1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

THE NONPRESCRIPTION DRUGS ADVISORY COMMITTEE

IN JOINT SESSION WITH THE ENDOCRINE AND

METABOLIC DRUGS ADVISORY COMMITTEE

Volume I

Thursday, January 13, 2005

8:00 a.m.

Versailles Ballroom

Holiday Inn

8120 Wisconsin Avenue

Bethesda, Maryland

PARTICIPANTS

Alastair Wood, M.D., Chair

LCDR. Hilda Scharen, M.S.,Executive Secretary

MEMBERS OF THE NONPRESCRIPTION DRUGS ADVISORY

COMMITTEE:

Neal L. Benowitz, M.D.

Terrence F. Blaschke, M.D.

Leslie Clapp, M.D.

Ernest B. Clyburn, M.D.

Frank F. Davidoff, M.D.

Jack E. Fincham, Ph.D.

Ruth M. Parker, M.D.

Sonia Patten, Ph.D.

(Consumer Representative)

Wayne R. Snodgrass, M.D., Ph.D.

Robert E. Taylor, M.D., Ph.D., FACP, FCP

Mary E. Tinetti, M.D.

MEMBERS OF THE ENDOCRINOLOGIC AND METABOLIC DRUGS

ADVISORY COMMITTEE:

Thomas O. Carpenter, M.D.

Sonia Caprio, M.D.

Dean Follman, Ph.D.

Michael R. McClung, M.D.

Steven W. Ryder, M.D.

(Nonvoting Industry Representative)

David S. Schade, M.D.

Morris Schambelan, M.D.

Nelson B. Watts, M.D.

Margaret E. Wierman, M.D.

Paul D. Woolf, M.D.

TEMPORARY VOTING MEMBERS:

Government Employee:

Susan Makris, Ph.D.

Special Government Employee Consultants:

Richard A. Neill, M.D.

James Schultz

(Patient Representative)

PARTICIPANTS (Continued)

FDA:

Jonca Bull, M.D.

Charles Ganley, M.D.

John Jenkins, M.D.

Robert Meyer, M.D.

David Orloff, M.D.

Mary Parks, M.D.

Curtis Rosebraugh, M.D.

C O N T E N T S

Call to Order and Opening Remarks,

Alastair Wood, M.D. 5

Conflict of Interest Statement,

LCDR Hilda Scharen, M.S. 9

Welcome and Comments,

Charles Ganley, M.D. 15

Introduction, Regulatory History and Overview

of Current Proposed OTC Program,

Mary Parks, M.D. 24

SPONSOR PRESENTATION

Introduction,

Edwin Hemwall, Ph.D. 39

Rationale for OTC Lovastatin,

Richard Pasternak, M.D. 46

Mevacor OTC Self Management System,

Jerry Hansen, R.Ph. 72

Actual Use Study Results,

Robert Tipping, M.S. 88

Medical Perspective and Conclusion,

Jerome Cohen, M.D., FACC, FACP 120

Questions from the Committee 135

FDA Presentation

Reproductive and Fetal Toxicity,

Karen Davis-Bruno, Ph.D. 228

Label Comprehension Study,

Laura Shay, RN, M.S., C-ANP 262

CUSTOM--Actual Use Study,

Daiva Shetty, M.D. 281

Nonprescription Simvastatin in the United Kingdom

Michael Koenig, Ph.D. 302

Questions from the Committee 324

P R O C E E D I N G S

Call to Order and Opening Remarks

DR. WOOD: If everyone would take their

seats, we are almost ready to begin. Well, let me

begin by welcoming you all to this committee to

discuss over-the-counter use of Mevacor. I am

going to begin by asking the committee to introduce

themselves, and I guess we will start on this side,

over here.

DR. RYDER: Steven Ryder, from Pfizer

Research, and I am the industry representative on

the Endocrine and Metabolic Advisory Committee.

DR. WOOLF: Paul Woolf, Crozer Chester

Medical Center.

DR. BENOWITZ: I am Neal Benowitz,

University of California, San Francisco, internal

medicine, clinical pharmacology and medical

toxicology, and Nonprescription Drugs Advisory

Committee.

DR. CAPRIO: I am Sonia Caprio, from Yale

University, pediatric endocrinologist.

DR. BLASCHKE: Terry Blaschke, clinical

pharmacology, Stanford University, on the NDAC.

DR. CARPENTER: Thomas Carpenter,

pediatric endocrinology at Yale, and a member of

the Endocrine and Metabolic Advisory Committee.

DR. FOLLMAN: Dean Follman, head of the

statistics group at NIAID, and a member of the

Endocrine and Metabolic Advisory Committee.

DR. DAVIDOFF: I am Frank Davidoff. I am

an internist and Editor Emeritus of Annals of

Internal Medicine. I am on NDAC.

DR. PATTEN: I am Sonia Patten. I am an

anthropoligist on faculty at McAllister College in

St. Paul Minnesota, and I am a consumer

representative on NDAC.

DR. MCCLUNG: I am Mike McClung. I am an

endocrinologist from Portland, Oregon, on the

Endocrine and Metabolic Advisory Committee.

DR. CLYBURN: I am Ben Clyburn. I am an

internist at Medical University of South Carolina,

and I am on the Nonprescription Drugs advisory

Committee.

DR. MAKRIS: Susan Makris. I am a

toxicologist with the Environmental Protection

Agency, Office of Research and Development.

DR. CLAPP: Leslie Clapp, pediatrician

from Buffalo, New York, a member of NDAC.

DR. SHADE: David Schade, University of

Mexico Endocrine Division, and member of the

Endocrine and Metabolic Advisory Committee.

DR. TAYLOR: I am Robert Taylor. I am a

clinical pharmacologist and internist at Howard

University, Washington, and I am a member of the

Nonprescription Committee.

DR. SCHAMBELAN: I am Morris Schambelan,

from the University of California in San Francisco.

I am an endocrinologist and a member of the

Endocrine and Metabolic Drug Committee.

DR. WOOD: Alastair Wood, I am a clinical

pharmacologist from Vanderbilt.

LCDR SCHAREN: I am Hilda Scharen and I am

the Executive Secretary for the Nonprescription

Drugs Advisory Committee, with FDA.

DR. TINETTI: I am Mary Tinetti, from Yale

University, Internal Medicine and Geriatrics, and I

am a Nonprescription Drugs Advisory Committee

member.

DR. WATTS: Nelson Watts, endocrinologist

at the University of Cincinnati, and member of the

Endocrine and Metabolic Drugs Advisory Committee.

DR. NEILL: I am Richard Neill. I am a

family physician on faculty at the University of

Pennsylvania.

DR. WIERMAN: I am Maggie Wierman,

endocrinologist, University of Colorado, and I am

on the Endocrine and Metabolic Drug Advisory

Committee.

MR. SCHULTZ: I am Jim Schultz and I am

just a patient representative.

DR. SNODGRASS: I am Wayne Snodgrass,

clinical pharmacology and medical toxicology and

pediatrics at the University of Texas Medical

Branch, on the NDAC committee.

DR. PARKS: I am Mary Parks. I am Deputy

Director, Division of Metabolic and Endocrinologic

Drug Products, with the FDA.

DR. MEYER: I am Bob Meyer. I am Director

of the Office of Drug Evaluation II, at the FDA.

DR. ROSEBRAUGH: Curt Rosebraugh, Deputy

Director, Division of Over-the-Counter Drug

Products.

DR. GANLEY: Charlie Ganley, I am the

Director of Over-the-Counter Drug Products, FDA.

DR. BULL: Good morning. Jonca Bull,

Director of the Office of Drug Evaluation V in the

Office of New Drugs.

Conflict of Interest Statement

LCDR SCHAREN: I am going to read the

conflict of interest statement. The following

announcement addresses the issue of conflict of

interest and is made a part of the record to

preclude even the appearance of such at this

meeting.

Based on the submitted agenda and all

financial interests reported by the committee

participants, it has been determined that all

interests in firms regulated by the Center for Drug

Evaluation and Research present no potential for an

appearance of a conflict of interest with the

following exceptions:

In accordance with 18 USC 208(b)(3), full

waivers have been granted to the following

participants. Please note that the following

consulting and speaking activities waived are

unrelated to Mevacor and its competing products:

Dr. Michael McClung for consulting for the sponsor

and a competitor for which he receives less than

$10,001 per year per firm; Dr. Morris Schambelan

for consulting with a competitor for which he

receives less than $10,001 per year; Dr. Paul Woolf

for consulting with a competitor for which he

receives less than $10,001 per year; Dr. Margaret

Wierman for being a member of the sponsor's and a

competitor's speaker's bureau for which she

receives between $10,001 and $50,000 per year from

the sponsor and less than $10,001 per year from the

competitor; Dr. Nelson Watts for being an advisory

board member for two competitors for which he

receives less than $10,001 per year per firm; Dr.

