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. All elements of the system

were evaluated in our CUSTOM trial. The system

emphasizes a collaborative care approach, designed

to support self-management while encouraging

interaction with healthcare professionals. In

fact, we will present data demonstrating that

consumers will seek out these partnerships with

doctors and pharmacists in the OTC setting.

[Slide]

The analysis of behavior evidenced

decisions about the purchase and use of Mevacor

OTC. The analysis carefully considered

interactions with healthcare professionals. The

label contains numerous messages about talking with

your doctor or pharmacist. Information about these

interactions was collected and was an important

factor in determining the appropriateness of use

decisions. We also wanted to document the positive

impact that this system had in creating new and

maintaining existing relationships with healthcare

professionals. Finally, we collected information

from participants about their diet and exercise

habits while on Mevacor OTC.

[Slide]

Turning now from study design to the

CUSTOM study results--

[Slide]

Before we get into actual behavioral

results, it is important to understand how

participants flowed through our study and to

introduce the various populations to be discussed

further into the presentation. In response to

study advertising, over 11,000 individuals called

our toll-free number. Of that group, 3316

scheduled an appointment and traveled to one of the

study sites. This group, called the evaluator

population, reviewed the label and the other

in-store components of the system and made a

decision about the purchase of Mevacor OTC; 2111

people decided not to purchase the drug and a

little over 1200 did choose to purchase. The

purchasers split into two main groups, those who

purchased but did not go on to actually use the

drug and a group that actually began to use the

medication. Finally, there was a subgroup of 398

uses who participated in our post-study survey.

[Slide]

This slide presents a brief overview of

the demographics of the evaluator population, and

59 percent were men. They had a median age of 53

years. As mentioned earlier, the recruitment ads

were designed to reach an ethnically diverse

population and we were pleased to see positive

results from this, as evidenced by a 28 percent

minority participation rate at this stage of the

study. Twelve percent of the evaluator population

was classified as low literacy based on the results

of a validated adult literacy questionnaire called

the REALM test.

[Slide]

Before discussion of behavior, and

specifically behavior that resulted in the

potential for an increased safety risk, it is

important to provide a summary of the actual safety

results from the use of lovastatin 20 mg in an OTC

setting. There was only one serious drug-related

event, an allergic reaction to lovastatin. One

death occurred in the study. A 50 year-old man

died of a stroke that was judged probably not

related to study drug. There were no serious

drug-related muscle or liver events. No new safety

issues were identified and lovastatin was generally

safe and well tolerated by this population in a

simulated OTC environment.

[Slide]

To better understand consumer behavior

regarding the Mevacor OTC label, it is helpful to

think about the label elements as falling into one

of four quadrants. The top and the bottom rows of

this table contain label elements for the initial

and the ongoing use decisions respectively. The

left column consists of specific safety warnings

and the right-hand column contains label benefit

criteria.

[Slide]

Safety warnings, summarized here, guide

appropriate behavior from consumers with these

conditions or situations so as to minimize the

potential for a safety concern.

[Slide]

Benefit criteria target an appropriate

population based on their age, presence of

additional risk factors and knowledge of their

complete lipid profile including triglycerides and

HDL. As mentioned earlier, these criteria were

written to be readily understood by the consumer

while allowing an approximation of eligibility

according to ATP III treatment guidelines.

[Slide]

It should come as no surprise that many

users in CUSTOM were not 100 percent compliant with

each and every element of this multi-factorial

label. A strict interpretation of the CUSTOM

results along these lines can be viewed as a less

than positive outcome, but if one sees some

distinction between these label elements; if one

believes that a "do not use if you are pregnant"

warning should be evaluated at a different level

than a specific age or lipid value cutoff; if one

believes that people should have the option to make

their own personal benefit assessment, then the

CUSTOM results will demonstrate that consumers can

be capable partners in the management of

cholesterol and heart health.

[Slide]

So, will consumers make appropriate

decisions about starting to use Mevacor OTC?

[Slide]

From the population of 3316 who evaluated

the product, there were 2111 who chose not to

purchase. An additional 64 purchased the product

but made a decision not to begin taking it. There

were 659 people who began to use the product in

compliance with both the label safety warnings and

benefit criteria.

[Slide]

Taken together, this totals 86 percent of

the population who came to one of the sites and

evaluated the product.

[Slide]

There were an additional 109 participants

who began to use the product despite a label safety

warning that was relevant to them. Let's look at

each of these groups more carefully.

[Slide]

Coming back to the study population slide,

I will next show you data from 2111 non-purchasers

and the 94 purchaser non-users.

[Slide]

This group of evaluators who chose not to

purchase the product provides strong evidence that

the label and the other in-store components of the

system are discouraging inappropriate people from

using the product. Seventy-nine percent of this

group indicated that they were not interested in

buying Mevacor OTC. Nearly two-thirds of this

subgroup stated that they believed Mevacor OTC was

not right for them.

[Slide]

The group of 94 who purchased but did not

go on to actually use the drug includes 64 people

who actually left the site with Mevacor OTC. The

majority cited that "my doctor advised me against

using it," or "I learned it was not right for me"

as a reason for not using the drug. These results

provide strong evidence that the post-purchase

components of the system are further discouraging

inappropriate use of the product.

[Slide]

Returning again to our population slide, I

100

will next show data from the 1059 people who

actually began to use Mevacor OTC, and remind you

that we are still addressing the first of our three

key questions, will consumers make appropriate

decisions about starting to use Mevacor OTC?

[Slide]

The target behavioral goals established

for the CUSTOM study were based on information from

label comprehension studies. Typically, a level of

80 percent is regarded as a reasonable benchmark

for correct and acceptable answers for each of the

individual label elements. Our pilot comprehension

studies of the CUSTOM label showed that most of the

individual label elements were understood by 80

percent or more of those tested and, most

importantly, the key safety warnings were

understood by more than 90 percent. We know that

label comprehension results do not always predict

behavior, but we decided to apply the same 80

percent benchmark in evaluation of our behavior

data, an even more rigorous test because it

required being correct on all label elements

101

collectively, not just individual criteria.

[Slide]

Indeed, for the safety criteria 90 percent

of the CUSTOM users demonstrated correct behavior

around all label safety warnings jointly, exceeding

the 80 percent benchmark and consistent with the

label comprehension results for the individual

safety messages.

[Slide]

Correct behavior according to the multiple

label benefit criteria was not as high. It was 66

percent of the users closely adhering to the

benefit criteria. Taken together with the label

comprehension results that exceeded 80 percent for

these elements and the excellent behavior around

the label safety warnings, this suggests that

consumers are understanding the label and are

applying more individual judgment on the benefit

criteria before beginning to use Mevacor OTC.

[Slide]

Looking jointly at all safety and benefit

criteria for the initial decision to use, which was

102

a prespecified hypothesis of CUSTOM, this

translates to 55 percent of the users behaving in a

fashion consistent with all label elements. This

number is obviously driven by the low adherence to

the label benefit criteria and is roughly the

product of the 90 percent and the 66 percent.

Let's now explore the behavior within each of these

bars more fully.

First, let's look at the safety warnings

directed at the initial use decision. Recall that

90 percent of all users exhibited behavior that

completely met the label safety criteria and 10

percent who did not comply with the label safety

warnings. This 10 percent corresponds to 109 of

our users.

[Slide]

Recall, this was an all-comers study.

There was good representation from all of the

safety decision areas among our evaluator

population, the orange bars.

[Slide]

There were very few people with these

103

conditions who went on to actually use Mevacor OTC

without speaking to a physician. There was no use

by pregnant women. Use by people in the other four

categories was low and there were no serious

drug-related muscle or liver events among them.

[Slide]

The difference between the number of the

evaluators represented in the orange bars with

these conditions and the number who chose to use

Mevacor OTC, the yellow bars, provides strong

evidence that the safety warnings directed at the

initial use decision are effectively discouraging

inappropriate purchase and use of Mevacor OTC.

[Slide]

Now let's look more fully at the benefit

criteria directed at the initial use decision.

These are label elements referring to age, lipids

and CHD risk factors. Recall that 66 percent with

behavior that met or closely met label benefit

criteria and the 34 percent who did not comply with

the benefit criteria--that 34 percent corresponds

to 357 of the user population.

[Slide]

But 72 percent of this group, based on

their risk factors and their 10-year risk for

104

coronary heart disease, should be considered for

lipid-lowering therapy according to ATP III

guidelines. Let's now look at the specific label

benefit criteria that cause people to fall into

this 34 percent group.

[Slide]

Eighteen percent of users did not know

their complete lipid profile. However, results

from the study-mandated baseline lipid exam

indicated that 93 percent of them had elevated

lipids, a measured LDL at or above 130 or a total

cholesterol of 200 or more. Fifty-one percent of

this group did not know their complete lipid

profile but they did know their total cholesterol

value. This group had a median LDL cholesterol of

165. So, while they did not meet the strict label

criteria, they are still very likely to obtain

benefit from lipid-lowering therapy.

[Slide]

Sixteen percent of the users had

self-reported triglycerides of 200 or higher. The

label advises consumers with triglycerides greater

than or equal to 200 not to use the product unless

directed by a physician. This is to minimize the

potential for use among people with possible

105

metabolic syndrome since they may require more

personalized medical care. However, results from

the study-mandated baseline lipid exam showed that

92 percent of this subgroup also had elevated

lipids, with a median total cholesterol or 253 and

a median LDL of 146. Nearly three out of four had

self-reported triglycerides less than 400. So,

again, while they did not meet all of our

conservative label criteria, they are still very

likely to obtain benefit from lipid-lowering

therapy.

[Slide]

Eleven individuals indicated they would

substitute Mevacor OTC for their prescription

cholesterol-lowering medication without consulting

their physician. This represents just one percent

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of our user population and a very small percentage

of the 609 evaluators who reported on being on Rx

lipid-lowering therapy.

[Slide]

Finally, there were 70 individuals, or 7

percent of our users, who were at higher CHD risk.

They reported having coronary heart disease, having

had a prior stroke or being diabetic and chose to

use Mevacor OTC without speaking to a physician.

[Slide]

Among the evaluators, there were 570 who

reported having coronary heart disease, a prior

stroke or diabetes. More than 70 percent of this

group chose not to purchase Mevacor OTC.

[Slide]

However, 167 of them did choose to use

Mevacor OTC and 97 of this group did it after

consulting with a physician. That leaves 70 higher

risk users from the earlier slide who began to use

Mevacor OTC without speaking to a doctor.

[Slide]

However, 26 of these 70 did have a

107

physician interaction at some point during the

study. Combining these 26 with the the 97 who

consulted a physician prior to using Mevacor OTC,

this totals 74 percent of this group who had an

interaction with their doctor prompted by the

Mevacor OTC self-management system.

[Slide]

Finally, it is important to note that 80

percent of this 70 had elevated lipids, and

two-thirds of them were not on lipid-lowering

therapy at the time they chose to start taking

Mevacor OTC.

[Slide]

Now let me summarize the results you have

just seen and address the first of our three key

questions, will consumers make appropriate

decisions about starting to use Mevacor OTC? From

our population of evaluators, there were 2111 who

evaluated and chose not to purchase. An additional

64 purchased the product but made a subsequent

decision not to begin taking it. Finally, there

were 659 people who began to use the product in

108

compliance with both the label safety warnings and

the benefit criteria. Taken together, this

represents 86 percent of the population that came

to one of the study sites and evaluated the

product. There were an additional 109

participants, representing just 3 percent of all

those who evaluated the product, who began to use

Mevacor OTC despite a label safety warning that was

relevant to them. The behavior of these 109

individuals created the potential for an increased

safety risk, however, there were no serious

drug-related muscle or liver events among

them--good evidence that consumers can select to

use Mevacor OTC appropriately.

[Slide]

Returning to the key questions, I will now

address both the second and the third questions

together for a moment since they are both directed

at the ongoing use decisions. While decisions

about initial use are important, even more

important are decisions regarding ongoing use

because only those who use the product long-term

109

are going to gain a clinical benefit or place

themselves at a potential safety risk.

[Slide]

Will the system allow consumers to

self-manage the potential safety risks over time?

From our population of 1059 users, there were 366

who actually experienced a new medical condition or

got a new prescription, thus providing an

opportunity to evaluate behavior regarding the

label safety warnings for ongoing use. Of these

366, 94 percent made a decision about ongoing use

of Mevacor that was consistent with the label.

Only 6 percent made a decision that was

inconsistent with safety warnings directed at

ongoing use decisions.

[Slide]

Will the system allow consumers to

self-manage their cholesterol over time and obtain

a benefit? Again, from our population of users, 74

percent obtained a follow-up cholesterol test or

had discontinued Mevacor OTC prior to the six-week

time point directed in the label. Of those users

110

who did get a follow-up test, three out of four

followed the label directives regarding the LDL

goal. Finally, there was an impressive 21 percent

reduction in LDL.

[Slide]

Again, based on label comprehension study

results, we evaluated decisions about ongoing use

against the prespecified 75 percent benchmark.

[Slide]

CUSTOM demonstrated behavior around all

label safety warnings for ongoing use jointly to be

94 percent. As with the safety warnings for the

initial use decision, this exceeded the target

benchmark and was consistent with label

comprehension results for the individual label

elements.

[Slide]

As with the initial use decision, fewer

adhered to the label benefit criteria, with 53

percent of the user population closely adhering to

benefit criteria for ongoing use decisions. Taken

together with the comprehension results for the

111

label benefit elements and the excellent behavior

around the label safety warnings, this again

suggests that consumers are understanding the label

and are making their own personal benefit

assessment for the continued use of Mevacor OTC.

