Mevacor 20 mg Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees December 13, 2007 Andrea Leonard-Segal, M.D

Mevacor 20 mgMevacor 20 mgMevacor 20 mgMevacor 20 mg

Joint Meeting Joint Meeting Nonprescription Drugs and Endocrinologic Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committeesand Metabolic Drugs Advisory Committees

December 13, 2007December 13, 2007

Andrea Leonard-Segal, M.D.Andrea Leonard-Segal, M.D.DirectorDirector

Division of Nonprescription Clinical EvaluationDivision of Nonprescription Clinical Evaluation

Joint Meeting Joint Meeting Nonprescription Drugs and Endocrinologic Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committeesand Metabolic Drugs Advisory Committees

December 13, 2007December 13, 2007

Andrea Leonard-Segal, M.D.Andrea Leonard-Segal, M.D.DirectorDirector

Division of Nonprescription Clinical EvaluationDivision of Nonprescription Clinical Evaluation

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Advisory Committee Meeting NDAC/EMDACAdvisory Committee Meeting NDAC/EMDACDecember 13, 2007December 13, 2007

IntroductionIntroduction

• 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

Advisory Committee Meeting NDAC/EMDACAdvisory Committee Meeting NDAC/EMDACDecember 13, 2007December 13, 2007

History of Development Program for History of Development Program for Nonprescription Mevacor 20 mgNonprescription Mevacor 20 mg

History of Development Program for History of Development Program for Nonprescription Mevacor 20 mgNonprescription Mevacor 20 mg


LovastatinLovastatin(10 mg – 80 mg/day)(10 mg – 80 mg/day)

LovastatinLovastatin(10 mg – 80 mg/day)(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)


Rx to OTC Switch ApplicationRx to OTC Switch ApplicationRx to OTC Switch ApplicationRx to OTC Switch Application

• Today is the 3rd 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 3rd 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


Mevacor Switch History: 2000Mevacor Switch History: 2000Mevacor Switch History: 2000Mevacor 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)



• 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



• 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



• 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


2007200720072007

• 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


What We Will and Will Not Address What We Will and Will Not Address TodayToday

What We Will and Will Not Address What We Will and Will Not Address TodayToday

• 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


I’ll Mention Issues for Deliberation I’ll Mention Issues for Deliberation Over the Next Few Slides….Over the Next Few Slides….

I’ll Mention Issues for Deliberation I’ll Mention Issues for Deliberation Over the Next Few Slides….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)


LDL-C Paradigm and Total-C Paradigm LDL-C Paradigm and Total-C Paradigm Target PopulationsTarget Populations

LDL-C Paradigm and Total-C Paradigm LDL-C Paradigm and Total-C Paradigm Target PopulationsTarget 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


Liver Function Test MonitoringLiver Function Test MonitoringLiver Function Test MonitoringLiver 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


Liver and StatinsLiver and StatinsLiver and StatinsLiver 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


Muscle WarningMuscle WarningMuscle WarningMuscle 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


Lovastatin and PregnancyLovastatin and PregnancyLovastatin and PregnancyLovastatin 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


Pregnancy WarningPregnancy WarningPregnancy WarningPregnancy 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


AmyotrophicAmyotrophic Lateral SclerosisLateral Sclerosisand Statins?and Statins?

AmyotrophicAmyotrophic Lateral SclerosisLateral Sclerosisand Statins?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


Self-Selection (SS)Self-Selection (SS)Self-Selection (SS)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


Self-SelectionSelf-SelectionSelf-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


Actual UseActual UseActual UseActual 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 thelabeling 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 thelabeling differences


2006 NDAC Meeting on Consumer 2006 NDAC Meeting on Consumer Study Design IssuesStudy Design Issues

2006 NDAC Meeting on Consumer 2006 NDAC Meeting on Consumer Study Design IssuesStudy Design Issues

Led to Change in SS Analysis Approach

Led to Change in SS Analysis Approach


SS Analysis Approach to CUSTOM In SS Analysis Approach to CUSTOM In 20052005

SS Analysis Approach to CUSTOM In SS Analysis Approach to CUSTOM In 20052005

• 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


NDAC 2006: Prioritize Label NDAC 2006: Prioritize Label Elements - Create HierarchyElements - Create HierarchyNDAC 2006: Prioritize Label NDAC 2006: Prioritize Label Elements - Create HierarchyElements - 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


Mevacor HierarchiesMevacor HierarchiesMevacor HierarchiesMevacor 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


Issue for TodayIssue for TodayIssue for TodayIssue for Today

Does lovastatin 20 mg meet the regulatory requirements for nonprescription marketing?

Does lovastatin 20 mg meet the regulatory requirements for nonprescription marketing?


Regulatory Requirements for Regulatory Requirements for Nonprescription MarketingNonprescription Marketing

Regulatory Requirements for Regulatory Requirements for Nonprescription MarketingNonprescription Marketing


1951 Durham Humphrey Amendment to 1951 Durham Humphrey Amendment to the Food, Drug and Cosmetic Actthe Food, Drug and Cosmetic Act

1951 Durham Humphrey Amendment to 1951 Durham Humphrey Amendment to the Food, Drug and Cosmetic Actthe 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


Prescription to Nonprescription Prescription to Nonprescription Switch ConsiderationsSwitch Considerations

Prescription to Nonprescription Prescription to Nonprescription Switch ConsiderationsSwitch 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?


AgendaAgendaAgendaAgenda

• Merck• Break• FDA• Lunch• Open Public Hearing• Discussion/Questions

• Merck• Break• FDA• Lunch• Open Public Hearing• Discussion/Questions

Documents

Mevacor 20 mg Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees December 13, 2007 Andrea Leonard-Segal, M.D