Neal Benowitz for consulting with a competitor for

which he receives less than $10,001 per year and

his spouse's stock in the sponsor which is sponsor

which is between $5,001 and $25,000 per year.

A copy of the waiver statements may be

obtained by submitting a written request to the

agency's Freedom of Information Office, Room 12A-30

of the Parklawn Building.

We would also like to note the Dr. Steven

Ryder is participating in this meeting as a

non-voting industry representative acting on behalf

of regulated industry. His function at this

meeting is to represent industry interest in

general and not any one particular company. Dr.

Ryder is employed by Pfizer.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement and their

exclusion will be noted for the record.

With respect to all other participants, we

ask, in the interest of fairness, that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

upon. Thank you.

DR. WOOD: In case any of you missed it,

this is obviously an unusual meeting and I wanted

to begin with summarizing some of the issues here.

We are usually asked on NDAC to consider

the approval of over-the-counter products for the

treatment of symptoms or diseases in patients where

individual patients can identify their symptomatic

problem and self-medicate to treat that problem.

Now, in such a setting the patient can expect that

they will derive benefit, usually symptomatic

relief, from the product that should be obvious to

the patient. Thus, the benefit to an individual

patient should be clear, and the individual

risk-benefit can be assessed both by this advisory

committee and, most importantly, by the patient.

So, they can ask the question how bad is my runny

nose, or how bad is my headache, and does it

justify the risks that are outlined on the package?

The patient can also usually answer the question

did this medicine help, after they have taken it

for some time.

The use of statins OTC is different. Our

justified faith in their efficacy and their

favorable risk-benefit profile is based on

population data showing that populations who

received these drugs and lowered their LDL do

better than similar patients who do not. But

individual patients cannot fully assess their

levels of cardiovascular risk because is not a

symptom, it is a statistical probability.

Additionally, they cannot fully answer the question

did this medicine help that we talked about earlier

since they are practicing preventive medicine.

Thus, in contrast to our usual model,

neither we nor the patient will ever know the

individual patient who benefits from a statin, be

that statin administered to them OTC or by

prescription. But, of course, we always know the

individual patient who suffers an adverse event.

In other words, this represents a new model for OTC

drug use, namely, seeking group benefit while

trying to assess and, of course, minimize

individual risk.

Now, I think understanding that dynamic

should be the overriding issue in our

deliberations. It should inform and direct our

discussions on the decision about the OTC

indications and it was used by the agency in

developing the questions that we will attempt to

answer later.

These questions are designed to force us

to discussion and to force us to come to some

conclusion on whether the benefits of OTC

lovastatin to the group outweigh the risk to the

individual; whether individuals can identify

themselves as appropriate for therapy; and, very

importantly, conversely, whether we think that

individuals at particular risks can be identified

and excluded from therapy; whether the method of

use, including all the self-screening and other

techniques that we will hear exhaustively, I am

sure, about later are appropriate; and, finally,

whether there are additional measures that we think

are required to maximize the benefit and minimize

the risk to patients from this product.

So, these are unusual issues for us to

debate on NDAC where we usually address symptomatic

treatments, and that is why I wanted to try and set

the stage before we start.

Let's get right to the presentations.

Charlie, do you want to start?

Welcome and Comments

DR. GANLEY: Before starting, I just

wanted to thank the members of both advisory

committees and the invited consultants for taking

time out of busy schedules to participate in this

two-day meeting.

I would also like to acknowledge the

efforts of the review staffs and project management

staffs of both the Endocrine and OTC Division for

reviewing the information in a relatively short

time and helping to put together this advisory

committee. As always, we greatly appreciate the

efforts of the advisory and consultant staff who

make all the arrangements to conduct these

meetings. I would also like to acknowledge the

efforts of the sponsor to respond to our questions

in the review process in a very timely manner.

[Slide]

I don't think I can be as eloquent as

Alastair in sort of laying out the issue here, but

this is, indeed, a new model for an OTC drug. It

is designed to treat an asymptomatic disease, which

is not typical for OTC drugs. It requires

long-term compliance to obtain a benefit. It

requires laboratory monitoring for the individual

to assess whether they have had a treatment effect

and then some benefit from therapy. But it also

requires a highly motivated individual to decide to

use the product in the first place according to the

product label for a long period of time.

[Slide]

Now, when I think what are the hurdles for

a drug coming to the OTC market, I usually divide

them into two things: what are the issues related

to the drug and what are the issues related to the

disease? Let me just touch on the drug-related

hurdles for OTC marketing.

The first is really that we have to make

some determination of the assessment of the

relative safety of the drug. What we mean by that

usually is what are the events that we are

concerned about. Almost all drugs in the OTC

market can be associated with serious adverse

outcomes and generally we make efforts to try to

minimize those; how often is this likely to occur,

and are there measures that can be taken to help

decrease this occurrence.

For the drug under review for today, there

have been serious adverse events associated with

therapy, particularly the possibility of serious

muscle injury. There are some questions regarding

what the risk is for liver injury. There also are

populations that may be at increased risk for this,

and can those individuals identify that they may be

at increased risk and make a decision whether they

want to use the product? Included in that are

questions regarding underlying liver disease or

individuals who have asymptomatic, undiagnosed

underlying liver disease. Pregnancy or use by

women of childbearing potential is an issue, and

also potential for drug interactions which could

lead to a possibility of increased risk for serious

muscle injury.

[Slide]

Now, the disease-related hurdles for OTC

marketing are that there are multiple steps for a

consume to assess their eligibility for

self-selection to use the product. It requires

some monitoring and knowledge of their cholesterol

levels. After initiating therapy, is there some

change in risk, such as the addition of a new

medication, that may necessitate the individual to

make a decision that they should stop the drug or

talk to a physician? Most importantly I think,

individuals need to understand, if they are going

to use this drug, that they really need to take it

for long periods of time to derive some benefit.

[Slide]

You are going to hear a lot today about

consumer behavior studies. Members of the

nonprescription committee, or many of them--we have

some new members today--are quite familiar with

some of the terminology. We are going to make

every effort, and I think Merck will probably make

similar efforts, to try to describe these studies

and what we tried to obtain from them.

The first type of study is a labeling

comprehension study, and these are simply studies

where we attempt to understand whether an

individual can comprehend the information on the

labeling. We use the results to adjust the

labeling prior to an actual use study or prior to

marketing the product. The results from these

studies are not always predictive about behavior in

that the consumer understands the labeling but

their behavior will be different in a real-life

setting.

Within the last several years we had an

example of this where we were reviewing a drug that

was clearly associated with significant risk of

drowsiness, and there was clear warning on the

label suggesting that they not drive. In the

labeling comprehension study the individuals

understood this with greater than 90 percent

comprehension but in the actual use study a half to

three-quarters of the individuals drove anyway. I

think what we lose in there is that people still

have their lives and they have to go to work, or

they have to pick up their children, and you don't

get around that by just labeling a product all the

time.

The other type of study is an actual use

study. I am not going to go into great detail. I

think you will hear more about this in Merck's and

FDA's presentations. There are two terms you

should know, one is self-selection. Self-selection

is an individual making a decision whether they are

going to use the product. De-selection is when an

individual has already made a decision to use the

product and they have to decide whether they need

to stop based on a lack of efficacy or the

potential for an adverse event.

[Slide]

The results of consumer behavior

studies--based on literacy and education we really

cannot expect 100 percent success for all the

objectives, and we do develop some hierarchy of

priority in determining what are the most important

things that we are trying to get across. All of us

here will have different thresholds for tolerating

behavior errors. Laura Shay, in this afternoon's

talk, will go into that a little bit. It is really

dependent on the health consequence of the error.

For example, in the case of Mevacor or any other

statin, if an individual develops muscle tenderness

or pain in the muscles we would like them to stop.

If they don't stop they risk potential for serious

injury. In those situations, we would expect

consumers to really understand that concept.

The other question with these types of

studies is that they are not perfect studies. They

are done in settings that are not totally

consistent with how the OTC market works. So,

sometimes it is difficult to extrapolate these data

to an OTC population.

[Slide]

The other thing I want to point out is

that you are going to hear a lot of different

analyses today. The FDA discussion is going to

focus on the "according to label criteria" and

Merck will cover that in addition to multiple other

analyses which I have listed here today. During

the presentations I think it is very important for

the committee to understand what analysis is being

discussed and what the definition of that analysis

is. As far as the committee is concerned, we don't

expect you to remember all these acronyms but we

are going to give you a quiz first thing tomorrow

morning to see if you do remember them!

[Slide]

Who is this product directed to? When you

think about this going into the OTC market the

obvious answer is it is the people with the

criteria on the proposed Mevacor label, but who may

actually use this? It could be any person who fits

the NCEP guidelines for treatment. It could be

simply people who have an interest in their health

and in lowering cholesterol, folks who may eat

cereal because of the potential to decrease your

cholesterol for example, or it could be the United

States population.