[Slide]

Combining all safety benefit elements for

the ongoing use decision together which, again, was

a prespecified hypothesis of CUSTOM, we see that 50

percent of the users behaved in a fashion

consistent with each and every label element.

Again, this is no surprise given the results from

the label benefit criteria, and is the product of

the 94 percent and the 53 percent.

[Slide]

Now let's explore behavior within each of

these bars more fully. First, let's look

specifically at the safety warnings directed at the

ongoing use decision. Here is the 94 percent

exhibiting behavior that completely met the label

safety criteria, and the six percent who did not

comply with the label safety warnings. That six

112

percent corresponds to 21 individuals from the user

population.

[Slide]

There were 693 of the user population who

did not experience a new medical condition or get a

new prescription during the study. That leaves 366

who did experience a new medical condition or a new

prescription and exhibited a behavior that could be

evaluated against the label safety warnings for

ongoing use. The three bars to the right represent

the number of users with each of these events.

[Slide]

And 270 of the 366 reported a new

prescription during the study. Only two were for a

potentially interacting medication where the person

did not inform their physician about taking Mevacor

OTC as directed on the label; 161 reported a new

medical condition while in the study and only three

of these were of concern. As discussed earlier,

there was the individual who had a stroke and died

before he could reveal to his physician that he was

taking Mevacor OTC. One individual was diagnosed

113

with coronary-artery disease and did not inform her

physician about the use of Mevacor OTC, and one

individual was diagnosed with diabetes and, again,

failed to inform his physician about use of Mevacor

OTC. Sixty-three reported an unexplained muscle

pain during the course of the study. All but 16

discontinued Mevacor OTC or spoke with a physician

about this.

[Slide]

Now let me summarize the results you have

just seen that address the second of our three key

questions, will consumers be able to self-manage

the potential safety risks over time? From the

population of 1059 users, there were 693 who did

not experience a new medical condition or get a new

prescription during the study. An additional 345

experienced and event and made a decision about

ongoing use that was consistent with the label

safety warnings. Taken together, this represents

98 percent of the user population. There were 21

participants, representing just two percent, of all

those who used the product who continued to use

114

Mevacor OTC despite a label safety warning that was

relevant to them. The behavior of these 21

individuals creates the potential for an increased

safety risk, however again, there were no serious

drug-related muscle or liver adverse events among

them--good evidence that consumers can manage

potential safety risks over time.

[Slide]

Turning now to the third and final of the

key questions, will the system allow consumers to

self-manage their cholesterol over time and obtain

a benefit? This question addresses behavior around

label benefit criteria directed at ongoing use

decisions. These are label elements directing

consumers to get a follow-up cholesterol test at

six weeks and comply with the LDL goal message.

[Slide]

And, 666 of our 1059 users, representing

63 percent, obtained a cholesterol test during the

study. An additional 11 percent discontinued the

study, many for an appropriate reason, before the

six-week time point directed in the label. This

115

totals 74 percent of our user population making an

appropriate decision about getting a follow-up

cholesterol test.

[Slide]

Looking specifically at the 666

individuals or the 63 percent of the users who got

a follow-up cholesterol test, 75 percent of this

group followed label directives regarding the LDL

goal message. This was largely composed of

individuals who achieved an LDL less than 130 and

made the decision to continue using Mevacor OTC.

[Slide]

Addressing another component of the third

question, how did the results of CUSTOM, an

uncontrolled, open-label study, compare to what is

known about the lipid-lowering effects of 20 mg of

lovastatin in controlled clinical trials?

[Slide]

In the CUSTOM trial a 25 percent reduction

in LDL was observed in a subset of individuals who

indicated they were fasting both at the baseline

and end of study measurements. Looking at the

116

entire study cohort, regardless of fasting status,

a 21 percent reduction in LDL was observed. These

results compare very favorably with the large

controlled clinical trials, AFCAPS and EXCEL, both

showing a 24 percent reduction in LDL with the 20

mg dose of lovastatin.

[Slide]

Turning now to data about consumer who

persisted with medication, before I present the

results let me remind you that CUSTOM was not

designed to be a persistence study. In fact, one

of the goals of CUSTOM and of the Mevacor OTC label

is to correctly influence people who shouldn't be

taking the product to stop taking it. With that in

mind, let's look at the CUSTOM persistence data.

[Slide]

Sixty-two percent of the user population

were persistent with therapy through six months of

the study. An additional 17 percent discontinued

Mevacor OTC for an appropriate reason, such as not

reaching an LDL goal, being advised by their

doctor, or learning that Mevacor OTC was not right

117

for them. Taking these together, 79 percent of our

user population made an appropriate persistence

decision regarding Mevacor OTC. This is consistent

with results from an earlier use trial of

lovastatin 10 mg. In that study 72 percent were

continuing with medication at six months and 49

percent were still on therapy at 18 months. These

numbers compare very favorably to what we know

about persistence with prescription statins.

[Slide]

Finally, what do we know about the

self-management system and its ability to direct

consumers to make appropriate decisions about diet

and exercise habits? A MEDFICTS dietary assessment

questionnaire was given to the user population at

baseline and at the end of the study. This

validated instrument provides a score to determine

if an individual is on an AHA step-one diet or the

more restrictive AHA step-two diet. Not only did

more individuals move to the stricter step-two diet

by the end of our study, but the number of users

who are not on either of the AHA diets decreased

118

from 17 percent to 11 percent.

[Slide]

Now let me summarize the results you have

just seen that address the third of our three key

questions, will the system allow consumers to

self-manage their cholesterol over time and obtain

a benefit?

[Slide]

From our population of 1059 users, 74

percent obtained a follow-up cholesterol test or

discontinued taking Mevacor OTC prior to the time

directed on the label. Of those users who did get

a follow-up test, 75 percent of them followed the

label directives regarding the LDL goal. Finally,

there was an impressive 21 percent reduction in LDL

cholesterol--again, good evidence that consumers

can manage their cholesterol over time and obtain a

benefit.

[Slide]

Moving now to an important question about

the ability of the system to promote consumer

interaction with healthcare professionals, CUSTOM

119

provides information from a variety of groups to

address this question.

[Slide]

Of the people who evaluated the product at

the site but chose not to purchase, 22 percent of

them reported that they did, in fact, talk to their

doctor before making this decision. Physician

interactions were reported by 57 percent of our

user population at some time during the study and,

finally, as I mentioned earlier, nearly three out

of every four of our higher CHD risk users had an

interaction with a doctor as a result of this

study.

[Slide]

In conclusion, the Mevacor OTC

self-management system discourages inappropriate

use of the product.

[Slide]

The majority of consumers who choose to

use Mevacor OTC will be appropriate for

self-management. They will gain a clinical

benefit, as evidenced by substantial LDL

120

reductions, and most importantly, will be at

minimal safety risk.

[Slide]

Lastly, beyond the direct pharmacologic

effect of the medication, the Mevacor system will

have important public health benefits that include

an increased level of interaction with healthcare

providers and a general improvement in heart health

awareness and behavior. That concludes my

presentation. Thank you for your attention. I

think it might be time for a break now?

DR. WOOD: Right. It sounded like a plea,

right! Why don't we take a break and be back,

ready to start, at 10:15?

[Brief break]

DR. WOOD: We will just wait one more

minute so people can take their seats.

Medical Perspective and Conclusions

DR. COHEN: Mr. Chairman, members of the

committee, representatives of the FDA, my name is

Jerry Cohen, and I am a full-time academician and

cardiologist at St. Louis University. I spent

121

nearly my entire career in preventive cardiology.

[Slide]

I want to start off by telling you that a

number of years ago, when I first heard about the

possibility of OTC statins, I was skeptical about

the notion and I had many questions. I am sure my

initial skepticism and the questions I had then are

similar to ones that you may have today. Your key

questions probably include something like the ones

that are shown on this slide.

[Slide]

First, is there really a need for an OTC

option? Can't we just do a better job of what we

are already doing, using the current treatment

model? Secondly, is Mevacor 20 mg really safe

enough for OTC use? Third, can consumers manage

cholesterol effectively with an OTC product?

Fourth, will OTC therapy divert consumers from a

physician's care and from heart-healthy lifestyle

practices? Finally, why should we do this? What

is the overall benefit-risk ratio of Mevacor OTC?

These are all important questions and you

122

have just seen compelling data that addressed each

of these questions individually. But in the end,

for me, it was the totality of the evidence taken

together which clearly convinced me that OTC

lovastatin therapy poses not only a minimal and

acceptable risk, but also, as we will see, has the

potential to provide an enormous public health

benefit. In other words, there is a highly

favorable benefit-risk ratio. So, let's review the

evidence.

[Slide]

The first question is shown here again on

this slide. Is there really a need for an OTC

statin option? Well, conversely, we might ask why

not solve our problem by putting more effort into

the current system of physician and patient

education and build an even greater awareness of

the cholesterol problem and the benefits of Rx

therapy? And, why not just continue to get more

aggressive with our national guidelines?

[Slide]

This is a slide you have already seen and,

123

as you have heard, despite our best efforts and the

creation of the National Cholesterol Education

Program 20 years ago, we have not made much

progress, particularly in the moderate risk primary

prevention group. As Dick Pasternak has shown us,

cardiovascular disease is still by far our nation's

number one killer and a huge treatment gap exists,

somewhere between 6-15 million Americans. With the

aging of our population, this will only get larger

in the near future.

While there are a lot of reasons for the

treatment gap, the major relevant factor to our

discussion today is that many untreated people are

reluctant to take prescription therapy. As you saw

earlier, with the availability of OTC statins many

of these same people are more likely to take

positive action with an OTC product.

[Slide]

The next question is of utmost importance,

is Mevacor 20 mg truly safe enough for OTC use?

[Slide]

I believe the answer is clearly yes.

124

Mevacor has an excellent and proven safety profile,

especially at this low dose. We are not talking

about a newly developed or newly released compound.

We are not awaiting the results of another study.

Lovastatin, as the first FDA-approved statin, has a

proven track record of safety with more than 17

years in market experience. This equates to more

than 27 million patient-years of treatment. As we

have seen, Mevacor has a safety profile reasonably

similar to placebo at up to twice the proposed OTC

dose.

If the product is safe at this dose, is

cholesterol too complex for consumers to accomplish

on their own? After all, high cholesterol is a

chronic, asymptomatic condition and it has been

said that this is somehow different from the way

OTC products are presently used by consumers.

First, let me say that the treatment of

chronic asymptomatic conditions is not a new

concept for OTC products. Consumers have been

taking OTC products for such conditions for many

years. In fact, over 35 million Americans are

125

currently using calcium supplements every day to

prevent osteoporosis. Approximately 26 million

people use low-dose aspirin for heart health, with

a quarter of those doing so on their own. This is

an interesting observation given the fact that both

aspirin and Mevacor have proven cardiac benefits,

and both are among the standards of care. Yet, the

risk of having a serious adverse event with

low-dose aspirin is actually greater than it is

with lovastatin 20 mg.

Perhaps the most relevant example to the

discussion today is that over 14 million Americans

are currently using heart health supplements, many

of which are of questionable safety and

benefit--questionable safety and benefit. So, if

the concept of OTC therapy for chronic asymptomatic

conditions isn't new, how strong is the evidence

that consumers can self-manage their cholesterol?

[Slide]

This slide reminds us of the key data that

we just saw from the CUSTOM study, as well as the

data from two previous actual use studies with OTC

126

lovastatin. There is a strong consistency in the

findings here. A vast majority, about 90 percent,

had pretreatment total cholesterol values of

greater than 200 mg/dL. Only a small minority were

already taking a statin at the time of the OTC

purchase. Most importantly, consumers did very

well with regard to our concerns about safety.

With safety labeling in mind, between 90-97 percent

appropriately selected the product. In addition,

about two-thirds appropriately selected, in

accordance with the labeling, for benefits.

Now, not everyone behaves strictly in

accordance with the label, but these data represent

what is likely to happen in the real world, and

that is what this OTC study, the CUSTOM study, was

all about, getting a real-world experience. What

is remarkable here is the consistency of the data

which, I might add, supports prior observations

showing that the large majority of consumers do

appropriately self-select for management of their

cholesterol.

[Slide]

But how does this compare to the current

state of prescription care when looking at the

results of statin therapy? When considering the

127

benefits of an OTC statin, all of the parameters

shown on this slide--obtaining cholesterol goal,

appropriate persistence with therapy, and an

average LDL cholesterol reduction--are, at the very

least, comparable to, if not better than what was

seen in the Rx population.

This may be surprising, or perhaps not so,

when considering the fact that self-selected OTC

users are different from and may be more health

conscious and motivated than many prescription

users. Whatever the reason, we can clearly see the

most important bottom-line outcomes which are the

key determinants of coronary heart disease

prevention. Persistence of therapy and the

magnitude of the LDL cholesterol reduction compare

very favorably to the prescription experience.

[Slide]

But no matter how appropriately consumers

manage this condition, it is not intended to be a

128

substitute for or to take the place of traditional

health care. So, we must ask will OTC divert

consumers from physician care and from

heart-healthy lifestyle practices? It is an

important question. And, it is important for us to

remember that the Mevacor OTC program was designed

to do just the opposite. It was designed to

encourage consumer interaction with their

healthcare providers in order to receive

appropriate therapy, whether that therapy be OTC

for those at moderate risk or prescription

medication for those at higher risk.

