpose of today’s meeting is to consider data in the 2007 resubmission that Merck provided to address issues that remained after the 2005 AC meeting

12. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 12 I’ll Mention Issues for Deliberation Over the Next Few Slides…. 2 Labels: Cholesterol Treatment Paradigms Underlying Liver Disease Muscle Warning Pregnancy Warning Amyotrophic Lateral Sclerosis and Statins Self-Selection Bridging to Actual Use (CUSTOM) 2 Labels: Cholesterol Treatment Paradigms Underlying Liver Disease Muscle Warning Pregnancy Warning Amyotrophic Lateral Sclerosis and Statins Self-Selection Bridging to Actual Use (CUSTOM)

13. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 13 LDL-C Paradigm and Total-C Paradigm Target Populations Today, we will not ask you to address the merits of the OTC target population defined by the LDL-C label paradigm since the target population is unchanged from 2005 and is considered acceptable We do request that the AC consider the merits of the target population defined by the alternative Total-C paradigm label Today, we will not ask you to address the merits of the OTC target population defined by the LDL-C label paradigm since the target population is unchanged from 2005 and is considered acceptable We do request that the AC consider the merits of the target population defined by the alternative Total-C paradigm label

14. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 14 Liver Function Test Monitoring The 2005 committee: –Recommended that baseline liver function testing and liver function monitoring for Mevacor 20 mg were not necessary –Generally found that the risk of liver toxicity with statins was low –Was not excessively concerned with the use of lovastatin 20 mg by those with undiagnosed liver problems The 2005 committee: –Recommended that baseline liver function testing and liver function monitoring for Mevacor 20 mg were not necessary –Generally found that the risk of liver toxicity with statins was low –Was not excessively concerned with the use of lovastatin 20 mg by those with undiagnosed liver problems

15. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 15 Liver and Statins Today we will not ask you to discuss the need for LFT monitoring in those with normal liver function because we are comfortable with the previous committee advice At Agency request, Merck provided additional data on use in those with asymptomatic liver disease. –We request the AC views as to whether those with asymptomatic liver disease can safely use lovastatin 20 mg without LFT monitoring –If not, whether labeling could minimize the risk to this population Today we will not ask you to discuss the need for LFT monitoring in those with normal liver function because we are comfortable with the previous committee advice At Agency request, Merck provided additional data on use in those with asymptomatic liver disease. –We request the AC views as to whether those with asymptomatic liver disease can safely use lovastatin 20 mg without LFT monitoring –If not, whether labeling could minimize the risk to this population

16. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 16 Muscle Warning In the CUSTOM study, 75% of subjects who developed unexplained muscle pain made a correct decision about stopping Mevacor use –FDA requested that labeling be developed to accomplish a higher rate of adherence with the muscle warning and that label comprehension testing should document this improvement Today we would like your views on the comprehension of the new label muscle pain warning In the CUSTOM study, 75% of subjects who developed unexplained muscle pain made a correct decision about stopping Mevacor use –FDA requested that labeling be developed to accomplish a higher rate of adherence with the muscle warning and that label comprehension testing should document this improvement Today we would like your views on the comprehension of the new label muscle pain warning

17. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 17 Lovastatin and Pregnancy Rodents –Fetal skeletal abnormalities occurred at high lovastatin exposures (40 and 80 X human exposure) Reports of congenital anomalies with human use exist, but no causal inference, trend, pattern, or association with lovastatin has been established Category X –Safety has not been established in pregnant women and there is no apparent benefit to therapy during pregnancy –Rx labeling recommends counseling adolescent patients about contraception Rodents –Fetal skeletal abnormalities occurred at high lovastatin exposures (40 and 80 X human exposure) Reports of congenital anomalies with human use exist, but no causal inference, trend, pattern, or association with lovastatin has been established Category X –Safety has not been established in pregnant women and there is no apparent benefit to therapy during pregnancy –Rx labeling recommends counseling adolescent patients about contraception

18. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 18 Pregnancy Warning 2005 Committee –Majority (18/23) thought that lovastatin is not so potentially toxic to the fetus as to prevent nonprescription marketing –All recommended that the pregnancy warning should be improved Today we request your views on the adequacy of the new label pregnancy warning 2005 Committee –Majority (18/23) thought that lovastatin is not so potentially toxic to the fetus as to prevent nonprescription marketing –All recommended that the pregnancy warning should be improved Today we request your views on the adequacy of the new label pregnancy warning

19. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 19 Amyotrophic Lateral Sclerosis and Statins? Today you will hear what is known and not known about whether there is a connection between statin use and ALS We will be interested in your thoughts on what role the state of our knowledge about this issue should have in making a decision about OTC statin availability Today you will hear what is known and not known about whether there is a connection between statin use and ALS We will be interested in your thoughts on what role the state of our knowledge about this issue should have in making a decision about OTC statin availability

20. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 20 Self-Selection (SS) 2005 Committee –Majority felt SS data were insufficient to show that OTC consumers can use lovastatin 20 mg safely and effectively without physician guidance –Expressed concerns about the ability consumers to self-manage their cholesterol with regard to self-monitoring and drug interactions 2005 Committee –Majority felt SS data were insufficient to show that OTC consumers can use lovastatin 20 mg safely and effectively without physician guidance –Expressed concerns about the ability consumers to self-manage their cholesterol with regard to self-monitoring and drug interactions

21. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 21 Self-SelectionSelf-Selection Today we request your views as to whether new data demonstrate that consumers could make an appropriate SS decision giving consideration to: –NCEP Adult Treatment Panel III Guidelines –Framingham CHD risk profile –Those already taking a statin And as a related issue, whether data support adequate comprehension of the muscle pain warning Today we request your views as to whether new data demonstrate that consumers could make an appropriate SS decision giving consideration to: –NCEP Adult Treatment Panel III Guidelines –Framingham CHD risk profile –Those already taking a statin And as a related issue, whether data support adequate comprehension of the muscle pain warning

22. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 22 Actual Use There are differences between the CUSTOM actual use study label and the two labels used in the SELECT self-selection study –We seek your advice as to whether the CUSTOM results on behavior related to LDL follow up testing behavior when muscle pain develops remain meaningful considering the labeling differences There are differences between the CUSTOM actual use study label and the two labels used in the SELECT self-selection study –We seek your advice as to whether the CUSTOM results on behavior related to LDL follow up testing behavior when muscle pain develops remain meaningful considering the labeling differences

23. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 2006 NDAC Meeting on Consumer Study Design Issues Led to Change in SS Analysis Approach

24. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 24 SS Analysis Approach to CUSTOM In 2005 For CUSTOM we applied strict label eligibility criteria to define correct self-selection decision making considering –Each component of the lipid panel –Risk factors for CHD –Contraindications to use 10% correctly self-selected “yes” based upon these criteria After listening to committee member discussion, we wondered if this had been too stringent an analytical approach For CUSTOM we applied strict label eligibility criteria to define correct self-selection decision making considering –Each component of the lipid panel –Risk factors for CHD –Contraindications to use 10% correctly self-selected “yes” based upon these criteria After listening to committee member discussion, we wondered if this had been too stringent an analytical approach

25. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 25 NDAC 2006: Prioritize Label Elements - Create Hierarchy NDAC discussed that it would be reasonable to change SS analyses approach –Pre-define hierarchy of critical label elements based upon risk/benefit….“deal breakers” Consumer must correctly decide whether, based upon these “deal breaker” elements, it is okay for him/her to use the product Correctness for other label elements is optional Prioritizing the label elements can be very difficult Since the NDAC 2006 meeting we have been recommending the hierarchy approach to sponsors of a variety of different types of products NDAC discussed that it would be reasonable to change SS analyses approach –Pre-define hierarchy of critical label elements based upon risk/benefit….“deal breakers” Consumer must correctly decide whether, based upon these “deal breaker” elements, it is okay for him/her to use the product Correctness for other label elements is optional Prioritizing the label elements can be very difficult Since the NDAC 2006 meeting we have been recommending the hierarchy approach to sponsors of a variety of different types of products

26. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 26 Mevacor Hierarchies 2006…Mevacor SELECT and LC studies in progress –Today you will see several post-hoc SS hierarchy analyses Consider what elements could constitute an appropriate hierarchy for statin self-selection 2006…Mevacor SELECT and LC studies in progress –Today you will see several post-hoc SS hierarchy analyses Consider what elements could constitute an appropriate hierarchy for statin self-selection

27. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 Issue for Today Does lovastatin 20 mg meet the regulatory requirements for nonprescription marketing?

28. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 Regulatory Requirements for Nonprescription Marketing

29. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 29 1951 Durham Humphrey Amendment to the Food, Drug and Cosmetic Act Formally differentiates Prescription from Nonprescription Drugs Criteria carve niche for Prescription Drugs: –Drug can be used safely only under supervision because of: drug's toxicity or other potentiality for harmful effect, or method of its use, or collateral measures necessary to its use Otherwise, the drug should be available without a prescription Formally differentiates Prescription from Nonprescription Drugs Criteria carve niche for Prescription Drugs: –Drug can be used safely only under supervision because of: drug's toxicity or other potentiality for harmful effect, or method of its use, or collateral measures necessary to its use Otherwise, the drug should be available without a prescription

30. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 30 Prescription to Nonprescription Switch Considerations Does the product have: –Acceptable safety profile? –Low potential for misuse and abuse? –Reasonable therapeutic index of safety? Can the condition to be treated be self- recognized? When used under OTC conditions is the product safe and effective? Do the benefits outweigh risks in OTC setting? Does the product have: –Acceptable safety profile? –Low potential for misuse and abuse? –Reasonable therapeutic index of safety? Can the condition to be treated be self- recognized? When used under OTC conditions is the product safe and effective? Do the benefits outweigh risks in OTC setting?

31. Advisory Committee Meeting NDAC/EMDAC December 13, 2007 31 AgendaAgenda Merck Break FDA Lunch Open Public Hearing Discussion/Questions Merck Break FDA Lunch Open Public Hearing Discussion/Questions