[Slide]

Other relevant information--OTC drug

advertising is regulated by the FTC, not by FDA.

This is important because advertising will lead

consumers to look into using this product. During

the course of the actual use study, when the study

was advertised, there was some direction given to

consumers that they could call an 800 number and

they should know their cholesterol. But you can

imagine, through advertising without some specific

details as to what you need to know or what the

risk may be, that you could include a much larger

population.

The other issue is the economic

implications of a switch. When considering a drug

for switch, FDA does not take economic

considerations into account during the decision

process. This doesn't just apply to OTC drugs; it

is also applicable to prescription drugs. So, the

cost of the drug is not an issue and insurance

coverage is not an issue.

So, with those remarks, I think I will

send it over to Dr. Parks who is going to give

another introduction and give some past history and

additional comments. Thanks.

Introduction, Regulatory History and

Overview of Current Proposed OTC Program

DR. PARKS: Good morning, Dr. Wood,

members of the advisory committee.

[Slide]

I will be presenting the regulatory

history of Rx to OTC switch for lipid-lowering

drugs. My presentation will also provide you an

overview of previously submitted applications for

nonprescription lipid-lowering drugs, including the

initial Mevacor over-the-counter proposal and its

deficiencies. I will provide an overview of the

current Mevacor application and, finally, I will

present to you areas for consideration on this

current program.

[Slide]

The first lipid-lowering drug proposed for

nonprescription use was a bile acid sequestrant.

It was thought to be an ideal candidate for

nonprescription use, at least from a safety

perspective. There were two advisory committee

meetings held on this application and the advisory

committee members concluded otherwise.

As a result of the second 1997 advisory

committee meeting, the FDA issued a guidance to

industry on the over-the-counter treatment of

hypercholesterolemia. That document concluded the

following: that hypercholesterolemia is a chronic,

asymptomatic condition requiring accurate diagnosis

and testing and, therefore, this condition should

remain under the directed care of a healthcare

professional. In short, a recommendation was made

that drug treatments for such a condition not be

sold over-the-counter.

[Slide]

In 1999 FDA received two applications

proposing the nonprescription use of a low dose of

two statins. Those statins were lovastatin and

pravastatin, and their applications were presented

at two separate advisory committee meetings in

July, 2000.

[Slide]

The medical OTC program back then proposed

the lowest dose of Mevacor for non prescription

use. This dose was 10 mg. The patient population

targeted included men over the age of 40 and

postmenopausal women. Patients could not have a

history of cardiovascular disease, diabetes or

significant hypertension, and they should not be on

prescription lipid-lowering thera[y. The total

cholesterol targeted was 200-240 and LDL

cholesterol of 130 or greater.

[Slide]

The advisory committee members raised

several issues in this application. For efficacy,

it was noted that the sponsor did not incorporate

current treatment guidelines. In particular, no

treatment goals were defined for the consumer. In

addition, clinical benefit could not be

extrapolated from clinical outcomes data for the

proposed dose of 10 mg and for the target

population. Finally, consumer comprehension was

poor in this program, underscoring the complexities

of treating hypercholesterolemia in the

nonprescription setting.

[Slide]

The safety concerns raised at that

advisory committee meeting were not necessarily

unique to lovastatin but are actually found for

other drugs in this class. For muscle, all statins

have been associated with rare cases of

rhabdomyolysis. Lovastatin is metabolized by

cytochrome P450 3A4 isoenzyme. This is the enzyme

involved in metabolism of multiple drugs.

Consequently, they were concerned that

co-administration with potent 3A4 inhibitors might

increase the risk of myopathy.

For hepatic concerns, all statins have

been associated with increases in hepatic enzyme

levels although these laboratory abnormalities

rarely result in serious clinical sequelae.

However, all statin labels recommend baseline liver

testing and for some testing is recommended

periodically after initiation of therapy. The

sponsor had to address how an over-the-counter

product could be marketed when the prescription

label for that product had recommendations for

routine biochemical safety monitoring.

Another issue raised was that clinical

studies for statins excluded patients with

underlying liver abnormalities, either clinically

diagnosed or chemically diagnosed. Consequently,

the safety of statins in patients with undiagnosed

liver disease had not been addressed.

Finally, all statins are labeled as

pregnancy category X drugs. This means that the

drug is contraindicated for use during pregnancy.

[Slide]

Since the July, 2000 advisory committee

meeting, several important events relevant to a

statin over-the-counter program merit discussion.

The first is that the 1997 guidance to industry was

withdrawn in the year 2001 as it was apparent

during the 2000 advisory committee meeting that

there was potential public interest in making

available safe and effective therapies for the

management of hypercholesterolemia in a

nonprescription setting.

Second, and very much an integral part of

the Mevacor over-the-counter program, was the 2001

publication of the National Cholesterol Education

Program ATP III treatment guidelines.

Recommendations made by the NCEP have established

the clinical practice guidelines for managing

dyslipidemia over the past two decades. These

recent guidelines establish new risk categories,

new goals of therapy, and were subsequently updated

in July, 2004 to recommend even lower LDL treatment

goals in patients with very high risk for a

cardiovascular event.

[Slide]

A detailed discussion of the ATP III

guidelines is beyond the scope of today's

presentation, but the publication of these

guidelines has been provided to all members of the

advisory committee in the background packages.

Relevant to this meeting is that the ATP

III guidelines establish new risk categories for

the treatment of dyslipidemia. These risk

categories identify the LDL cholesterol for which

drug therapy should be initiated. It identifies

the LDL cholesterol goal for which drug therapy

should be targeting. There are essentially three

categories.

The first includes patients who have

established coronary heart disease or CHD risk

equivalents. These are patients who have diabetes,

peripheral arterial disease or clinical

manifestation of atherosclerosis. These patients

are at high risk for cardiovascular events. Their

10-year risk of having a cardiovascular event

exceeds 20 percent.

The second category includes patients who

have two or more risk factors for heart disease.

The NCEP definition for risk factors includes an

HDL that is less than 40, tobacco smoking,

hypertension, a family history of early coronary

disease and age according to gender. This category

of two or more risk factors is considered

intermediate risk for heart disease.

The third category are the low risk

category patients. These are patients who have no

or only one risk factor for heart disease.

While the next two days we will emphasize

drug therapy for hypercholesterolemia, it should be

noted that the ATP III guidelines are

recommendations on a background of lifestyle

changes. The importance of diet, exercise and

lifestyle modification cannot be emphasized enough

in the management of coronary heart disease.

[Slide]

In the current program to be discussed

today the sponsor has proposed Mevacor

nonprescription therapy to the following patient

population, a primary prevention population with

less than or equal to 20 percent 10-year risk of

coronary-heart disease without underlying chronic

conditions that would complicate consumer

self-management. The product label proposes a

consumer select a product according to the

following: Males 45 years or older; females 55

years or older. The age cutoff for women is

intended to exclude all women of childbearing

potential in order to avoid inadvertent exposure in

pregnancy. The LDL cholesterol should be between

130 and 170, and consumers should have at least one

of the following, smoking, HDL of less than 40,

family history of early coronary disease and

hypertension.

The intent of this particular product

label is that if a consumer can actually

self-select appropriately on the first criterion,

that is, age according to gender, they

automatically have one risk factor for

coronary-artery disease. If they then can

self-select appropriately on the third criterion,

that is, having at least one of the following, they

will automatically have two or more risk factors

for coronary heart disease. So, the summary here

is that the target population is actually the two

or more risk category that I described in an

earlier slide based on the NCEP guidelines.

The proposed dose for a nonprescription

prescription lovastatin is a fixed daily dose of 20

mg. There is no recommendation to titrate up or

down to meet treatment goals.

[Slide]

The treatment goal defined in this

population is an LDL less of 130, and this is in

accordance with the NCEP guidelines. The NCEP does

define secondary goals for therapy, for example, if

a patient has hypertriglyeceridemia then non-HDL

might be a second goal of therapy. This was not

incorporated into the program, however, it was

recognized that patients would need to actually

have fasting lipid profiles to follow this, and it

is also very complicated for consumers to

understand secondary goals of therapy.

In order for consumers to actually follow

current treatment guidelines, this proposal

requires that they know the following things:

Consumers need to know their baseline cholesterol

values, and they need to know their cholesterol

values while they remain on therapy. Consumers

also need to know their baseline risk and changes

in health status that might alter the risk-benefit

ratio of continuing lovastatin 20 mg.

[Slide]

You will hear from the sponsor momentarily

how their clinical program addresses the

deficiencies noted in the July, 2000 advisory

committee meeting. For efficacy, the sponsor has

summarized the LDL-lowering results of two

previously submitted clinical studies, EXCEL and

AFCAPS. They also summarized LDL-lowering results

from the actual use study submitted specifically

for this NDA. Based on these results, one can

expect on average a 24 percent reduction in LDL

cholesterol with the lovastatin 20 mg dose.