[Slide]

This slide shows the system worked. Not

only did the majority of users, as shown in the

middle bar graph, consult healthcare professionals

about their OTC use, 22 percent of the people who

didn't even purchase the product consulted a

physician or doctor or a healthcare provider as a

result of the OTC program. Also of considerable

importance, three out of four higher risk consumers

interacted with their healthcare providers as a

129

result of the OTC experience. These data clearly

demonstrate that Mevacor OTC is not an isolated

self-care product but is complementary care which

encourages interaction with healthcare

professionals.

[Slide]

As shown in this slide, consumers do not

get complacent about their heart-healthy behaviors

as a result of taking Mevacor OTC. More than 90

percent maintained or improved their heart-healthy

lifestyles of diet and exercise, confirming that

Mevacor OTC did not distract consumers from these

important interventions. Any of you who saw the

headline story today in "USA Today" about the new

diet guidelines can see that diet and exercise are

being emphasized more than ever.

[Slide]

So, I think we can say that there is a

clear need for OTC statins. There is an acceptable

safety profile and there is demonstrated

appropriate and effective consumer behavior without

diversion from other heart-healthy practices. But

130

in the final analysis what is most important,

considering all OTC users--all--is the overall

benefit-risk ratio.

[Slide]

In answering this question let us first

see how Mevacor OTC can narrow treatment gaps. OTC

can directly increase the number of moderate risk

individuals treated. Although these are rough

estimates, our analysis shows that an approximate

4-5 million moderate risk individuals will likely

seek OTC treatment. Thus, by focusing on this

moderate risk group, the treatment gap

substantially narrows.

In addition, not estimated here, we also

know that there will be some moderate risk

individuals who will be seen by their physicians

and put on prescription therapy as a result of

heightened awareness of their cholesterol problem

stemming from the OTC program.

[Slide]

Likewise, in the high risk group there

will be an estimated 1-2 million people who will

131

communicate with their doctors and possibly be put

on prescription therapy as a result of the OTC

program. Finally, in terms of this bar graph, we

also know from the CUSTOM data that, while not

ideal, there will be some usage of the OTC product

in this higher risk group. What are the

consequences of such use? Compared to otherwise

taking no action, which surveys suggest is the

usual outcome, I would submit to you that this is a

favorable result--a very important recognition.

The overall effect of OTC statin

availability is narrowing of the treatment gaps for

both the moderate and higher risk groups. Now, OTC

statin therapy is not a panacea for the entire

treatment gap and it will not fix all the problems.

But it is also very compatible with our current

efforts which may be increased in terms of the

effectiveness of Rx and any subsequent change in

the guidelines. These are not mutually exclusive

types of intervention. However, as shown, it will

substantially reduce the size of the gap by

reaching a portion of the at-risk population which

132

is not currently being reached.

[Slide]

Now I would like to consider the

population shift in the distribution of LDL

cholesterol which will occur as a result of OTC

Mevacor. This slide displays the distribution of

baseline LDL values, shown here in blue, among the

CUSTOM users.

[Slide]

The overlay, now shown in yellow, shows

the end of study, and this is the CUSTOM actual use

data, with LDL levels achieved. Together, they

clearly demonstrate the classic leftward shift in

the LDL distribution. This is a direct effect of

Mevacor OTC. Given the strong positive graded and

continuous relationship between LDL cholesterol and

risk, as was shown by Dick Pasternak in an earlier

slide, this means that nearly all users will

potentially benefit by a reduction in coronary

heart disease risk. Think of that!

[Slide]

It is of interest to note that this goal

133

of shifting the population curve is not a new

concept. In fact, over ten years ago the expert

panel of the National Cholesterol Education

Program, Dick Carleton's panel, published these

curves that show the potential complementary and

additive benefits of an increased focus on primary

prevention to our current treatment efforts.

The blue line here is the cholesterol

distribution at that time which has not changed

much since 1991. The yellow dotted line projects

the effects of treatment per the then existing ATP

guidelines if they were widely applied. And, the

orange dashed line shows how the complementary

effect of a 10 percent decrease in cholesterol

further shifts the curve, and this is similar to

what we have just observed with OTC Mevacor in the

CUSTOM data set that I showed you with the blue and

yellow bar graphs.

[Slide]

Finally, and most important, is the

projected overall benefit of Mevacor OTC.

Utilizing the CUSTOM risk distribution and assuming

134

a conservative coronary risk reduction of 25

percent--AFCAPS/TexCAPS actually showed a 37

percent overall reduction--for every one million

consumers taking the product, we can expect to

prevent between 25,000 and 35,000 coronary events

over the next ten years. Given the strong safety

profile, the overall benefit-risk ratio is clearly

highly favorable.

It was in recognition of this fact that

our colleagues in the U.K. approved the use of an

OTC statin last year. They got it; they saw the

benefit in terms of the benefit-risk ratio being

highly favorable. The time is ripe for this

important OTC option to be available to consumers

in the United States. Many consumers are

concerned, informed and motivated and are already

active in terms of their own health care. We

should provide them with better and safer options

than what is currently available to them OTC. With

aging of our population, now is the most opportune

time to make possible an OTC stain option.

In closing, we have asked ourselves many

135

questions that at first glance seem new and

potentially challenging. But when we look at the

strength and totality of the evidence we also see

that we have a great opportunity for reducing the

burden of cardiovascular disease.

Mr. Chairman, members of the committee, my

hope is that today we can look at the totality of

the evidence and recommend approval of Mevacor OTC

to reduce the huge burden of cardiovascular disease

in the United States. The challenge is before us,

but so too is the opportunity. Thank you for your

thoughtful consideration.

Questions from the Committee

DR. WOOD: Thank you, and thanks to the

sponsor for sticking so well to the time. Let's

take about 30 minutes of questions from the

committee, or less if we run out, and then we will

move on to the first of the FDA presentations after

that and before lunch. Questions from the

committee? Neal?

DR. BENOWITZ: I actually have a lot of

questions but I will just start with one to let

136

other people have a chance. One of the issues that

is really important for over-the-counter

medications is the patient's capacity to understand

benefits versus risks. This is something that we

deal with in practicing medicine as well, and one

of the things that is always an issue is when you

talk about relative risk changes in primary

prevention.

You may be talking about a 35 percent

reduction of risk, but looking at the data that are

presented, it really is looking at a 2 percent or

2.5 percent change in absolute risk over six years.

Nowhere do you really talk about absolute changes

in risk, and I think that is an important question

for a patient. They have to know that 25 people

have to take this medicine for six years, at a

minimum, to prevent one event. It is true that

there is great population benefit, but when we are

talking about individuals there needs to be some

consideration to give an individual the information

to make a benefit-risk appraisal. You did talk

about absolute risk for safety issues, but you

137

didn't talk about absolute benefits.

So, I would just like to hear someone

address the question of how do we really give the

patient the proper information to make an

intelligent risk-benefit analysis.

DR. WOOD: Who wants to take that?

DR. HEMWALL: I will at least start. I

guess what you are asking is to somehow also

include in our education and support materials more

explanations of what really is meant by a reduction

in risk for heart disease. In this case we are

talking in the realm of 25-50 percent, depending on

which study you look at and the patient population.

That is certainly possible. In fact, that would be

something we would be more than willing to put in

the right perspective for patients so they would

understand that, and make that as part of their

decision.

DR. WOOD: I think what he is asking is if

you have a similar percent reduction in relative

risk across different populations, the absolute

risk will be reduced differently in the lower risk

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group. Is that what you are getting at, Neal?

DR. BENOWITZ: Exactly. In secondary

prevention it is easier because the absolute

benefit is great. But the debates in primary

prevention have always been the small absolute risk

benefit.

DR. WOOD: I think that is the question.

DR. PASTERNAK: Just to amplify it--thanks

for the question and it is an important question.

There are a couple of responses to that. First of

all, people make those choices--low risk or

moderate risk people make those choices every day

when they decide to go running, when they go on a

diet, when they take an aspirin. So, people are

capable at some level of making that kind of

decision.

Second of all, as Dr. Cohen showed at the

very end, we think there really is a substantial

benefit to this population, and the number needed

to treat--and we can discuss whether the right

number is 28, 38 or 48--is actually a fairly

favorable number in terms of preventing an event.

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It is comparable to the number that is needed to

treat that is seen in some of the secondary

prevention trials.

Finally, you are correct that I focused on

relative risk, but my principal aim in discussing

that was not to obscure the low absolute risk but

to make it clear to everyone that the relative risk

reduction is consistent across a wide variety of

populations, a wide level of risks. It has been

said by some that there is no benefit to this and I

think understanding and comparing relative risks is

a way to get at understanding that.

DR. WOOD: Dr. Woolf?

DR. WOOLF: I have a question for Mr.

Hansen. You have a very elaborate display that

will be in the pharmacy for the patient to decide

to go on Mevacor OTC or not. Are there other

models that have been previously used in the

pharmaceutical industry that have helped to guide

the patient to the appropriate or inappropriate use

of a drug? If so, what are they?

MR. HANSEN: To be honest, this is

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unprecedented, and this program that we have put

together has gone to more lengths to help the

consumer out, both with the healthcare professional

and to do it on their own, than anybody has done in

the past.

I think the example of the one that got

the closest was smoking cessation products. It was

mandated in their NDA that they did have support

materials. There were audio tapes available and

there was a support program that they could enroll

in, and enrollment in that was fairly high.

I think the other precedent with smoking

cessation is that there was a commitment that

smoking cessation products not be sold in

convenience stores, and that commitment--even

though it was ten years ago--is still being upheld

today. So, in essence, those two are the closest

but obviously we are breaking some new ground.

DR. WOOD: Dr. McClung?

DR. MCCLUNG: I want to come back to the

issue about the absolute risk and benefit. The

absolute risk numbers have a time element, or at

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least the number needed to treat has a time element

in it. We have been told about the two percent

reduction in absolute risk and the retrospective

population that would have met the criteria for

OTC, but that was over a five-year interval of

time. And, the absolute risk for the side effects

was described in the CUSTOM study over a six-month

interval of time.

If I have done my math correctly, if there

is a 2 percent reduction in absolute risk over 5

years, that is 0.2 percent over half a year. And,

we are told that the incidence of muscle symptoms

in the CUSTOM study was 60/1000 patients or 0.6

percent, and that 16 of those patients had muscle

symptoms and continued therapy, which is an

incidence of 0.16 percent, not very different from

the absolute benefit that would be derived.

So, I concur strongly that we ought to

make sure that we communicate what the absolute

risk and the absolute benefit is, and to put it in

the context that not only physicians can

understand, which is often not the case, but

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certainly to put it in a perspective that patients

can understand.

DR. WOOD: Dr. Watts?

DR. WATTS: I would like a little more

information about the patient interactions in the

CUSTOM trial, or the subject interactions. In the

reading material I think there was mention about

the time involved, but I would like a better

explanation of how much time each individual spent

trying to master the material in the package

insert, and also a little more information about

the circumstances at the testing center. We were

told that there was a display set up, but we are

not told whether that really matches the

surroundings that a patient or prospective buyer

would be in with competing products, other people

passing through, distractors that might interfere

with their attention span to the material they are

expected to master.

DR. WOOD: Does somebody want to respond

to that?

DR. HEMWALL: Well, I understand your

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question to be along the lines of how realistic was

the pharmacy setup in the CUSTOM study at the study

sites. There were, in fact, store front settings

in strip malls. They were set up to appear as if

they were operating pharmacies but, of course, when

one walked in, it was clear that they were not an

operating pharmacy but they had simulated shelf

setups and the consumer was asked to actually go

and evaluate the material as if it were on the

shelf with mock other products next to it. But it

was not a fully functioning pharmacy.

Although we have done other studies in

pharmacies, some of the questions that we tried to

answer in these various studies caused us to do

different things in design and this was clearly a

self-selection and then an ongoing use study.

Therefore, we elected not to do this particular

study in working pharmacies. But we did try to

mimic that experience. But in all of these

studies--and I think FDA recognizes tha--you can

only get so close to creating the true, natural

environment when you are also doing a study that is

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conducted under IND with all the appropriate

regulations that go along with that.

DR. WATTS: The other part of the question

was the amount of time the average subject spent

reading or trying to comprehend the package insert

material.

DR. HEMWALL: We did not record that

amount of time. Again, they had as much time as

they wanted. They not only had the package to look

at on the shelf with the shelf display--the same

one that is shown here--and interact with those

materials but there are tear-pads that they could

remove, go home and get further information. So,

in fact, a lot of people, as Bob Tipping explained,

actually went home and came back later, either

after having consulted with a physician or gotten

their number somehow and returned. So, in some

cases the amount of time they had to consider the

product was several days. In other cases they made

the decision within several minutes and probably,

you know, an entire range within that.

DR. WOOD: Dr Tinetti?

DR. TINETTI: My question relates to

discussions that have taken place concerning the

safety and benefit in an elderly population, which

145

I will define as greater than 75, given the little

data that exists in your studies. As I looked at

it, in the AFCAPS/TexCAPS, the exclusion criteria

was age over 73. The average age was upper 50s to

lower 60s. It looked like in the actual use study

there were also very few very elderly people. So,

without evidence of either benefit or safety in

this age group, how comfortable do you feel?

Particularly, these people have multiple

co-existing conditions. It is clear they are a

target audience for you because it was mentioned

several times this morning that the aging

population is one of the important reasons to push

forward with this.