The clinical benefits of lovastatin 20 mg

were extrapolated from the AFCAPS study. This was

a 5-year placebo-controlled outcome study

evaluating lovastatin 20-40 mg daily, and the

primary endpoint was a composite of unstable

angina, nonfatal MI and coronary-heart disease

death.

[Slide]

For safety, the sponsor approached these

issues by re-evaluating the EXCEL and AFCAPS

database. These two studies provided lovastatin

exposure data from close to 10,000 patients. The

sponsor also evaluated their global post-marketing

safety database from marketing until present. This

is approximately 17 years worth of marketing,

providing approximately 27 million patient-years of

exposure. Although not on this slide, the sponsor

has also reviewed clinical trial safety data for a

similar statin, simvastatin.

[Slide]

The conclusions from these databases, at

least for muscle and liver safety concerns, are the

following: The risk of myopathy and rhabdomyolysis

is extremely low; that the 20 mg dose, if labeled

adequately and understood by the consumer, is an

acceptable dose for over-the-counter use. There is

little to no hepatic risk in patients with normal

hepatic function.

The safety of lovastatin in patients with

asymptomatic liver disease, including viral

hepatitis, was not addressed in well-designed

prospective studies. However, the sponsor has

submitted an abstract of a study in approximately

40 patients and a retrospective study using

lovastatin and other statins in patients with

baseline elevations in liver enzymes. The results

of these studies and the rationale from the sponsor

as to why these data are sufficient to remove any

recommendation for liver monitoring in a

nonprescription setting will be presented by the

sponsor.

Given the small number of patients

evaluated in one study, the retrospective nature of

the other and the exclusion of patients with

certain liver diseases in that study, the FDA finds

these data problematic and difficult to conclude

that patients with any form of asymptomatic liver

disease can initiate lovastatin without periodic

monitoring, at least based on these data submitted.

[Slide]

With respect to pregnancy safety issues,

preclinical studies were conducted and reviewed

under the prescription NDA. You will hear from Dr.

Karen Davis-Bruno the FDA's conclusion on

preclinical studies submitted to that NDA. This

product will retain its category X labeling based

on the following: First, the FDA's interpretation

of these data and, second, based on agreement or an

understanding between the FDA and the sponsor that

the risk of continuing therapy with lovastatin

during pregnancy outweighs any benefit and the drug

should, therefore, remain contraindicated for use

during pregnancy.

A greater concern is the use of lovastatin

in women of childbearing potential who may

subsequently become pregnant while on therapy. Dr.

Davis-Bruno's presentation is to provide the

advisory committee members with background

information to assess whether the risk of

inadvertent exposure during the first trimester of

pregnancy has been adequately addressed. This is

particularly relevant as you hear the results of

the actual use study presented by Dr. Daiva Shetty

and the ability of women of childbearing potential

to make appropriate decisions on the purchase and

use of this product.

[Slide]

Over the course of the day and a half, we

ask that you give consideration to the following:

A critical outcome study of nonprescription

lovastatin use is not practical, and an analysis of

AFCAPS/TexCAPS does represent the best available

data to date for some estimate of clinical benefit

associated with over-the-counter lovastatin 20 mg.

However, several caveats of extrapolating

from this database must be kept in mind. The first

is that this was a post hoc analysis and that some

of the comparisons no longer maintain the

comparison of randomized treatment groups. None of

the subgroups elected by the sponsor fully reflect

the over-the-counter population as AFCAPS included

patients who were titrated to 40 mg and were also

treated to a lower LDL cholesterol goal. Finally,

long-term benefit observed with AFCAPS assumes

adherence to therapy in the over-the-counter

setting.

We must also remember that over time

changes in individuals' health status may occur.

These changes may result in a change in the risk

classification for a patient such that more

aggressive therapy is needed than what lovastatin

20 mg might achieve.

[Slide]

Many of the safety issues will be

addressed primarily through labeling, and the

effectiveness of this approach is evaluated in one

six-month actual use study. Similar to the

efficacy concerns, the impact of changes in health

status and the use of interacting drugs on the

safety of lovastatin over-the-counter must be

considered, particularly in the long term. This

concludes my presentation. Thank you.

DR. WOOD: Thank you very much. Let's

move straight on to Dr. Hemwall's presentation from

the sponsor.

Sponsor Presentation

Introduction

DR. HEMWALL: Advisory committee members,

guests, FDA staff, I am Ed Hemwall, representing

Merck Research Labs and Johnson & Johnson-Merck

Consumer Pharmaceuticals.

[Slide]

Today we will be discussing our new drug

application for nonprescription lovastatin at a

dose of 20 mg a day, with the proposed trade name

of Mevacor Daily, however, throughout today's

discussions and in your written background it is

referred to as Mevacor OTC. The indication we are

proposing for the OTC label is to help lower LDL

"bad" cholesterol, which may prevent a first heart

attack.

[Slide]

As Drs. Ganley and Wood have noted, the

concept of an OTC lipid-lowering drug and the

accompanying self-management system that we propose

represents an unparalleled challenge to the

consumer in the OTC world. But it also represents

an unparalleled opportunity to have an impact on an

important public health problem in the United

States.

Your predecessors on these committees

reviewed an earlier version of this proposal, as

described by Dr. Parks, for the 10 mg dose, in

2000, and they concluded that the benefit of the 10

mg dose was not sufficiently established with

regard to cardiovascular risk reduction and,

although the safety in an OTC setting was generally

accepted, there remained many questions, which Dr.

Parks has noted and which we are prepared to

address today.

Finally, the ability of the consumer to

appropriately self-diagnose and use the product

required further investigation and that is the

cornerstone of our submission to be discussed

today, the CUSTOM study.

So, as noted, a few weeks after the last

meeting in 2000, in part motivated by those

discussions, FDA did lift the negative guidance

which discouraged development of

cholesterol-lowering drugs for over-the-counter use

and this opened the door for a series of

constructive interactions between FDA and J&J-Merck

for approving the OTC labeling approach and the

designs and the objectives of additional consumer

research studies, which we have done, and we are

very appreciative of the guidance we have received.

[Slide]

Since that time, our development team has

conducted extensive research to establish and test

an improved approach to OTC cholesterol management.

We have had input from the Food and Drug

Administration and outside academic experts in the

field of lipid management and primary prevention of

cardiovascular disease. We have increased the

proposed dose to 20 mg and instituted a treatment

to the LDL cholesterol goal approach for our

primary prevention target population that is

consistent with the most current clinical

guidelines established by the National Cholesterol

Education Program.

We conducted a sophisticated actual use

study, called CUSTOM, in which over 3000 consumers

evaluated this OTC option in a naturalistic OTC

setting, and over 1000 consumers elected to

purchase and use the product for up to 6 months.

All this was part of a comprehensive consumer

education and support program which we will review

with you today.

[Slide]

The overriding question which you have

been asked to contemplate today is can an OTC

option enable consumers to have a greater role in

the prevention of cardiovascular disease? In order

to address the question we will examine the OTC

target population and the labeling eligibility

criteria which allow approximation of that

population. We will look at the role of the

Mevacor self-management system and, importantly,

the role of the healthcare professional in

directing and encouraging achievement of

cholesterol goals and heart-healthy behaviors

through a collaborative care approach. Also, the

ability of consumers to act in general accordance

with the label. The criteria that are on the label

are intended to maximize both benefit and safety in

the OTC environment. And, we will look at the

overall benefit-risk relationship for the

individual and, more importantly, for the

population at large.

[Slide]

Our presentation today will be that

following my brief remarks Dr. Richard Pasternak

will discuss the rationale for OTC availability of

a statin drug in this target population and he will

include an overview of efficacy and safety of

lovastatin. Then, Jerry Hansen will provide some

insights generated from our extensive consumer

research and the development of the OTC

self-management system, which is on display over

there and I invite members of the committee, during

the breaks, to take a look at it and also some of

these exact same materials are in your briefing

documents. After Jerry, we will have Bob Tipping

who will review the results of our actual use

studies, with principal focus on the CUSTOM study

which tested the key elements of the

self-management system. Finally, Dr. Jerry Cohen

will complete our presentation with the perspective

of a preventive cardiologist, and the potential

public health impact of increased access to a

statin in a consumer-friendly lipid management

system.

[Slide]

The following slides outline our

consultants whom we have here with us, with

expertise in several topics, who are here today to

provide additional perspective on some of the

questions which may arise during your deliberations

over the next two days. Rather than read through

the entire list of names, we have provided a

complete list of these experts, in handouts printed

on yellow paper, at your seats.

So, that concludes my introduction. I

would now like to introduce Dr. Richard Pasternak.

Dr. Pasternak is a former member of the National

Cholesterol Education Program guidelines panel and

co-author of several associated publications, and

we are really proud to have him now as part of our

Merck clinical research team. He will review the

rationale behind over-the-counter Mevacor.

Rationale for OTC Lovastatin

DR. PASTERNAK: Thanks, Ed.