And a related question, I haven't heard

much discussion, or in the materials, about the

softer, if you will, more subjective adverse

outcomes related to statins that always anecdotally

have been discussed--depressive symptoms, mild

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cognitive changes. I was just wondering what

discussions and concerns have been raised in those

areas.

DR. PASTERNAK: Well, both those questions

are important. You are correct, in the

AFCAPS/TexCAPS trial most elderly were not

included. I think our answer to that is that if

one looks across all of the clinical trials at

subgroups such as they exist, the elderly group has

a result that is consistent in terms of relative

risk, often greater in terms of absolute risk

reduction than younger groups.

The two trials that addressed the most

elderly include PROSPER, a study of pravastatin,

and the Heart Protection Study, a study of

simvastatin. They were specifically designed to

look at that question and in those, including the

age groups you just mentioned, there was a highly

statistically significant benefit that was

homogeneous with the results in other groups.

So, I think that the weight of the

evidence for statins in the elderly is that

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relative risk is consistent and the absolute risk

is often even greater because the absolute risk in

that population is very high.

I am not quite sure of the answer to the

other question. Others on the panel might wish to

respond but, you know, statins have been looked at

for a long, long time now. One of the points of

our ACA/AHA/NHLBI statement in 2002 was to try and

review all of these other notions that statins

might somehow be doing something else that people

need to worry about, whether it is something

important like cancer or other less important

issues. As you probably know, there are also those

who are arguing on the other side, that they are

useful. I think most of those observational kinds

of looks have not borne out in either direction and

we have to stay focused on what we know these

things do.

DR. WOOD: Frank?

DR. DAVIDOFF: Yes, I am having

considerable difficulty interpreting the CUSTOM

study, as interesting as it is, because it seems to

148

make the assumption about user eligibility based on

several criteria that are on the product label and

that are widely accepted, but it does not take into

account other primary prevention strategies that

are easily available to people and are widely used,

in particular low-dose aspirin.

So, I will limit my question to that,

which is were data collected on how many people

were taking low-dose aspirin in the CUSTOM study?

Because from what we have seen of the data with

low-dose aspirin, it reduces risk over the longer

term by just about the same amount that statins

would in a primary prevention setting. Albeit,

aspirin does have certainly its own risk profile,

which is another issue, I just have difficulty

knowing what the actual risk and, therefore, what

the actual benefit would be for people who enter

this trial or who took OTC statins in the

marketplace because we really don't have an idea of

what their risk status is if we don't know if they

were taking low-dose aspirin.

As a related sub-question, are there data

149

on potential marginal benefit for taking statins in

addition to low-dose aspirin? Because there may

be, in which case that would be encouraging, but

there may not be.

DR. HEMWALL: There are a lot of questions

within that one question. Yes, we do have the

information on who took low-dose aspirin in CUSTOM

and we can get to that in a minute. But I think

the larger question revolves around the concomitant

use or the additional benefit with regard to taking

low-dose aspirin and a statin. I would like to

introduce Dr. Tony Gotto, who is willing and able

to comment on that particular topic.

DR. GOTTO: I am Tony Gotto, from Weill

Medical College. We recorded the participants in

AFCAPS/TexCAPS who were taking aspirin. We didn't

differentiate between whether it was low dose or

regular aspirin, but just aspirin use. In

virtually all of the secondary prevention trials

with statins there has been a high use of aspirin,

in the CARE study about 80 percent, and that is

about typical for the secondary prevention studies.

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There was significant aspirin use in AFCAPS/TexCAPS

as well. This group was very active physically and

there was a major emphasis on lifestyle changes for

all of the participants in this study with group

sessions, and we hammered away at diet and

exercise, and these were very health conscious

individuals. I think they certainly qualitatively

reminded me of the description of the typical OTC

patient. But all of the statin trials have shown a

benefit on top of aspirin use, on top of beta

blocker use, ACE inhibitor and various other things

that are controlled for. And, low-dose aspirin has

not been approved by FDA yet, has it, for primary

prevention?

DR. PEARSON: I would like to comment. I

am Tom Pearson, from the University of Rochester.

I had the opportunity to chair the American Heart

Association primary prevention writing group which

endorsed the use of low-dose aspirin for the

primary prevention of heart disease.

Part of the issue directly related to the

question is that, in fact, in January was presented

151

an analysis looking at randomized, controlled

trials of a statin, pravastatin, with the

observational arm of aspirin use. This was

presented as part of a presentation to the FDA

advisory group on metabolics. The suggestion is

that there is at least an additive effect and very

possibly a synergistic effect which you could, in

fact, bring into a variety of mechanisms to explain

that. But it is at least additive, and some of our

statistical friends would suggest it is even

synergistic.

DR. WOOD: Thanks.

DR. SCHAMBELAN: My question gets back to

the self-management system and the specific issue

of the pharmacy interaction. Is the plan not to

market this OTC product in convenience stores and

supermarkets in which there is not a pharmacy? Is

that going to be specifically interdicted? It

seems like a lot of educational materials would not

be available in that kind of a setting, and that is

certainly where a lot of OTC products are sold.

MR. HANSEN: Yes, we are clearly

152

recommending that this be sold in stores with a

pharmacy only and no other outlets.

DR. WOOD: Dr. Snodgrass?

DR. SNODGRASS: I will just ask one

question. It relates to the risk-benefit ratio

considerations and that is, what is the risk of not

being evaluated by a physician? That is basically

my question. I realize they attempt to involve

healthcare professionals in this but it seems to me

that there are a number of causes of so-called

secondary dyslipidemias, besides diabetes and

thyroid, obstructive liver disease and renal

failure. I don't know that patients who will have

some of these conditions or some degrees of them

will be aware of this. I think there is also the

issue that those persons in your study who knew

enough to know about their cholesterol may, of

course, have had some interaction with their

physicians so you may have selected away from those

who would less likely have this knowledge.

DR. WOOD: Someone want to take that?

DR. COHEN: Yes, thank you for the

153

question. I can understand the first part of it

but help me if I am not answering quite the

question that you asked afterwards.

If we look at the benefits of this program

overall, it really necessitates, in terms of proper

use, that the person knows something about himself

or herself with regard to the label. Indeed, the

CUSTOM study showed exactly that. So, someone who

has never seen a physician, who doesn't know their

blood pressure--they know whether they smoke, they

know their age and they could qualify just on that,

and the family history, and not have any other

medical knowledge except that they don't know their

lipids which, of course, is part of the labeling

there.

So, I think in this situation if someone

took it without knowing what their cholesterol is,

again, you would have to come back to a high enough

risk patient who would benefit regardless of what

that was. And, we can pick a number, whether it is

higher or lower or exactly what we would expect as

an average, and this might happen over a period of

154

time with other people being involved and not

knowing their cholesterol.

If you shift their curve to the left, then

I think we will see, as Dick Pasternak showed on

his slide, a reduction in risk estimates based on

the LDL reduction that will be achieved using the

Mevacor OTC product. The issue is, is the safety

there for that person who is unknown, and I think

from the data that we have seen here this morning

that the safety is there. So, that benefit-risk

ratio for that person who has not seen a physician,

who has not been evaluated is still favorable I

think. Certainly, hopefully, he or she will see a

physician more likely because of the result of

reading the label, being in the program,

recognizing the importance of knowing these data

and getting follow-up than they would have perhaps

otherwise. Does that address your question?

DR. WOOD: Can I just follow-up on that

question? It seems to me that there is an

underlying assumption that is somewhat untested and

probably wrong. That is, the comparison for OTC

155

lovastatin that should be made is one against

physician care which is 100 percent perfect--

[Laughter]

--and that is what I mean by probably

wrong. How do we know it is probably wrong? Well,

the first way we know it is wrong is that almost

the only way that someone can get a cholesterol

measured in this country is by going to a

physician. So, almost by definition and going back

to Dr. Snodgrass' question, the population that you

have studied has to be a population of patients who

have failed to receive adequate cholesterol control

in spite of being seen by a physician.

Then, the second part of the question

relates to toxicity and following the warnings.

Again there is an unspoken assumption, which is

also I think probably wrong, and that is that if

patients, indeed, saw a physician the warnings

would be clearly followed explicitly and

absolutely. And, we know from lots of data--you

know, just think of three drugs that have been

withdrawn, Bacyol, Resulin and cisapride--in each

156

of these cases there were explicit warnings on the

drug label and in each of these cases, and in the

case of Resulin particularly, we know that only a

tiny percentage of patients were following the

specific monitoring warnings that were out there.

So, I was a bit surprised that you all didn't

address that in the presentation.

DR. COHEN: Well, let me just come back to

your first point, and that is that these are

patients who may have seen a physician and the

physician didn't act appropriately. We don't know

that. In fact, the physician may have acted quite

appropriately in the sense that they assessed the

risk, they recognized high cholesterol, and perhaps

wanted to recommend an Rx therapy. What is unique

about this population is that it is an OTC-driven

type of population where they say, you know, Rx is

for a sick guy. I am a healthy person. I am

concerned that my cholesterol is too high. I will

continue doing whatever, including buying other

heart-healthy supplements.

So, I think these people may be in the

157

system. They may be seeing their physician and we

have data to show that. But, in fact, I think they

are, for whatever reason, not following through in

terms of an Rx or not getting an Rx in the first

place, perhaps related outcome the healthcare

system.

DR. WOOD: There is another response.

DR. HEMWALL: I do want to acknowledge

your comments, Dr. Wood. In fact, we are not

trying to compare to the healthcare system here. I

think in one of the earlier slides that Dr. Cohen

showed, we did pretty well according to what is

currently in the literature about management of

statin therapy, certainly not worse.

DR. WOOD: I just wanted to be polite!

Dr. Follman?

DR. FOLLMAN: Yes, I would like to discuss

the issue of potential under-dosing with the

over-the-counter strategy for Mevacor. First, Dr.

Cohen had a slide, I think it was 181, which showed

the distribution of baseline LDL levels. I have a

copy of that here, and I was counting up the

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percentages greater than 170 and it looks like

about a third of the patients in the CUSTOM study,

with all the scrutiny, etc. that was involved in

that study, had LDL levels which are not in

accordance with the label and they would probably

be better off being seen by a doctor and getting

optimal statin dosing and therapy. So, there is

this concern about potential under-dosing at the

point of purchase.

Another thing has to do with the potential

under-dosing over time. So, if you look at the

label at the back of the box or some of these

brochures, etc. that you have, there isn't really

mention made, as far as I could tell, of the

importance of getting LDL tests, say, every year.

So, the way this is being marketed or proposed is

chronic treatment. So, you just keep using it

presumably forever. So, for a person like that who

is going to continue to use it and not recognize

that his LDL is creeping up past 170-200, or

something, seems to me an error of omission in the

label.

So, two issues about under-dosing, one at

the time of purchase and then concern about upward

drift which won't be recognized by the label, or

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encouraged to be discovered by the label.

DR. PASTERNAK: Dr. Hemwall is going to

have a comment about the last part of that with

respect to the label, but we obviously would have

loved it if everybody who had an LDL over 170 had

more potent LDL-lowering than was available from 20

mg of lovastatin. But, remember, these are people

who didn't get any other therapy.

I have heard a lot, not only in the

context of thinking about this but kind of on the

street, about the potential under-dosing with 20 mg

of lovastatin. Remember a couple of things. First

of all, there is this 1:1 relationship that for

every milligram/deciliter LDL lowering there is one

percent change in risk. So, while it is not the

optimal risk lowering that a very large dose of a

very potent statin in a very high risk population

will achieve, remember, we saw on the average 20-25

percent LDL lowering and that is associated with a

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substantial relative risk reduction of roughly 25

percent. So, it is true that greater degrees of

risk reduction are possible, but this is still a

very impressive degree of risk reduction and

certainly comparable with the kinds of things

people try to do every day to improve their risk.

In terms of the LDL test, I think it is

the same sort of comment. We would have been

delighted if everybody had behaved appropriately--a

comment that is kind of consistent with Dr. Wood's

a moment ago. When in other settings we have

tested how physicians do with respect to LDL

monitoring, there is that same problem. So, it is

not optimal. It is not optimal in this population

and it is not optimal in the standard of care these

days.

DR. HEMWALL: I just wanted to make sure

we gave a complete response to the question with

regard to the messages that are in our materials

for ongoing monitoring not only of your

cholesterol--and the label specifically says if you

have reached goal get your cholesterol tested once

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a year--but it also says that one should be on the

lookout for any change in their health condition

and that they should see their doctor for any

change in those conditions. We actually measured

that in CUSTOM. We had people, as Bob Tipping

pointed out, develop diabetes that didn't go to

their doctor during the course of the CUSTOM study.

Another feature of the support and

management system is the ongoing communication that

goes on well beyond, into the future, where they

will be receiving communications and regular

messages within the materials. I urge you all to

look at the materials that are in the box that we

provided for you. Also the newsletters that come

on a periodic basis when one opts into the program

all encourage that retesting and the continual need

to reevaluate your health status and the need to

see a doctor.

DR. WOOD: Dr. Watts?

DR. WATTS: The success of the program is

in large part dependent on the patient's accurate

knowledge of their cholesterol level to know

162

whether they are appropriate to initiate their

therapy, and their follow-up cholesterol level to

know whether they are reaching goals. What I

haven't gotten a clear picture of, though it may

have been woven into all this, is information about

the validity of patient self-reports of their lipid

results, both for the initial assessment of whether

they are appropriate candidates for OTC Mevacor and

for subsequent studies to know whether they are

meeting goal.

MR. HANSEN: This is going to be a tag

team because I am going to first start with the

general population knowledge of cholesterol numbers

and the ranges because that is important if this

product is approved in the general market. Then

Bob Tipping will come up and show you exactly the

people in CUSTOM who did know their numbers and how

accurate were they in those self-reported numbers

because we did test at the end of the study. So,

if I could have slide 1938?

[Slide]

This is in the general population. We did

163

the study this year, and it shows a couple of

things. First of all, awareness of total

cholesterol numbers was virtually 100 percent and

that is why it is not on the chart. Then, what you

will see is the subfractions of LDL, HDL and

triglycerides.

There are a couple of things on the chart,

first of all, the knowledge of these terms--and

this is just knowledge of the terms--has increased

over time but it is certainly higher for total

cholesterol than the subfractions but we are making

progress.

Now I would like to go to slide 1943

because this is getting closer to home. This is

actually do people know their own values?

[Slide]

This, again, is on an ongoing basis and we

will show you trends. So, this is total

cholesterol and can people describe their own

cholesterol? For the most part, their total

cholesterol--over 90 percent can describe it. Only

28 percent can give you a specific number but 91

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percent can describe it as either being high,

borderline high or normal.

[Slide]

If you go to the next slide, you will see

that there is a drop-off on LDL but still pretty

good numbers. Less know their specific number but,

again, they have heard from their doctor or know

for themselves and they can describe it as either

being high, borderline high or normal.

Now, the real key question is how did

people in CUSTOM who said they knew their range do

compared to their actual values, and Bob Tipping

will show that.

DR. WOOD: Well, the other question, going

back to my point, is presuming they heard from

their doctor that that is normal, that may not fit

with the criteria from the panels. Do we know

that? Do we actually know that when a patient says

their cholesterol and their LDL is normal that that

means that they don't fit the treatment criteria as

dictated by the various recommendations?

MR. HANSEN: If we don't answer your

165

question we will come back, but I think what Bob is

going to show is that people were able to describe

either their exact number or whether it was in a

range of either normal, high or low. Then we went

back and looked at those numbers and he will tell

you how well they were able to match those up. I

think that will get to your question but, if not, I

will clarify.

MR. TIPPING: Thanks, Jerry. Before I

describe some numbers for you, let me just remind

you a little bit of the design where behavioral

decisions were based on an individual self-reported

value but we did obtain the baseline actual

measured values so we were able to address the

question of what is the accuracy or the validity of

that.

With our user population, we had 660

individuals who reported that they knew their value

and then we were actually able to obtain the

baseline value, and for 76 percent of them those

two values agreed with regard to the ranges

described.

DR. WOOD: Dr. Schade?

DR. SCHADE: Yes, I have a question. I am

having trouble finding the information, and it may

166

be me, but my question is about diabetes. I

understand this may not be the direct population

being targeted but they actually represent a huge

risk for atherosclerosis, but as I understood it

from the presentation earlier this morning, the

labeling or the package insert is going to state

that if you have diabetes you should not take this

drug. Is that right or am I confused about that?

How are you actually handling a case when a patient

knows they have diabetes?

DR. HEMWALL: Yes, that is one of the

messages right in the main part of the label, that

you are not to take the drug if you have diabetes,

without first checking with your doctor. So, it is

not a contraindication but it is a statement that

says that you need to talk to your doctor if you

have diabetes. In fact, we hope that if they find

out that they do, they may need more comprehensive

care than simply an OTC.

DR. SCHADE: Yes, that would be of concern

to me only because I can see a rush of patients

coming in, pointing to me, saying that they cannot

take this statin and, by definition, other statins.

It would be worrisome to the patient as well. I am

concerned about that.

167

DR. HEMWALL: Well, that is a good

concern, and I would want to take that into

consideration with the team as far as perhaps even

putting more of that information in the educational

materials about the importance of having your

lipids treated and to see your physician. It is

not that it is a bad thing if you are a diabetic to

take a statin, but more that you should be doing it

in collaboration with your physician.

DR. SCHADE: Yes, I think some more

explanation is needed because most of my patients

who have diabetes read something and they

immediately think it contains sugar, or something,

because all these cold medicines and everything

else contain that same statement and I get lots of

calls when a patient gets a cold--can I take this,

168

this and this? And, inappropriately, they end up

not taking something that would help them.

DR. HEMWALL: That is good advice. We

would want to factor that into our materials.

DR. WOOD: That is a good point. Dr.

Carpenter?

DR. CARPENTER: Going back to your earlier

description of a lot of this process, challenging

or raising new approaches to how we structure the

paradigm of practicing preventive medicine, I

consider that a great deal of obstacles and certain

patients' access to various medications is cost. I

just wondered if anyone has speculated whether

insurance coverage for statins would change with an

over-the-counter designation and if that would have

any impact on getting this to the people of concern

in contrast to using it as a prescription.

DR. WOOD: Well, it may well do but I

think it is probably not the remit of the committee

to address the financial issues, however

controversial that might be, unless the FDA wants

us to address that.

DR. MEYER: I would say it is to the

degree that the issue of the overall benefit to the

population has been raised, which also isn't

169

strictly our purview. I think it might be

interesting to hear the answer to the question.

DR. WOOD: To rephrase the question, will

it be covered under insurance? Is that the

question?

DR. CARPENTER: Is there any information

to indicate that with a change to over-the-counter

status it would substantially affect availability

because of lack of insurance coverage?

DR. WOOD: And I would extend the

question, and would it result in other statins

being taken off coverage for Rx?

MR. HANSEN: This was a key concern of

ours because the goal of our program was to

actually get people into the system and get on

either OTC or prescription therapy if possible.

So, we actually went out and did a study, an

independent study with Towers Parent that was

published in The Journal of Managed Care Pharmacy,

170

in November, and the results were pretty

interesting. We had a good representation of most

of the large managed care organizations and they

have covered over 100 million lives, and the

findings were that they view cholesterol as very

different than they do allergy or heartburn, like

with the recent switches of Claritin and Prilosec,

that cholesterol is for more serious treatment.

They also recognized, as we showed in the treatment

gap, that most of the treatment today is with the

high risk people with higher dose statins. So,

they really don't feel like they would be capable

of down-shifting or downstreaming those consumers

because that would be bad medicine and, in fact,

they may be liable for that. So, we do not see any

evidence that there will be any major changes in

formulary.

The only balanced statement I will give to

that, however, is that if a person did come in and

they were appropriate for the OTC label and were

not on prescription lowering at the time, managed

care said, hey, there is not a problem. As long as

171

they are appropriate for OTC, they can try that

product and if they don't get to goal, certainly,

we would put them on prescription therapy--so, a

clear delineation between the person who is on an

Rx today. No, we are not touching those people.

In the future, if they fit the OTC profile,

potentially.

DR. SCHWARTZ: Sandy Schwarts, University

of Pennsylvania. I have been advisor to some of

the PBMs and to some of the medical insurers

regarding Medicare coverage decisions. You have to

be careful. They make their own coverage

decisions. But I think it is safe to say that an

OTC preparation would not be covered by current

plans, but also that it almost certainly would not

affect the other current statins on therapy because

of the dosing differential for treatment targets.

For example, even PPIs, people who require higher

doses of PPIs can still get coverage under almost

every insurance plan in the country while you can

get low-dose PPIs over-the-counter.

DR. WOOD: Dr. Neill?

DR. NEILL: I have a couple of questions.

Several of the speakers have mentioned the

treatment gap for these moderate risk patients, and

172

I am interested in data, if you have it, that looks

at all 11,000 callers, of whom 3300 were evaluated,

and in those groups how many were treatment

eligible and how many were already on treatment pre

and post CUSTOM? In other words, I am looking for

evidence of efficacy that this self-management

program does what you suggest that it would do when

it is OTC in this CUSTOM study. Then I have a

second question after that.

DR. HEMWALL: Well, the first answer is

fairly simple. We did not collect that kind of

information from the callers regarding their

demographics or the type of information that you

are looking for.

DR. NEILL: As a family doctor that takes

these phone calls when advertisements end up on

television, I am anxious to know for those 7000 or

6000 patients that did not present to be evaluated,

what was the enticement for the 3000 that did, and

173

what was the dissuasion for those that did not?

DR. HEMWALL: Well, again, this may be in

part an artifact of doing a study where you don't

have a pharmacy in your local neighborhood which

would carry the product in the real world. So, in

the seven geographic areas in which we conducted

the study, each had two sites. Here, in the

Washington Beltway area, we had a site I believe in

the Silver Spring area and one up--there is a

northern side and a southern side and I can't

remember the exact cities. We can get that.

But the point was that a lot of people

realized, once they made the phone call, that they

might have to either travel to a study site or they

decided that there was something that was

inconvenient for them and they didn't want to

participate. They weren't given very much

information, as per FDA working with us on the

protocol--not to explain to them a lot about the

study, other than that it was, indeed, a study; it

was not something were you were actually purchasing

a retail product. Although they were also told

174

that they would have to purchase the product and

that may have dissuaded a lot of people who thought

they were going to get free medicine.

DR. WOOD: You have a second question?

DR. NEILL: I will hold it till later.

Thanks.

DR. WOOD: Dr. Clyburn?

DR. CLYBURN: We heard a lot about the OTC

population and how they are interested in

prevention and not necessarily wanting to

acknowledge that they have any chronic illness like

hyperlipidemia. Are we going to facilitate their

denying that they have hypertension, obesity and

hyperglycemia by putting medicines over the counter

to treat hyperlipidemia?

DR. WOOD: It sounds like perfection is

the enemy of the good, right?

DR. HEMWALL: I am not really sure I

understand the question. Could you repeat it,

please?

DR. CLYBURN: We spent a lot of time

hearing about the OTC population being different

175

than the regular population, and that they are

unwilling or don't want to acknowledge any chronic

illness, are more interested in prevention. Are we

going to make them feel good about themselves with

over-the-counter medications and allow them to deny

other illnesses?

DR. HEMWALL: No, I don't think that is

the case but I think Jerry Hansen, who has done an

awful lot of the consumer research and has a better

understanding, may be able to address that

question.

MR. HANSEN: This is a tough question

because it has kind of emotional behavioral

insights involved with it. So, I am not exactly

accurate but I think I can say, after talking to

30,000 consumers over the past seven years, I can

probably get pretty close. Hypertension and

diabetes are viewed very differently by a consumer

than is high cholesterol. I think you have

probably all seen that in your practices.

The burden that high cholesterol has that

those other ones don't is that diet and exercise is

176

usually tried first and if you don't succeed, that

is considered a failure by the patient and

oftentimes by the doctor as well. So, this is a

situation where the patient really doesn't want to

admit they failed or admit that they are sick and

would like to try an intermediate step in between,

whereas we don't see that with hypertension or some

of the more serious conditions like diabetes.

DR. WOOD: Dr. Clapp?

DR. CLAPP: My interest is in the labeling

of the product with regards to women who are under

55. Apparently, the reason that it has a pregnancy

X categorization is because of the risk to the

fetus to women of childbearing age. In this

regard, the product is being marketed for women who

are over 55. I am not sure if there is clarity on

the package with regards to the reasons that women

under 55 should not take the medication. Since

that doesn't seem to be addressed, should that be

listed in terms of "do not use if you are a woman

of childbearing age," rather than a woman who is

pregnant or lactating.

DR. HEMWALL: Yes, I think we can probably

add additional language to the label in that

regard, but it is important to recognize that the

177

reason that this drug is category X is because

there is no benefit to treating a woman during the

short term of pregnancy for lipid lowering, and

there is an equation which goes into category X.

And, if there is no benefit whatsoever, then even a

small amount of risk renders it to be

contraindicated and that is why the statins are

category X, because there is no benefit to treating

high lipids during pregnancy.

But the labeling question is a good one.

In fact, other OTCs have already adopted that. As

you well know or many of you may well know, the

NSAID category of drugs, which encompasses quite a

few of the OTC products, do have concerns about

disruptions in the pregnancy or harm to the fetus

with regard to inhibition of prostaglandin

synthetase and all over-the-counter NSAIDs carry

specific labeling warnings about not using the

product in the third trimester with that exact type

178

of language which you suggest. So, certainly,

there is room to strengthen the message in the

Mevacor label beyond just do not use if you are

pregnant or breast feeding.

DR. CLAPP: Then my question to you is

additionally that if the reason for under 55 is

because of concern of pregnancy--

DR. HEMWALL: No, the 55 is according to

the NCEP guidelines as a risk factor. One of the

risk factors is age for heart disease, 55 for women

and 45 for men. The paradigm is know your lipids,

between 130 and 170, and have two additional risk

factors, and you automatically have one of those

risk factors by having the age for men or women.

DR. CLAPP: So, then teasing out the risk

to the unborn fetus, should there be something

specifically noting that women of childbearing age

should avoid this medicine because of the risk to

the fetus, unless they are prescribed the

medication by a physician?

DR. HEMWALL: I think the message would be

more along the lines of if you are planning on

179

becoming pregnant you should not be taking this

drug. The data that we have so far, and we would

be happy to go into much more detail, is that the

risk to the fetus, as seen in clinical outcomes, is

very much similar to what would normally be a

category C drug but, in fact, if a woman is

inadvertently exposed in an unintended pregnancy

the risk to the fetus is very small.

DR. WOOD: Could I make a suggestion--this

is obviously a very important topic--but that we

hold this until after the next presentation which

is going to address this directly, and then we can

come back to it in detail if we want? Dr. Parker?