[Slide]

Good morning, ladies and gentlemen,

members of both panels, the FDA and guests. I am

Richard Pasternak. Prior to joining Merck this

past September, I spent 22 years at Harvard Medical

School in cardiology and preventive cardiology and

that provided me with the kind of opportunities and

privileges to participate in some of the activities

that Ed Hemwall just mentioned.

[Slide]

Given my own strong and long-term interest

in preventing heart disease, I am delighted to be

here today to share with you the rationale for

consumer access to an over-the-counter statin

option. I believe that Mevacor OTC can further our

current efforts in cardiovascular treatment through

improved collaboration between healthcare

professionals and the consumer, resulting in a

potentially significant expansion of prevention of

heart disease in America. I recognize that this

is, as Dr. Wood pointed out in his opening remarks,

a very novel pathway that is being proposed and

that there a number of important and very tricky

issues to consider in the next two days. But, by

the end, I hope that when you look at the strength

and weight of the evidence you will agree that the

benefit and risk arithmetic strongly favors an

option for consumers to have access to OTC Mevacor.

The rationale I plan to review today is

compelling and straightforward. It begins with the

problem, the enormity of the current cardiovascular

public health burden in the United States today in

which huge treatment gaps continue to exist. Next,

I will outline the proposed Mevacor OTC target

population and the well-known product efficacy and

safety information of lovastatin 20 mg. Finally, I

will conclude by discussing the potential for

Mevacor OTC to actually improve public

cardiovascular health, both directly and

indirectly, through increased consumer awareness

action.

[Slide]

The problem is clear and known to everyone

in this room. Cardiovascular disease is the number

one cause of death and disability in the United

States today. If something is not done it will

continue to be our greatest health problem. The

annual number of coronary heart disease events is

over a million per year, with an accompanying

enormous economic impact.

As shown in the graph at the bottom of

this slide, with our aging population our situation

is only going to continue to worsen. In fact, with

our current system it is projected that over the

next 50 years the incidence of coronary heart

disease will double to nearly 30 million.

[Slide]

It is well-known that reducing cholesterol

is one of the most important actions that we can

undertake to reduce the risk of heart disease, and

I could have chosen a number of different figures

to illustrate this but I have taken this figure

from our ATP III update which depicts a log linear

relationship between LDL cholesterol and the

relative risk of coronary heart disease. There is

a well-known and well-accepted relationship between

lowering LDL and risk reduction, such that for each

one milligram/deciliter change in LDL cholesterol

there is roughly a one percent change in risk. New

information now also tells that the lower the LDL

cholesterol, the lower the relative risk even down

to levels below 70 mg/dL.

[Slide]

So, are we making progress in battling

this disease? Well, despite our knowledge of the

importance of cholesterol reduction, we have not

been very successful at the population level. In

fact, over 15 years of advances in treatment

strategies and guidelines we have produced really

minimal, if any, movement in the average total

cholesterol in the United States population. Our

national public health goals, as outlined in

Healthy People 2000, have not even met a relatively

modest goal. And, current data suggests that the

relatively unambitious goal for Healthy People 2010

is also in jeopardy.

[Slide]

Why? Well, there are many reasons for

this problem. One of the major reasons is that

there are minimum number of individuals actually

being treated with cholesterol-lowering therapy.

In 2000, the NHANES data showed us that while we

were doing a pretty good job of getting individuals

tested for their cholesterol, in fact less than a

third to a fifth of people with elevated

cholesterol levels were actually treated, and here

I don't mean treatment with drug therapy only; this

is treatment with either diet or drug therapy.

This isn't due to lack of available therapy or

insufficiently aggressive guidelines.

[Slide]

In fact, our guidelines recommend that a

great number of individuals should, in fact, be

treated. This figure shows estimates of the number

of Americans recommended for treatment by the ATP

III guidelines. Roughly 25 million people are at

high risk or already have heart disease and are in

need of secondary prevention therapy. There are

also roughly 11-18 million individuals at moderate

risk in need of primary prevention.

[Slide]

Today, less than half the people who

adverse event in the high risk group are actually

being treated, representing a major gap. More

importantly however for our discussions here, an

even smaller number of people who are at moderate

risk are actually being treated, with an estimated

60-70 percent treatment gap.

[Slide]

Most of the focus of prescription therapy

has been, and this is appropriate, for the

secondary prevention group. We certainly propose

that that continues. So, what we do propose today

is for you to consider the addition of an OTC

statin option to help increase appropriate

treatment in the moderate risk primary prevention

group, a group, according to the ATP III

guidelines, in need of more and specific attention.

[Slide]

Now that we understand the problem and

have identified a group in which an OTC option

might play a positive role, it is important to

clearly define a target population that is, one,

consistent with the NCEP guidelines and that, two,

can benefit from over-the-counter statin use.

[Slide]

You have already heard a brief outline of

this from Dr. Parks and time doesn't permit me to

go through ATP III guidelines in detail. You do

have this in your background package. But for

those of you not familiar with the format of the

ATP guideline, let me take a moment to walk through

the layout.

The horizontal rows here are organized

around four designated risk groups. In fact, the

moderate risk group that Dr. Parks referred to is

really divided into two. Each column then lists

the specific LDL goal; the level of LDL at which

therapeutic lifestyle change is recommended for

initiation; and the level at which drug therapy

should be considered for initiation in each of the

four risk groups.

In keeping with the guidelines, we are

proposing the primary target of OTC should be those

at moderately high risk, with two risk factors and

a 10-20 percent 1-year Framingham risk with LDL

levels greater than 130, thus, qualifying for drug

therapy.

In addition, however, we believe it is

appropriate to consider OTC treatment for the group

listed as moderate here. In fact, when we on the

NCEP panel recognized the benefit of this group,

the cutoff level for consideration for drug therapy

was driven, in large part, by pharmacoeconomic

considerations. Throughout our presentations today

we will refer to the proposed OTC target

collectively as the moderate risk population.

[Slide]

It is important to understand how this is

actually approached in an OTC label. In

consultation with the FDA, we considered and found

it impractical to have consumers actually calculate

their Framingham 10-year coronary heart disease

risk score, something, unfortunately, most doctors

don't even do. Therefore, our OTC label approach

utilizes a surrogate for the Framingham

calculation. The OTC label includes people with

elevated LDL cholesterol above 130 who have two

risk factors, such as age or family history, and

also includes the NCEP treatment goal of LDL less

than 130.

It is important to point out that the

proposed OTC label directs treatment within the

context of a comprehensive cholesterol management

approach, not just drug therapy. Consumers are

encouraged to include lifestyle changes such as

diet and exercise before and during use of the

product. The Mevacor OTC program also includes a

comprehensive self-management system to reinforce

these lifestyle changes. Most importantly, the OTC

system was designed not to be solely reliant on

self-care. At the center of the OTC system, as you

will see, there is a collaborative care approach

taken that encourages healthcare professional

interaction throughout.

[Slide]

The most critical element of OTC

consideration is the proven efficacy and safety of

lovastatin 20 mg. Statins as a class have a

long-standing and, as you have heard,

well-documented history of efficacy and safety.

Literally hundreds of thousands of patients have

been studied in controlled clinical trials, and

hundreds of millions of patient treatment years

have been accumulated in the more than 17 years

since these products have been on the market.

[Slide]

The accepted efficacy and safety of this

class was summarized in a joint statement issued on

behalf of the American College of Cardiology,

American Heart Association and National Heart, Lung

and Blood Institute, in which I was privileged to

participate. I won't read the statement in its

entirety but the key point is that statins, as a

class, have clearly proven benefit and are

extremely safe, with a low frequency of adverse

events in comparison to the very large number of

patients receiving these drugs.

[Slide]

This slide illustrates the depth and

breadth of clinical trial experience with statins

across all risk groups from the very high secondary

prevention at the top of this pyramid where

individuals in the trial had an over 50 percent

10-year risk of heart attack or cardiac death, down

to the bottom of the pyramid, the large primary

prevention base that was studied in the landmark

AFCAPS/TexCAPS trial, a trial which showed benefit

of lovastatin in a patient population all the way

down to roughly a 6 percent 10-year risk of MI or

cardiac death.

[Slide]

Importantly, these studies showed that

regardless of the population studied in concomitant

risk, there was a significant and similar magnitude

of relative risk reduction from 25 to 50 percent in

all these studies.

[Slide]

Similarly, other endpoint studies have

also shown that significant relative risk reduction

is also achieved across different levels of

baseline LDL, and I have applied some of the trial

data to the earlier slide that I used. In fact,

with the addition of data from the Heart Protection

Study, which was analyzed after ATP III in 2001, we

see that relative risk reduction and, therefore,

treatment benefit occurs at LDL levels below the

2001 ATP III cutoffs for considering drug therapy.

HPS was, in fact, one of the trials that led to the

2004 update.