DR. PARKER: My question is about the

label comprehension study. My question is whether

or not it is adequate. My understanding is that

there were 696 patients and that over half of them

were under the age of 45, and less than 10 percent

of them were over 65. I guess I have a little

trouble with that. If the purpose of the label

comprehension study is to assess whether or not the

label is adequately comprehended, the target

180

population for users is really small in that. So,

I would like someone to address that.

I understand from the slide presented that

looked pretty good, greater than or equal to 80

percent had acceptable responses on the measures.

What about those that were incorrect, and was that

data used in redeveloping the label so that it was

more adequately understood? How was the data from

the label comprehension used in CUSTOM?

DR. WOOD: Somebody want to address that?

MS. LEVY: My name is Stephanie Levy, and

I run the label comprehension studies. If you

could just ask me your questions one by one, I will

be happy to try to answer them.

DR. PARKER: Could you address the

adequacy of the study, number one--696 patients,

less than half of them in the target age--excuse

me, half of the participants in the label

comprehension study were under the age of 45.

MS. LEVY: Yes, we designed this study in

conjunction with advice from FDA. It was designed

to be a representative sample. However, we did

181

feel it was important to supplement for low

literacy groups, but it was felt to be important to

include people who were not in the target group to

confirm that they were not appropriate to use the

product as well. In terms of women under 55, we

did have 254 women in the study of that age group.

DR. PARKER: So, 255 [sic] women that

would not be users of the drug were tested on their

ability to comprehend the label. Is that correct?

MS. LEVY: That is right, because

comprehension is supposed to test among the people

who can use the product, do they recognize that,

and among those who can't use the product, can they

recognize that as well.

DR. PARKER: What was the performance on

the label comprehension study of understanding your

eligibility based on your age alone?

MS. LEVY: I can show you information that

shows the self-selection among that group of women,

but we don't have data that links that that is the

reason but, certainly, we have self-selection among

that group of women, if you would like to see it.

DR. WOOD: I think the question is, is

there an age-related difference in the

comprehension study. Is that the question?

182

DR. PARKER: Did these people understand

the label well enough to be able to decide whether

or not they are age eligible?

MS. LEVY: Could I have slide 1751,

please?

[Slide]

These are the self-selection scores, both

men and women in the different age groups. We

looked at correct/acceptable scores and also

correct and acceptable separately. You can see

among the women under 55 years old, and there were

254 of them, 92 percent got a correct or acceptable

score; 76 percent completely correct saying that

they could not use the product.

DR. PARKER: Thank you.

DR. WOOD: I know we have more people who

want to ask questions. I just want to be sure I

have covered everybody at least once. Is there

anyone who has not had a chance to ask a question

183

and wants to ask one that I missed?

[No response]

Then let's go to Dr. McClung.

DR. MCCLUNG: I want to come back to the

differentiation--this is an easy question, by the

way, that has a specific answer--in the jargon we

have heard today, the OTC versus the Rx guys, one

of the strong justifications for having Mevacor be

over-the-counter is that patients would accept an

OTC medication more than a prescription medication.

Let me ask exactly how that question was asked

where you got those answers. Was is asked "would

you prefer to have a prescription or

over-the-counter remedy for your heart health

program?" Or, was the question asked "if

lovastatin was available over-the-counter and by

prescription, would it make a difference in your

selection on the basis of lovastatin availability

in those two ways?"

If you compare a prescription drug and an

OTC drug, you have described that people who want

OTC things don't want to see themselves as sick.

184

The other distinction is that patients see

over-the-counter preparations as being natural and

safer in some ways than chemical prescription type

drugs. So, to compare prescription drugs with

over-the-counter preparations like vitamin E isn't

quite the same as comparing the acceptance of a

specific product, in this case lovastatin, and a

prescription versus in an over-the-counter

circumstance. So, can you describe actually how

you asked the question to derive the data that you

presented to argue that over-the-counter

availability would increase the interest among

those who might choose to take it?

MR. HANSEN: Yes, let's look specifically

at slide 58 if that answers the question. I

believe it has the exact wording of the question.

[Slide]

So, what the National Consumer League did,

because this was a concern of theirs as well and

they wanted to understand what is the magic of OTC,

they went out and asked people who were untreated,

either at potential or known moderate risk to

185

themselves, which of the products you would more

likely take action with.

The further description of this was that

they are exactly the same product, exactly the same

dose. The only thing that differs here is the

distribution of the product. So, here are the

results that you see, which one would you rather

consider taking? Again, this was 20 mg Mevacor or

the equivalent, whether it is OTC or Rx. You can

see that 3:1 they would much more likely take

action with an OTC than a prescription, which is

the basis for our being resistant to Rx versus OTC.

So, that is exactly how the question was worded and

exactly how it was put into perspective, that this

is exactly the same drug, the only thing that

differs is how you get it.

DR. MCCLUNG: Does that assume that the

cost is the same? Many people with prescription

drugs are paying $15 for an Rx drug and they are

paying whatever it is for an over-the-counter, so

did that make any financial assumptions?

MR. HANSEN: I can't remember whether in

186

this exact survey they did put a price around it or

not. We have had other surveys however where we

put a price range, and we have certainly not

finalized the price for Mevacor, but in the range

of 75 cents to a dollar a day, just to put it into

perspective. And the numbers you see there are

very consistent across studies, that people, in

that price range for an OTC, would prefer--at least

the person we are targeting, would prefer to try

OTC first versus Rx.

DR. WOOD: Dr. Woolf?

DR. WOOLF: To me, the CUSTOM study is a

pivotal study so I would like to get some more

information about exactly how it was conducted,

sort of the nuts and bolts.

In the simulated pharmacy, what was the

role of the nurse/pharmacist? Did this individual

provide guidance if asked; provide guidance without

being asked? What exactly did this person do?

Secondly, what was the cost to the

participant for the drug, and how does the cost

compare to what it is likely to cost in the

187

marketplace if it were approved for

over-the-counter use?

MR. TIPPING: Your question was in the

CUSTOM study design what was the role of the study

site nurse that was acting as a pharmacist, and

what was the cost of the medication. The study

site nurse was there to answer questions but was

specifically instructed not to volunteer any

information. So, the participants could interact

with them in a couple of fashions. They could ask

a specific question about the label and they would

get an answer to that specific question. Or, they

could initiate, of their own accord, a full

eligibility--is this product right for me? At that

point the nurse would take them through all the

eligibility criteria.

The second part of your question had to do

with the cost of the product. It was $15 a box.

DR. WOOLF: And how does that likely

compare to what it would be if it were marketed?

MR. HANSEN: Again, we haven't finalized

the price. It is certainly within the range of

188

what we charge in the marketplace.

DR. WOOD: Dr. Watts?

DR. WATTS: We have heard a lot of

information about the patients who self-selected to

use Mevacor OTC, but I don't recall hearing much

about the patients who decided not to use Mevacor

OTC, and that information might be helpful in

getting some idea of how effective this approach

would be in making inroads to this treatment gap.

So, I would like to know, if possible, what

percentage of those who chose not to take the drug

would have been candidates for the drug, that is,

the proper age, the proper LDL cholesterol and

other risk factors.

DR. HEMWALL: While we are getting that

slide, I think Bob is going to have an answer for

you, but we don't have as complete information on

the people that were evaluators as we do on the

people that were users. We have some information

on some evaluators who went through an eligibility

assessment but our information is less complete on

them just because that was the way that we were

189

able to maintain hands-off on making sure they made

the decisions on their own.

MR. TIPPING: Thank you for that question.

It had to do with the people who didn't purchase

the product. Right? If I could have the slide

that we just talked about?

[Slide]

I am glad to get that question because we

feel that this is a very important group too. If

you recall from my presentation, there were over

2000 of these individuals who took the time to come

to the site and do an evaluation of the product and

then chose not to purchase.

They broke out in this fashion: 438

indicated that they needed more information and

they left the site and didn't come back. There

were 1673 of the 2111 who decided not to purchase.

Of that group, applying all the label criteria--age

and everything--98 percent of them were ineligible.

In fact, if you come down a little bit more, there

is 64 percent that is a subset of the 1673 and it

is an important subset because they specifically

190

said they don't think Mevacor OTC is right for

them. So, in this subset virtually each of them

was found to be ineligible by some component of the

label.

DR. WOOD: Dr. Taylor?

DR. TAYLOR: For your product to be

effective over the long haul, a high degree of

compliance is needed and you have shown in your

CUSTOM that you did get some fair results. I am

curious, did the individuals know that they were in

a study? For example, did they sign a consent

form?

The second question is were they provided

any incentives for returning to improve their

compliance?

MR. TIPPING: Yes, your question was did

the participants in CUSTOM have to sign a consent

form. That was the first part of your question.

The answer to that is yes, but only after they had

gone through the process and made a purchase

decision.

Your second question I think had to do

191

with incentives--

DR. TAYLOR: To return; follow-up

basically.

MR. TIPPING: No, there were no

incentives--

DR. TAYLOR: For example, travel stipends,

cash stipends?

MR. TIPPING: Only at the end of the study

after all the decision processes had been made,

there was reimbursement for travel. But during the

whole course of the study as behaviors were being

observed there were no incentives to return to the

site. I would also remind you that they had to

come back and actually purchase the drug, or if

they needed a test or wanted a test, purchase the

test. So, no real incentives to encourage--

DR. TAYLOR: But they received something

at the end as a sort of end of study incentive?

MR. TIPPING: At the end of the study they

were reimbursed for their expenses for traveling

back and forth to the sites. There was no

knowledge that that was coming during the course of

192

the trial.

DR. WOOD: That wasn't in the consent

form? That is hard to believe. So, they just got

a Christmas present at the end and that was

astonishing to them?

[Laughter]

Presumably, just while we are thinking

about that, the people who didn't show up and

dropped out presumably didn't get the payments?

Which is the question which I think is being

addressed by Dr. Taylor, one of them.

MR. STRUBLE: My name is Bill Struble. I

am part of the clinical team at Merck. To answer

your question about compensation, the advertising

for the study did indicate that they would be

reimbursed for time and travel, as well as the

consent form. It was designed not to be a

sufficient amount to be an inducement or an

incentive, and that was done in conjunction with

the institutional review board. They didn't get

that money until the end of the study, as Bob had

said.

DR. TAYLOR: Did they know how much they

were going to get at the end of the study?

MR. STRUBLE: We told them what the amount

193

would be when they returned at the end of the

study, yes.

DR. TAYLOR: And on average, how much was

that? Do you remember?

MR. STRUBLE: Pardon?

DR. TAYLOR: On average, how much was

that?

MR. STRUBLE: They were to receive $35 per

visit and $75 at the end of the study because we

had an extensive list of questionnaires that they

had to go through at the end of the study. What

you have to keep in mind is that they were

responsible for paying for their medication, as

well as purchasing the cholesterol tests, and we

considered that when we decided what the

reimbursement should be because there is also time

and travel expenses that were involved in that.

MR. TAYLOR: The other question I had was

what percent of your participants that were users

194

had insurance?

DR. HEMWALL: We have that answer. It

will take a minute to get it.

DR. WOOD: Why don't we move on to the

next question and then you can come back to that?

DR. HEMWALL: The answer is 43 percent.

DR. WOOD: Let's go on to Dr. Neill.

DR. NEILL: Currently, the ATP III

guidelines recommend that anybody that has an

elevated LDL be evaluated for secondary causes of

dyslipidemia before treatment, and if those causes

exist they be treated, and if they are still not at

target that treatment be initiated to get them to

target. Am I hearing that the ATP IV guidelines

will remove that requirement or recommendation?

This is clearly only a guideline.

DR. PASTERNAK: Yes, it is clearly only a

guideline, and as far as I know, there is no ATP IV

planned yet, unless somebody in the room knows

something I don't know. Remember, the label

enjoins the user to seek the attention of their

doctor at some point, and suggests that they have

195

to have their LDL cholesterol measured.

DR. NEILL: I am going to interrupt

briefly because I actually looked at the box that

was used in the study and there is nothing on the

exterior of the box anywhere that suggests that you

need to see a physician to be evaluated for

secondary causes of dyslipidemia. Now, I am

presuming, because they have another LDL, that at

some point that has happened but that is a

presumption that appears to have been made based on

the fact that a consumer can walk into a pharmacy

and know their LDL. I don't know whether that is a

valid presumption to make, but the question is only

peripherally related to that. It is more related

to whether or not that is something that we believe

is necessary and, if so, is there some way that

that is included within this self-management

package that exists that I haven't looked at yet?

DR. PASTERNAK: Someone else on our team

may remember some of the details of it, but we

certainly do recognize that there are secondary

causes of hyperlipidemia and that a physician needs

196

to consider that for patients.

DR. HEMWALL: Again, I think it is all

about the overall program that was intended to get

consumers to their physicians, and these are

primary prevention people that are otherwise in

good health but they are warned in the label

against having diabetes and also, as you probably

noticed, if their triglycerides are above 200 they

should not be taking the product if they don't talk

to a physician.

So, there are a number of touch points

which allow the consumer to recognize that they

need to talk to a physician but it is not the same,

obviously, as being worked up completely for high

lipids, and may not be what actually happens in

medical practice as well.