[Slide]

Turning to lovastatin specifically, there

is a well documented benefit. There are two major

mega-trials that include over 15,000 patients, as

you have heard. The EXCEL study was a 48-week

efficacy and safety study with up to 80 mg daily of

lovastatin. The AFCAPS was a 5-year outcomes trial

studying lovastatin 20-40 mg in a primary

prevention OTC-like population. At 20 mg LDL

reduction is in the range of 20-25 percent; HDL

increases of 6 percent and concomitant total

cholesterol decreases were seen. Importantly in

the AFCAPS trial, a 37 percent reduction in a first

coronary event was seen in this moderate risk

population study.

[Slide]

Here the AFCAPS data is displayed with

respect to its primary endpoint in a relative risk

plot. The first line here represents the total

AFCAPS cohort demonstrating the 37 percent risk

reduction that I just mentioned. Although, as was

pointed out by Dr. Parks, direct measurement of a

benefit in an OTC target population is not

possible, we are able to at least look at subsets

of AFCAPS that allow an estimation or approximation

of how risk reduction in an OTC population might

look.

[Slide]

This next group is such a subgroup. It is

a subset of the total cohort which achieved the OTC

goal of less than 130 mg/dL and, again, a similar

degree of risk reduction is seen.

[Slide]

Seen here is the subset within AFCAPS in

this post hoc analysis that strictly meets the

proposed OTC label eligibility criteria and

received only 20 mg of lovastatin throughout the

five years. Of course, the confidence intervals

are broader because the population is smaller. But

it seems clear that there is a similar risk

reduction that is achieved with 20 mg of lovastatin

in the OTC eligible population as in the entire

cohort. There are homogeneous results across these

different subgroups.

[Slide]

Given the proven efficacy of lovastatin,

let's turn our attention to the critical discussion

of the safety of lovastatin. As the first approved

statin in 1987, lovastatin does have extensive

in-market safety experience with, as has been

mentioned, 17 years of data for a total of more

than 27 million patient treatment years.

The clinical data to support safety again

includes AFCAPS and EXCEL with daily doses from

20-80 mg. You will see that there is a wide safety

margin for lovastatin 20 mg with safety data up to

40 mg comparable to placebo.

[Slide]

Let's examine the potential concerns,

first looking at the liver. Lovastatin is

generally safe regarding the liver. We do

recognize that currently all statin labels suggest

baseline and most suggest periodic LFT monitoring.

Our current knowledge regarding liver safety,

however, has evolved. We know that asymptomatic

moderate elevations of liver enzymes are seen with

all statins and, in fact, are seen with virtually

every lipid-lowering agent. The elevations are

dose and potency dependent. They are often

transient and resolve with continuing therapy.

Importantly, there has been no demonstrated

association or causality with permanent liver

disease with statins.

As you have seen in the background

package, we believe that liver enzyme testing is

not necessary and is, therefore, not being proposed

for the 20 mg dose in the OTC label-defined

population. We are clearly prepared to address any

questions from the committee and have experts

available to respond to this important issue.

[Slide]

Looking at the lovastatin clinical data,

this table examines cases of consecutive ALT

elevations exceeding three times the upper limit of

normal. As you can see, LFT abnormalities by this

definition with lovastatin 20 mg are exceedingly

rare in both the EXCEL and the AFCAPS trial, and at

20 mg not statistically significantly different

from what was seen in the placebo groups.

[Slide]

To analyze the potential safety concerns

outside of the clinical trials environment in the

marketplace, we refer to Merck's worldwide adverse

experience system. The WAES database is comprised

of spontaneous reports of adverse events in a

post-marketing experience. It is voluntary

reporting system. Reports are often incomplete and

dependent on the terminology of the reporter and

are not by case definitions. It includes all

reports independent of perceived causality. Of

course, because of the way the data is collected,

it can't provide incidence rates.

[Slide]

From this data set we can see that, as

expected, the number of WAES reports of acute liver

failure associated with lovastatin is very low.

During the more than 27 million patient treatment

years there have been only 25 reported cases of

acute liver failure and upon outside expert review

none of these cases could be clearly attributed to

lovastatin.

[Slide]

Turning to muscle safety, while muscle

pain symptoms do occur occasionally, actual muscle

toxicity is extremely rare with low-dose statins.

It occurs with all statins and fibrates, and it

occurs particularly when these two are combined.

Since muscle pain symptoms usually occur prior to

actual muscle toxicity, this potential side effect

is often recognizable by the patients. Patients

recover when the drug is stopped and progression to

rhabdomyolysis is rarely seen at any dose.

[Slide]

Going back to EXCEL and AFCAPS data, this

table displays the frequency of CPK elevations

greater than 10 times the upper limit of normal.

Again, we do not see statistically significant

differences between placebo and lovastatin in

either the 20 mg or the 40 mg doses. Both EXCEL

and AFCAPS show low numbers and a very low rate.

[Slide]

While the definition of myopathy and

rhabdomyolysis is evolving and sometimes confusing

because it is used differently in different

settings, using the definition shown here in these

studies, there is additional data that with low

doses there is no evidence of an increased risk of

rhabdomyolysis. Across both trials there was a

total of three reported cases of rhabdomyolysis for

both 20 mg and 40 mg of lovastatin, one in the

lovastatin-treated group and two in the placebo

group. The one case with lovastatin in AFCAPS

occurred post surgically in a patient being treated

for prostate cancer. The patient had been taken

off lovastatin before surgery.

[Slide]

Post-marketing experience also shows the

rarity of rhabdomyolysis directly related to

low-dose lovastatin. Again, out of 27 million

patient treatment years with lovastatin, there have

been a total of 336 spontaneous reports of

rhabdomyolysis. This equates to a reporting rate

of approximately 1/100,000 patient treatment years,

and 158 of these reports occurred without the use

of a potentially interacting drug, and while not

all reports indicate dose, 41 of the events were

reported to have occurred with lovastatin 20 mg.

[Slide]

As previously stated, the potential for

muscle concerns does increase when lovastatin is

used in combination with certain potentially

interacting drugs. Therefore, the OTC label takes

a conservative approach by instructing consumers to

talk to a doctor or a pharmacist if they are taking

any prescription medication, listing potentially

interacting drugs on the package insert and in

corresponding educational materials. With regard

to these potential drug interactions, strong CYP3A4

inhibitors can increase plasma levels of certain

statins and their active metabolites. But a key

question for you to consider is whether this

increase translates into comparable increases in

symptomatic myopathy at the proposed OTC dose.

[Slide]

The AFCAPS trial, interestingly, actually

helps us address this concern since the study was

conducted before we knew details of the potential

concerns with 3A4 inhibitors and co-administration

in AFCAPS was actually allowed. Even in this kind

of worse-case example we see similar numbers

between groups for musculoskeletal adverse events,

defined either broadly or narrowly, when we compare

lovastatin-treated patients and placebo patients.

Thus, while co-administration of a CYP3A4 inhibitor

may increase the relative risk of adverse events

the absolute risk appears to remain extremely low.

[Slide]

From the spontaneous reports WAES database

we see that there have been 178 reports of

rhabdomyolysis with interacting drugs. Since cases

of co-administration with fibrates, in this case 96

of these 97 were gemfibrizole and cyclosporine, are

likely to be patients for conditions already under

the care of a physician this concern for OTC usage

is primarily with niacin and strong CYP3A4

inhibitors. There are 34 reports of rhabdomyolysis

with niacin and 28 reports with strong CYP3A4

inhibitors. Approximately two-thirds of these

cases include dose information and only 29 of the

total of 178 were reported with the 20 mg use.

Therefore, the data supports the conclusion that

the clinical consequences of drug interactions with

lovastatin 20 mg are unlikely given the strong

clinical trial evidence, given the extensive

in-market use over the last 17 years, and given the

OTC labeling instructions that, as you will see,

are effective in guiding consumers away from

concomitant usage of potentially interacting drugs.

[Slide]

Also regarding safety, as detailed in your

background package, there is the regulatory

pregnancy labeling category for prescription

lovastatin. This has already been noted by Dr.

Parks. Since their initial approval, all statins

have been designated pregnancy category X. This

original classification was due to the non-specific

findings in animals observed at many multiples of

the therapeutic dose. Against this background,

since there is no benefit to treat women with

elevated lipids during the relatively short period

of pregnancy, all statins have been assigned the

category X labeling to contraindicate use in

pregnancy. Even though there has been no clear

signal from animal or human data, the proposed

Mevacor OTC label contains strict warnings of "do

not use if you are pregnant or breast feeding."

There is data supporting the safety of lovastatin

in pregnancy and we are fully prepared to address

any questions from the committee and have experts

available to provide the proper perspective on this

important topic.

[Slide]

Therefore with respect to both efficacy

and safety, lovastatin has a very strong product

profile in support of OTC use. There is

significant benefit that has been demonstrated for

the proposed OTC population on drug, clearly, both

in terms of cholesterol-lowering efficacy and in

terms of CHD risk reduction. Lovastatin has a very

large safety database demonstrating a wide margin

of safety at the proposed OTC dose. Potential

risks will be further minimized by effective

consumer-friendly labeling and education.

[Slide]

So, even though there is an appropriate

target population in need of treatment and a

positive product profile, is there really a

consumer need for an OTC statin option--a question

you will need to consider carefully? Our research

tells us that there is demand for an OTC option.

In the survey carried out this past year by the

National Lipid Association, the details of which

are also in your background package, they found

that compared to five years ago the majority of

consumers are now making more health decisions on

their own and, importantly, 72 percent of

cholesterol concerned consumers surveyed said they

were interested in learning more about an OTC

statin option.

In another survey from the National

Consumer League, three out of four consumers at

moderate risk and not taking prescription therapy

said they prefer an OTC option for health

prevention.

Further proof of this interest can be seen

by the fact that consumers already purchase more

than a billion dollars worth of heart health OTC

products yearly. That includes everything from

supplements like garlic and vitamin E to foods that

claim heart-healthy effects, such as oatmeal and

orange juice.

Finally, as many of you in this room know,

earlier this year the U.K. approved nonprescription

Zocor, simvastatin, 20 mg for over-the-counter

consumer use.

[Slide]

Finally, let's consider how this OTC

option can help address the public cardiovascular

health problem that I outlined for you at the

beginning of my presentation.

[Slide]

Looking at the distribution of total

cholesterol among the U.S. population aged 45 and

greater, we see that, like many biologic functions,

there is a bell-shaped curve. Unfortunately, the

peak of this curve is hovering around an elevated

level clearly greater than the desired cholesterol

level delineated by ATP III.

[Slide]

What we are suggesting is that the Mevacor

OTC option provides us with a unique opportunity to

have an increased focus and consumer involvement in

a comprehensive cholesterol management program that

is ideally capable of achieving a leftward shift of

this curve, in fact, a targeted population approach

to CHD prevention.

[Slide]

To conclude, today we have seen that there

is an enormous and growing cardiovascular public

health problem that has not been adequately

addressed. A key concern is the large moderate

risk population which deserves preventive treatment

but is achieving relatively little focus from our

current medical system. We believe that the weight

of the evidence indicates that this problem can be

improved with Mevacor OTC, a drug that has proven

to be appropriate for OTC from both efficacy and

safety standpoints. There is clearly strong

consumer interest in this OTC option, giving us the

potential to greatly improve public cardiovascular

health.

[Slide]

The key question that remains is can a

consumer appropriately use Mevacor OTC in an OTC

setting? The remainder of the presentation today

will focus on that important question and I would

like to now turn the podium over to Mr. Jerry

Hansen, Vice President of New Product Development

and Consumer Research, to begin the discussion.

Thanks very much for your attention.

Mevacor OTC Self-Management System

MR. HANSEN: Good morning.

[Slide]

Today I will be reviewing the Mevacor OTC

label and self-management system. It is important

to note that the exact label and system I will be

discussing were fully tested in the CUSTOM use

trial which is why it is important to review them

prior to the presentation of the CUSTOM data.

[Slide]

As was stated, the key issue today is

whether consumers can play a greater role in

cholesterol management. To that end, we have

studied over 34,000 consumers over a number of

years in the following areas, consumer

understanding, including attitude and behavior;

label development and comprehension; development of

the self-management system; and the actual use

studies. I will discuss the first three areas and

Bob Tipping will follow me with a review of the use

studies focusing on the CUSTOM use trial.

[Slide]

Our first step in developing the label and

system was to gain an in-depth understanding of

consumers who are likely to take action as a result

of the OTC availability. The demographics of those

interested is fairly representative of the U.S.

population. They are older, which is consistent

with the proposed label, but income, race and

education levels are very similar to U.S. averages.

What is most interesting is that while demographics

are representative, their attitudes and behaviors

regarding their health are very different.

[Slide]

These people are extremely active in their

own health care and believe in the idea of

preventing disease. They are more likely than the

general population to be knowledgeable on health

issues; to diet and exercise; to take aspirin for

heart health; and to take vitamins and supplements.

[Slide]

Despite their high involvement in their

own care, they also have strong relationships with

their doctors. Over 80 percent see their doctor at

least once a year. Over 70 percent have had a

cholesterol test in the past year, and about 80

percent have discussed cholesterol with their

doctor. A good way to characterize those

interested is that they are motivated, health

conscious consumers.

[Slide]

So, with this high involvement in their

health care and their doctor, why not prescription

therapy versus OTC? Well, an important finding is

that these people have a general reluctance to

prescription therapy and prefer instead to make

lifestyle changes or to use OTC medicines.

[Slide]

Good evidence of this as it directly

relates to OTC statins comes from a recent study

conducted by the National Consumer League. The

sample included people at moderate risk for

coronary heart disease but who were currently

untreated with statin therapy. This chart shows

that there is a strong preference and greater

likelihood of action with OTC. This group is three

times more likely to consider taking an OTC,

recommending it to a family member or friend, and

seeking more information about it than a

prescription.

[Slide]

This slide outlines the reasons why the

same population prefers OTC. On this graph the OTC

preference is in yellow and the preference for Rx

is in blue. This preference is driven both by

practical reasons, such as better convenience

because it is easier to buy and easier to keep

taking every day but, more important, provides

further attitudinal insights. When asked to

describe a cholesterol prescription user versus an

OTC user, they generally feel that a prescription

is for someone who is sick and that an OTC is for

someone who is healthy like themselves.

[Slide]

So, incorporating this consumer learning,

we designed the Mevacor OTC self-management system

to be far more than just a pill in a box. So, the

label and support program we have developed through

rigorous testing over several years offers support

and education that is unprecedented for an OTC

product. The process we employed included

designing a program that is consistent with

treatment guidelines but is also understandable by

consumers. We incorporated iterative consumer

feedback from those likely to use, and then

developed language and multiple tools to ensure we

effectively communicated key messages. Finally,

the program offers a comprehensive approach to

clinical management, including addressing lifestyle

changes such as diet and exercise.

[Slide]

Healthcare professionals play an important

role in consumers' OTC decision process. Data

shows that for any OTC product, for no matter how

long it has been on the market, consumers usually

consult a healthcare professional before using it.

Nearly 80 percent of consumers say that a doctor's

recommendation is very important in their decision

about whether or not to purchase an OTC for the

first time, and 64 percent say a pharmacist's

recommendation is very important. It is not

surprising then that most consumers interested in

Mevacor OTC will do so in partnership with their

healthcare professional. In fact, over 80 percent

claim they will talk to their doctor before using.

A key element of our program, therefore, is to

facilitate and encourage this interaction.

[Slide]

Because the package label is at the core

of Mevacor OTC, our first step was to create a

label that effectively communicates. The label and

support materials are in your background for your

review and, as Ed stated, the entire system is over

there, at the side of the room, that you can review

during breaks.

The key label messages include an OTC

target consistent with NCEP guidelines. This was

approximated on the label by targeting those with

an LDL between 130 and 170. It is also for men 45

years and older and women 55 years and older. And,

the user should also have one additional risk

factor. These include positive family history,

smoking, low HDL and high blood pressure.

[Slide]

People who have liver disease, are

pregnant or breast feeding, or allergic to

lovastatin should not use the product. There are

also strong messages for those at higher CHD risk

to not use and to see their doctor about possible

prescription therapy. Finally, there are clear

safety warnings about potential drug interactions

and muscle pain.

[Slide]

Again, taking a comprehensive approach to

cholesterol management, the label instructions

include encouraging lifestyle changes and

cholesterol testing. Before using you must have

tried diet and exercise to reduce your cholesterol,

and had a fasting cholesterol test within the past

year. Users are also instructed to test their

cholesterol at six weeks to see if they reach goal.

If they do, they should keep taking Mevacor OTC

daily, test at least once a year and continue to

diet and exercise.

[Slide]

As stated earlier, we believe Mevacor is

not purely self-care but a collaborative

partnership with healthcare professionals. So, the

label strongly encourages this interaction by

telling users to consult with their doctor or their

pharmacist if they have any questions. Examples

include that if someone does not reach their LDL

goal they should talk to their doctor because OTC

may not be enough for them. They should also talk

to their doctor if there is any change in their

health, and talk to their doctor or pharmacist if

they start any new prescription therapy.

[Slide]

Label comprehension testing was conducted

to ensure clear communication. The methodology

included testing in a representative sample and in

low literacy and ethnic subgroups. Again, the

label used was the identical label used in the

CUSTOM trial. The study employed both correct and

correct/acceptable scoring, with acceptable

generally referring to checking with the doctor.

[Slide]

The full results of the label

comprehension studies will be presented by FDA but,

in summary, the label results were very strong,

with over 80 percent or more correct/acceptable for

most measures and 90 percent or more

correct/acceptable for key safety messages. The

label, therefore, is very effective at

communicating key messages across all groups and

also effectively communicates that consumers should

ask their healthcare professional if they have any

questions.