DR. NEILL: I may be missing this but I

don't see any of those things on the exterior of

the package, and I haven't heard with they are in

the self-management materials that are available

for consumers before they make the purchase. Now,

I have new bifocals and that could be a big part of

197

the problem--

[Laughter]

DR. HEMWALL: I am looking at the label

and it says do not use unless directed by your

doctor, if you have very high LDL cholesterol, that

is, above 171; if you have high triglycerides,

above 200; or if you have a health HDL, good

cholesterol, above 60. Also, do not use if you

have had a stroke, diabetes--

DR. NEILL: I have found it.

DR. HEMWALL: Okay, and this is expanded

upon within the materials, of course, to give more

context to all that information. Referring to one

of the earlier questions, we are not saying you

shouldn't use a statin if you have these conditions

but you should see a doctor first.

Also, I want to correct a statement we

gave a little earlier about insurance coverage.

That 43 percent number was for people who had

prescription coverage, not just health insurance,

and 82 percent had health insurance.

DR. WOOD: Frank?

DR. DAVIDOFF: Yes, I am interested in the

apparent difference between the apparent

requirements for approval of an over-the-counter

198

drug, that might be used by many millions of people

on an over-the-counter basis, versus the

information or evidence requirements for that same

drug to be given to a much smaller number of people

in a prescription setting. Because it appears that

here, if a decision is made to go forward with OTC

lovastatin, it would be on the basis of a single

non-randomized, non-controlled, short-term study

with no major clinical endpoints but, rather, a

surrogate variable measured.

That prompted me to start thinking about

the opportunity that industry had here to actually

provide a landmark study. This is a historic

opportunity. If an OTC drug for chronic use for

primary prevention is to go forward, there would be

the opportunity to demonstrate that it was, indeed,

the statin that was having the benefit. Because I

can envision a scenario in which there was a

placebo arm in the CUSTOM study but, because there

199

is such a strong interaction with physicians, there

might have been at least as much, or perhaps almost

as much benefit from having been interactive with

physicians and it may not have been the drug at all

that really produced much of the primary preventive

benefit. I would like to ask the question why a

placebo arm was not included.

DR. HEMWALL: Well, first let me address

one of your comments where you said this would be

available to a much wider group of people. I don't

think that the OTC population could ever come close

to the Rx population that is currently receiving

statins.

But having said that, the question that

you are asking about the placebo control and the

level of rigor that is required for an OTC switch

is quite different from that required for the

original approval of a drug as a new chemical

entity, and I think our colleagues from the FDA

would be willing to speak on that. This is the

standard for OTC drugs to actually show consumer

behavior in the hands of the consumers, and in

200

these observational studies typically placebos are

not used because they are open-label and the

consumer knows what they are getting.

Also, I might add that we have done three

earlier studies of this same type of actual use in

our first application so that we do have quite a

range of data, using different studies designs,

with very consistent results, as shown by Dr. Cohen

in one of his later slides.

DR. DAVIDOFF: But if I may, the day a

drug like this goes over-the-counter it is

available to the entire U.S. population, much more

than the limited and targeted population that is

available by prescription. So, I think that that

is a substantial difference.

The other point is that we really don't

know the efficacy of an over-the-counter statin

over six years or five years in an over-the-counter

situation. Even if we did know that, we wouldn't

know how much of that was attributable to the drug

being available over-the-counter and how much of it

was due to the interaction with physicians. The

201

CUSTOM study is actually a rather complex

intervention study. The intervention consists of

more than just the drug.

DR. HEMWALL: That is absolutely right.

That is exactly what the program is intended to do,

to be more than just a drug, but to create that

level of education and awareness among the

consumers that use it to get them to interact with

the healthcare system as well, whether it be a

pharmacist or doctor, and that is what we actually

intended to show with CUSTOM.

Keep in mind that, despite the limitations

of the open label, we did have a 21 percent

reduction in cholesterol across the entire

population of those that fasted at both baseline

and at the end of the study, and an overall 24

percent which is very consistent with the placebo,

controlled trials.

DR. DAVIDOFF: If I may, that is in the

group in whom you did manage to measure both at the

beginning and at the end. It doesn't take into

account the larger denominator of people who would

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be likely to take this in an open over-the-counter

situation. Furthermore, we don't know how long

that lasted because they weren't followed for five

or six years. So, I would repeat that we do not

know the efficacy. It is probably not zero but I

don't think it is 20 percent.

DR. WOOD: Frank, just to follow-up on

that, I am having some difficulty following that.

Isn't that also true for every Rx study that we do?

I mean, you know, we study ACE inhibitors in heart

failure and we extrapolate that to the entire

population with heart failure and make conclusions

from that. I am struggling to understand what the

difference is here, particularly when you have such

a large database of efficacy, real efficacy not

sort of symptomatic efficacy.

DR. DAVIDOFF: Yes, but that efficacy

begins to melt away when you take into account

long-term adherence; when you take into account the

degree of risk to start with. This is a much lower

risk population than the prescription drug risk

group. And that is true for all primary prevention

203

studies. I repeat, I don't think it would be zero

but I think to rely on efficacy data and to make

direct extrapolation from efficacy data from the

randomized trials to the over-the-counter

situation, even including data from CUSTOM--I have

some difficulty with it. That is really all I am

saying.

DR. WOOD: Dr. Patten hasn't spoken.

DR. PATTEN: Yes, I would like to ask a

question about the AFCAPS/TexCAPS cohort in the

post hoc analysis. We are given figures for the

size of the cohort and we are given the initial

gender breakdown, with 5608 men and 997 women, but

we are not given a gender breakdown after that.

So, I would be interested to know if enough women

made it into subpopulations 2 and 3, where event

rates were examined, so that we know that gender is

or is not a factor here in the event rate.

DR. HEMWALL: In the complete AFCAPS

cohort there were about 900 women and the same

magnitude of risk reduction was seen although it

did not reach statistical significance. So, if you

204

were to slice that further into the OTC cohort,

then you would also not see the same level of

statistical significance but the magnitude of risk

reduction was similar. We have an expert here on

women's cardiovascular issues who can address more

completely the role of risk reduction in women,

which may in some cases be different, if you would

like to hear some discussions along those lines if

that is part of your overall question.

DR. PATTEN: It is.

DR. HEMWALL: I will introduce Dr. Sandra

Lewis.

DR. LEWIS: Sandra Lewis. You know, women

are different and women have been included in many

of our trials. I was the lead investigator of the

subset looking at the CARE study which looked at a

group of women who had had a heart attack but had

total cholesterols less than 240. At that time we

were not treating patients who had total

cholesterols less than 240, independent of risk.

So, this was a secondary prevention trial, and the

women in the CARE trial actually had a more

205

significant reduction in myocardial infarctions,

stroke, risk of cardiac death, bypass surgery,

angioplasty. There are women included in many of

our secondary prevention trials and also in some of

the primary prevention trials. The risk reduction

across the board is very similar to the men

although, because of numbers, they may not reach

statistical significance because of small numbers.

And we need to get more women into these studies.

I think particularly the differences

between a woman's perception about cardiovascular

disease is really key to this OTC question. Women

look at responsibility for having developed heart

disease as having done something bad, and they are

very anxious to be proactive about their health,

patient centered responsibility. So, for a woman

to have the option to take a product that is going

to make her heart healthy, instead of being told

that she has an illness, is a really positive

thing. We have an epidemic of cardiovascular

disease in this country. We have decreased our

mortality rate for men. So I see this as a

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tremendous opportunity for a very special group of

women that would take the opportunity to benefit.

DR. WOOD: We have two more questions, Dr.

McClung and then Dr. Follman, unless there is

someone else.

DR. MCCLUNG: Let me ask you briefly about

the muscle complication of statins. Is there a

relationship between time of exposure and the

probability of experiencing muscle problems? That

is, is there a susceptible cohort that is more apt

to develop the problem early in exposure or does

the risk increase exponentially with long exposure,

or is the risk simply linear with time?

DR. WOOD: Maybe I can answer that for

you. From the Baycol database, many of the people

there developed rhabdomyolysis very quickly when

they were switched from one drug to another, and

many of them virtually within a few days or weeks

when they were switched. The reason that may be a

relevant database is that the incidence there was

much higher than has been with any other drugs.

Now, for this one I don't know.

DR. MCCLUNG: But is that quite the same

thing? Switching from one drug to another could be

a difference in drug. But if a patient is on a

207

drug that is known to cause that, is the

probability of experiencing the problem in the

first six months of exposure different than in

their third or fourth year of exposure?

DR. WORTMANN: My name is Robert Wortmann.

I am from the University of Oklahoma. I didn't

hear the last part of your question. The first I

think had to do with when do people who develop

muscle complications from statins do that? Is it

linear with time or is it sudden? And, it is all

over the map. There is no consistent pattern with

statins that are still available. Some can get it

right away; others after weeks; others after

months; others after years. Cerivastatin was a

different compound than those that are still

available. It is metabolized differently and I

think it had reasons why it developed more rapidly.

There was a second part to the question?

DR. MCCLUNG: No, I just restated it in a

208

clearer way the second time.

DR. ORLOFF: Let me just make a comment

from the FDA side, that it is the impression from

everything we know about statins that there is no

cumulative dose-related toxicity, and I think that

is what Dr. McClung is asking. There are a lot of

unknown factors that go into the development of

myopathy but it does not appear to be related to

duration of use per se.

DR. WOOD: Dr. Follman, you have the last

question unless someone else has something.

DR. FOLLMAN: Thanks. I just wanted to

expand on what Dr. Davidoff was talking about

earlier. I am new to the over-the-counter world

and I think things are different here than in the

prescription world. So, if we are evaluating the

evidence for a prescription drug we compare placebo

to the treatment. That is because in the real

world the drug isn't available to anyone so it is

proper, I think, to compare, say, a statin to

nothing, say, in 1988. This is a different world

now when we are considering the over-the-counter

209

use of Mevacor. Statins are currently available so

I think the question in my mind is not whether

statins work compared to nothing, but how would

statins in an over-the-counter world compare to the

way statins work in the current prescription world.

So, the numbers of efficacy that we have

heard quoted, say, the number needed to treat 25,

48 or whatever, is for the statin versus nothing

comparison. I think the relevant comparison is how

would they work in a prescription world compared to

an over-the-counter world. We don't really have

evidence of that directly here. But, in my mind,

the ideal thought experiment would be to randomize,

say, cities to the current prescription world or to

an over-the-counter world and then see what the

cardiovascular event rates would be comparing city

to city. I realize that is not doable whatsoever,

but I think that gets at the idea of, you know, you

can't compare statins versus nothing; you have to

compare statins to some partial use of statins.

If this is approved, there will be some

people who take Mevacor over-the-counter who would

210

have used prescription statins if we didn't approve

it and they might get better treatment. So, I

think there is not really direct evidence on this

comparison that I am interested in, prescription

versus over-the-counter as opposed to statin versus

nothing.

Interestingly, in the packets that you

gave us there was what I would probably term sort

of an approximation to this thought experiment I

just mentioned, which is the lipid-lowering

component of ALLHAT where they randomized about

10,000 patients to either a fixed dose of

pravastatin 40 mg versus usual care. So, you can

think of the fixed dose of pravastatin as sort of

an over-the-counter world and then the usual care

as a prescription world because in that trial

people on the usual care arm got prescription

statin as they felt it was necessary. During the

course of that trial about 30 percent of the people

in the usual care arm ended up on a statin, and

overall there was no difference in CHD event rates

between the usual care and the fixed dose of

211

pravastatin arms in this long trial with a lot of

people.

So, to me that is somewhat relevant to

this. It is a different drug, and so on. It is

not a pure comparison with the prescription world

to the over-the-counter world but it seems to be

the closest approximation and the most evidence

that we have available. I think it is not very

promising for an over-the-counter statin if you

take ALLHAT seriously as an approximation for this

thought experiment.

DR. WOOD: Didn't ALLHAT show that there

was no difference between the arms?

DR. FOLLMAN: Right.

DR. WOOD: So that would seem positive.

DR. PASTERNAK: I would like to respond

just to the ALLHAT issue. I had the opportunity to

write the editorial discussing the ALLHAT results,

and the title of my editorial is consistent with

the comment I am about to make, which is "Less is

Less." The important part to understand about

ALLHAT is that the delta LDL, the difference

212

between the treatment group and the control group

at the end of the study was about 12 percent total

cholesterol difference.

The other important point to consider for

ALLHAT is that if one looks at the point estimate,

yes, it is correct that it was not statistically

significant, it was a negative study. But the

point estimate of risk reduction fits exactly along

this log linear line. That is, the group had about

a 10 percent risk reduction because the sample size

wasn't statistically significant.

So, our point and my point in that

editorial was--and I think it is important to think

of this in the context of the individual who is

getting treatment--that there is risk reduction

associated with LDL lowering. For those

individuals who get a 20-25 percent LDL lowering,

as we have shown will happen with 20 mg of

lovastatin, their risk will be lowered by 25

percent. It gets very complicated comparing one

study to another, and I think it is important to

view ALLHAT as fitting in the context, not as a

213

study which proves that that particular statin or

that particular way of administering a statin

doesn't work.

DR. FOLLMAN: I guess I would just

say--you know, you mentioned that in that trial

there is a delta LDL of about 11 percent or so, and

I am wondering would that be the delta LDL or

something even smaller in a prescription versus

over-the-counter world. The issue to me would be

would we be improving the public health with

over-the-counter Mevacor compared to the usual

prescription world we have now?

DR. WOOD: That may need at some point

some comment from the over-the-counter people to

explain the criteria for approving an

over-the-counter drug I guess. But that could wait

until after lunch. Dr. Caprio had a question.