[Slide]

So, once we had a clear understanding of

the potential users and had developed an effective

label, we went on to develop the Mevacor

self-management system. The goal of the system was

to provide additional information and tools to

reinforce key label messages and to emphasize

lifestyle changes. In developing the system we

incorporated feedback from external experts,

including professional organizations, key opinion

leaders and consumer behavior specialists. We

learned that consumers like to receive information

in different ways so we offer multiple methods of

delivering information to appeal to these different

learning styles. Importantly, all elements of the

system are part of our proposed NDA labeling and,

therefore, will be required in the marketplace.

Like the label, the system I will describe was also

fully tested in the CUSTOM study.

[Slide]

In the CUSTOM study the self-management

includes three major health components,

pre-purchase, in-store and post-purchase. But

importantly, the program strongly encourages

healthcare interaction through first looking at

pre-purchase assistance.

[Slide]

The most common way that the consumer will

learn about Mevacor OTC is through advertising. In

this advertising there will be extensive

communication and education, including the

importance of knowing your cholesterol numbers and

highlighting that OTC is not right for everybody.

To help consumers determine if it is right for them

the program will offer eligibility assistance by

directing them to their doctor or pharmacist if

they have any questions. It also offers access to

trained product specialists who will be available,

toll-free, to answer questions about Mevacor and

related services such as cholesterol testing.

[Slide]

The next step a consumer is likely to take

is to visit a store to learn a little more about

the product. So, let's review the in-store

assistance we will provide. In-store assistance

includes extensive support in the pharmacy.

Importantly, we are proposing that Mevacor be sold

as a pharmacy care OTC. To support this, we will

be providing extensive pharmacist and staff

training. We will also provide enhanced retail

communication including interactive tools that will

support the label.

[Slide]

I will now talk about each of these in

more detail. Pharmacy care OTC is a new approach

developed by the American Pharmacists Association

and other key pharmacy groups. The goal here is to

provide expanded support for more novel Rx to OTC

switches by facilitating greater interaction

between pharmacists and consumers.

The features include that manufacturers

will voluntarily distribute the product only in

stores with a pharmacy; that it be available on the

open shelf with current OTC products and not behind

the counter; that pharmacist intervention is not

required but strongly encouraged; and there is an

expansion of supportive services such as

cholesterol testing and counseling.

[Slide]

As I stated, we will be providing

unprecedented in-store education and support for

Mevacor OTC. Here is an example of a novel store

shelf device we have developed and tested. It

highlights two decision processes including

information for first-time buyers primarily, should

you take it, and repeat buyers, with messages

regarding getting to goal. It also offers extra

tools such as tear-pads and eligibility wheels.

These directly support the label but allow people

to answer questions in a more interactive way.

Finally, the shelf communication strongly

encourages dialogue with the pharmacist which

further supports the concept of pharmacy care OTC.

[Slide]

Now we will review post-purchase

assistance. This includes programs and tools to

support the consumer after they purchase the

product and take it to their home.

[Slide]

Post-purchase assistance includes

materials in the package, including an educational

brochure; package insert Q&A; a quick start guide;

and incentives for cholesterol testing.

[Slide]

Regarding cholesterol testing, this is a

very important component of the Mevacor OTC system.

Our toll-free number and our website offer

assistance on obtaining cholesterol numbers and

where to get tested. We will also be offering in

each box a high value coupon toward the six-week

cholesterol test.

We have learned that doctor-directed

cholesterol testing continues to be where most

consumers prefer to be tested. However, other

testing options are becoming increasingly available

including tests in the retail setting, walk-in

clinics, and at home.

[Slide]

Another important part of post-purchase

assistance is the ongoing adherence program. This

includes a toll-free hotline and website,

educational video and American Heart Association

cookbook, ongoing newsletters, postcards, and

e-mail reminders.

[Slide]

This is how the adherence program works.

It is customized to correspond to the date the user

started taking the product. This ensures that the

message is relevant to them at that point in their

therapy. For example, the first three months focus

on eligibility and treatment to goal, while later

communication focuses on diet, exercise, long-term

adherence and health professional interaction.

[Slide]

While not a requirement, most consumers

interested in Mevacor OTC want to and will partner

with their healthcare professional while using.

Therefore, we have structured the system to

encourage and facilitate this.

[Slide]

To support this interaction, the program

encourages ongoing dialogue concerning any

questions regarding Mevacor OTC including testing

and monitoring. The program also includes a risk

referral program for those who are identified at

higher risk and then directs them to their doctor

for possible prescription therapy.

[Slide]

Here is an example of one of the

doctor/pharmacist tools. In each package will be

two cards, a doctor card and a pharmacist card.

Users can fill out the inside of these cards with

information such as when they started taking

Mevacor and list any other medications they may be

taking. The doctor can then add this information

to the patient chart and the pharmacist to the

medication record.

So, as I have shown, the Mevacor OTC

self-management system is comprehensive and offers

the tools for a consumer to self-manage their

cholesterol. However, each element of the program

also strongly encourages healthcare professional

interaction as needed.

[Slide]

In summary, those likely to take action as

a result of Mevacor OTC differ from the general

population, with these people being highly

motivated and health conscious. The

self-management system offers multi-faceted and

unprecedented support to reinforce key label

messages and was designed to drive interaction with

healthcare professionals. Both the label and the

support system were submitted as proposed NDA

labeling and, therefore, will be required in the

marketplace. We have further demonstrated the

feasibility of executing this commitment in the

marketplace with key partners including retail,

pharmacy and testing companies.

[Slide]

Finally, if approved, we commit to

extensive post-marketing surveillance to monitor

actual use in the marketplace and we will use this

data to modify our program as necessary. That

concludes my presentation. I know we are scheduled

for a break now.

DR. WOOD: Let's just go straight on to

Robert Tipping's presentation.

MR. HANSEN: Dr. Wood, I do just want to

warn you that this is about 30-40 minutes and gets

more technical.

DR. WOOD: That is okay.

Actual Use Study Results

MR. TIPPING: Thank you, Jerry and good

morning to members of the advisory committee and

representatives of the FDA.

[Slide]

I am Bob Tipping, a director in the

clinical biostatistics department of Merck Research

Labs. Today I will share with you some of what we

have learned about how consumers use Mevacor OTC

and the self-management system that you have just

heard about.

The data I will present today addresses

three key questions about consumer behavior: Will

the Mevacor OTC self-management system allow

consumers to make appropriate initial decisions

about the use of the product? Will they be able to

self-manage the potential safety issues over time?

And, will they be able to self-manage their

cholesterol over time and obtain benefit?

[Slide]

To address these questions I will be

showing you data from the large behavioral trial

called CUSTOM, the Consumer Use Study of OTC

Mevacor. It is important to realize that CUSTOM is

a large trial, over 3300 participants and 800,000

data items. Given the time constraints of this

meeting, I will not be able to show you all of the

data. Instead, I will focus on those results that

address the key questions about consumer behavior.

[Slide]

Let me briefly review the CUSTOM study

design. Participants were recruited using TV,

print and radio advertisements. Ads did not

include specific eligibility criteria. The ad

campaign included ads designed to communicate to an

ethnically diverse population and included a

toll-free number for interested individuals to call

for an appointment.

[Slide]

Study sites were set up to simulate an OTC

retail environment. This included a shelf display

and drug package consistent with marketplace plans.

CUSTOM was an all-comers study. All participants,

regardless of their label eligibility, were able to

make a purchase decision. Participants reviewed

the label and the other in-store components of the

system to assess if Mevacor OTC was right for them.

They were allowed to leave and return later if they

felt they needed more information. The option to

purchase a cholesterol test was available. Study

site nurses were trained to act as pharmacists and

could answer questions but did not volunteer

assistance unless asked by the participants.

Interested participants were required to purchase

study drug.

[Slide]

After making the initial purchase

decision, participants were followed for six months

of self-guided behavior and product use with

minimal intervention. Visits were not scheduled.

Participants returned to the site at their own

initiative to purchase additional drug or a

cholesterol test. Behavior around obtaining a

follow-up cholesterol test following treatment to

the goal messages and new medical conditions and

prescriptions was observed.

[Slide]

Baseline and end of study lipid values

were collected from participants who purchased the

study drug in a way to have minimal impact on

participant decisions. These lipid values allowed

us to assess the lipid-lowering effect of

lovastatin 20 mg a day in an OTC setting.

[Slide]

At the end of the study eligibility

information was collected. Participants were asked

about new prescriptions, new medical conditions and

adverse experiences. Information about diet and

exercise and the reasons for inappropriate

decisions were also collected.

[Slide]

A post-study survey was conducted in a

subset of users to obtain additional information

about specific behaviors.

[Slide]

You have seen this slide a few minutes ago

when Jerry Hansen presented the Mevacor OTC

self-management system.