DR. CAPRIO: I have a question. Given the

increasing prevalence of non-alcoholic fatty liver

in our population, I haven't seen anything

recommending testing for NFTs prior to starting

this. This is quite concerning because we are

214

seeing patients with very high ALT.

DR. HEMWALL: That is an excellent

question, and we actually have a fairly

comprehensive answer to that question. It may not

be that we want to start off on that discussion

right now. I will ask Dr. Wood.

DR. WOOD: I think I agree.

DR. HEMWALL: But we do want to come back

to it.

DR. WOOD: So, why don't you think about

that over lunch and we can start with that when we

get back from lunch? How about that? Is that

okay with you?

DR. CAPRIO: Yes.

DR. WOOD: Neal?

DR. BENOWITZ: I have two very specific

clinical pharmacology questions and I just want to

follow up. I know we talked a lot about this on

the compliance issue. One is that there was a

statement in the brochure that we got about renal

disease and changes in lovastatin metabolism, that

that would be contraindicated. I didn't see that

215

in the package insert stuff.

The second thing is that these are health

conscious people, taking dietary supplements and I

didn't see anything about interaction with dietary

supplements, like St. John's wort and things like

that.

The compliance issue--just thinking back,

I have had a lot of experience with smoking

products over-the-counter and there are two

important issues that I think we have to think

about. One is that even for short term, even for

three-month OTC instruction, compliance is

terrible. Most people stop taking it after a few

weeks. The more you comply, the better you do and

I am very concerned that this six-month trial will

not reflect the six years that it takes for a

number needed to treat at 40.

The other thing is the cost issue. Cost

is a big question. That has certainly been raised

with the smoking products. If we did these

calculations right, four boxes at $15 a box is 33

cents a pill versus the projected 75 cents to a

216

dollar pill which would also enhance compliance in

a six-month trial. So, I think I need some

reassurance that people are not going to be just

throwing away their money by taking the pill

intermittently or taking it in a way that is not

going to benefit them. So, those three questions.

DR. HEMWALL: I heard a question on

labeling warning or statement on renal disease. As

of our understanding, there is no concern with

renal disease with the 20 mg dose. We haven't put

that in the label but that is something that is

often seen in OTC drug labels and, certainly, if

there were data to support it and FDA were in

agreement we would consider putting that in.

I want to answer a couple of those

questions about compliance over the long term. I

think we do have some good data. It is certainly

not five- or six-year data but this is data that is

fairly unique for an OTC drug. Could I have the

slide that shows the 076 results?

[Slide]

This is a study that we did with 10 mg in

217

our earlier program. Although the dose is

different, I think it is important to see the

compliance that goes over an 18-month period. The

top line shows the number of pills being taken over

the time frame, representing the percentage of

people that were 75-100 percent compliant over this

time frame. Then, the bottom line shows the actual

number of people that stayed on drug during that

time frame.

So, you can see that after about 18 months

we have about 50 percent still taking OTC Mevacor

under the simulated conditions of an actual use

trial. These numbers actually compare very

favorably to what is seen in the prescription

environment, and the numbers are in fact, in some

cases, dramatically worse than this. These numbers

are perhaps most consistent with what is seen in

patients that are taking a statin for secondary

prevention after having had their first coronary.

But the numbers for people in primary prevention

are much lower than this, probably falling off to

about 30, 35 percent, and those data are in our

218

background package in your materials.

The other thing to point out is that there

is a strong precedent with over-the-counter aspirin

which people take every day fairly easily and

simply without any concern. We have very good data

from the aspirin manufacturers on compliance over

the long term. So, we think that that is also

typical of users who might use a product like this,

the heart-healthy, motivated consumer, which would

again show that they would have higher compliance

levels possibly than their prescription

counterparts.

DR. WOOD: Was there someone else who

wanted to comment?

[Slide]

DR. HEMWALL: This is just a review of all

the studies that have looked at compliance with

statins over different time periods. Of course,

even these studies only go out to two years at

most, where the persistence rates vary from 25

percent to 64 percent, and then looking at the

three Mevacor studies that we have so far for six

219

months and one for 12, and it doesn't have the full

18 months on this slide for the 076 study. Those

are the numbers that compare to what is published

for prescription statins.

DR. WOOD: Any other comments?

[No response]

In that case, I have to do the usual

bureaucratic stuff. In the spirit of the Federal

Advisory Committee Act and its Sunshine Amendment,

the committee should refrain from discussing this

topic during lunch, any other breaks or this

evening. Please save your discussion for the open

forum of the meeting. I am told on good authority

that it is all right to ask a waitress if this is a

low cholesterol lunch and it is all right to look

for an asterisk on the menu! Let's try and be back

at 1:15 and we will start promptly at that point

with the liver function test discussion.

[Whereupon, at 12:15 p.m., the proceedings

were recessed for lunch until 1:15 p.m.]

220

A F T E R N O O N P R O C E E D I N G S

DR. WOOD: As I promised before we broke

for lunch, we are going to give the first few

minutes to the sponsor to present some of the liver

data. So, if the sponsor is ready, let's get

started.

DR. HEMWALL: Thank you, Dr. Wood. We had

a question before the break about liver function

monitoring and I want to see if I have the question

right. It is looking at people that might have

undiagnosed liver disease that would take the

product without having a baseline test.

DR. WOOD: I think there were two

questions. One was excluding people who might have

liver disease and I guess unasked there, but

relevant, is whether these people are truly at

greater risk for developing liver disease after

they take the product. Then the second question I

think was related to whether there was a real risk

of liver disease from this product at this dose, at

least that was my understanding of the question.

Is that right? Okay, the questioner acknowledges

221

that.

MR. HEMWALL: We will start by introducing

Dr. Paul Watkins who will address this from the

perspective that he has in the academic frame.

DR. WATKINS: Paul Watkins, University of

North Carolina. I guess I will address the second

question first. That would make sense to me. The

question is can statins at this

dose--lovastatin--cause significant liver injury?

That is the question that I heard.

The sponsor has provided a lot of data in

the packet about this. The original concern about

statins as being potentially liver toxic came out

of preclinical studies which showed that in certain

animal species that drugs, and lovastatin in

particular, caused hepatocellular necrosis. Then,

when the drug proceeded into man, there were

observed LFT elevations, alanine aminotransferase

elevations. So, a reasonable assumption was that

severe live toxicity was a problem.

However, in the last five years there has

been a re-thinking of the issue. In the

222

preclinical models, you can actually reverse the

toxicity by nutritional supplementation and

mevalonate, suggesting that this is a pharmacologic

action related to the cholesterol-lowering

property. Furthermore, in man, in all the clinical

trials that have been done, there really has not

been a signal for clinically significant liver

disease relative to placebo arms. And, in the

post-marketing reports, although there have been

reports of severe liver injury, including acute

liver failure, the incidence has not been

distinguishable from the anticipated background

after 27 million patient-years. So, the true risk

of severe liver disease is extremely low and

indistinguishable from the anticipated background

incidence of idiopathic liver injury.

I am sure there is data the company could

show to back that up if there are any specific

questions, but the consensus is that liver

monitoring is not useful during treatment with the

drug. As I say, I don't think that is in

contention. The question is are there

223

subpopulations where there may be a higher true

risk of significant liver injury, and preexisting

liver disease is the question raised.

That has been addressed, and in the

sponsor's book there are the study results of

Chalasoni et al., at the University of Indiana,

that looked in a large database at patients who had

abnormal liver tests, abnormal serum ALT, and were

started on statins, followed for six months and

compared it to a larger population of people who

have chronic liver disease, elevated ALT, and did

not go on statins, and found no difference in the

incidence of mild and severe ALT elevations between

the two groups.

I understand there is a larger study being

done at Kaiser right now by the company that has

preliminary data that supports the same observation

that the incidence of ALT elevations is not

increased in patients who have preexisting liver

disease.

But I think the fact is we know that

patients who have preexisting liver disease do not

224

have a very significant risk certainly of having

severe liver injury when going on lovastatin from

the post-marketing experience. That is because

about one-third of patients who have hyperlipidemia

have fatty liver somewhere in that spectrum. And

two percent or up to two percent of the American

population has chronic viral hepatitis. And, what

the Chalasoni paper showed us was that physicians

who dutifully measure baseline ALT will still start

some of those patients on statins in spite of an

elevated ALT.

As Dr. Wood pointed out, physician

compliance with monitoring for liver events is

notoriously poor, and in the Chalasoni experience

only about 50 percent of patients had a baseline

check at all. So, given this enormous background

of chronic liver disease in the population and the

incomplete and poor nature of monitoring, I think

it is reasonable to assume that in the 27 million

patient-years there are many million that reflect

people with underlying liver disease and, in spite

of that, there is this remarkable track record of

225

safety where you really cannot distinguish a signal

above the anticipated noise.

So, in summary, there will be people

undoubtedly who don't read the label or don't know

they have preexisting liver disease who would go on

and take the drug. But it is my opinion, and I

know Keith Tolman's as well, that the risk in terms

of liver injury is very small for those

individuals.

DR. WOOD: Dr. Caprio, does that help?

DR. HEMWALL: I wanted to follow-up with

something that Dr. Watkins mentioned, and this is

the Kaiser Permanente study. I also wanted to make

sure that the committee is aware that there is an

application in review by FDA to relax the liver

function monitoring requirements in the lovastatin

Rx label to be more consistent with the idea that

an OTC might be available that does not require

liver function monitoring.

One of the key questions at hand where the

data are still fairly sparse, although the

Chalasoni study was just mentioned, is the concern

226

about people that do have undiagnosed liver disease

and what would happen to them if they took a statin

without having a baseline liver function test.

And, there is a study that is under way where the

results have come in that we have only been able to

share preliminarily with FDA, but they have been

kind enough to allow us to share that with the

committee today. But keep in mind that the FDA

have not actually reviewed all of this data and

given us their own input on it. Can I have the

first slide?

[Slide]

This is in the Kaiser Permanente database

where we looked at two different patient cohorts,

those that were exposed to lovastatin with evidence

of liver abnormalities; those who were unexposed,

patients with the same level of evidence of liver

abnormalities but who did not take lovastatin, and

then examining lab inpatient and outpatient

databases used in the exact same way for both

cohorts. Next slide.

[Slide]

The disease inclusions covered virtually

any type of etiology that would result in liver

disease so that we are covering all the bases where

227

we have, in fact, been a little weak in that in the

Chalasoni study, done in Indiana University. We do

have patients with viral hepatitis. So, the

retrospective chart review as done and we found the

following--next slide.

[Slide]

There were approximately 7000 patients

exposed to lovastatin with liver disease, and we

used Hy's Rule as the endpoint which is multiple

lab abnormalities in a well-defined and accepted

outcome endpoint for liver disease. And, the total

person-days of people exposed to lovastatin in this

group was, as you can see, over two million, with

an incidence rate of 2.6/10,000 proceeding to

having more advanced liver disease as defined by

Hy's Rule. In the control group there are about

37,000 individuals who did not receive lovastatin

but had liver disease and were followed to reach an

outcome defined by Hy's Rule, and there were 626

228

patients who had that outcome. That makes an

incidence rate of 11/10,000 person-days. So, the

incidence rate with those exposed to lovastatin is

actually statistically lower than it is with those

not taking lovastatin, and we won't draw any

conclusions from that and we will let FDA review

the entire study, and also the various cuts of the

data that are still forthcoming. But I thought it

would be important for the committee to know that

this study has been done and at least the

preliminary numbers are looking very strong in

favor of the liver safety of lovastatin even in

people that have preexisting liver disease.

DR. WOOD: Unless there are any burning

questions, let's move on. Dr. Davis-Bruno?

FDA Presentation

Reproductive and Fetal Toxicity

DR. DAVIS-BRUNO: My name is Karen

Davis-Bruno.

[Slide]

I am a supervisory pharmacologist in the

Division of Metabolic and Endocrine Drugs. I have

229

been asked today to provide you with an overview of

the lovastatin nonclinical or animal developmental

data.

[Slide]

As a means of introduction, what I will

first do is provide an overview of pregnancy

category labeling in accordance with the Code of

Federal Regulations, or the CFR. Then I will

discuss CDER's interpretation of the lovastatin

developmental data which supports the current

pregnancy category labeling. Then I will move on

to a discussion of CDER's interpretation of the

developmental data.

I should add that Merck has submitted an

extensive amount of developmental data, over

roughly a 24-year period which represents roughly

40 such types of studies. So, in the interest of

time constraints, I certainly can't go into details

of every single one of those studies but, instead,

what I will do is provide a broad overview of

CDER's analysis of that submitted data. As I

mentioned, the data is subject to interpretation

230

and I will try to point out areas where our

interpretation differs from that of Merck's.

One of the differences in data analysis

between the sponsor and CDER is in the definition

of maternal toxicity. This has implications in

determining the clinical relevance of these animal

findings that were observed, and I will spend a

good deal of time discussing that.

Lastly, I will briefly define CDER's

interpretation of the drug-related fetal and

neonatal findings, which include fetal and neonatal

mortality; developmental delays and skeletal

malformations.

[Slide]

The Code of Federal Regulations, or the

CFR, specifies pregnancy category labeling for drug

products. This slide summarizes the various

categories in order of increasing human concern,

from A down to X.

It is noteworthy that the determination of

a specific category depends not only on the human

data but also the animal data that is available,

231

and certainly the relative risk-benefit ratio that

is perceived. So, for example, pregnancy

categories A and B, which you see at the top of the

slide, are reserved for cases where there is no

perceived human risk.

Category C, which is shown in the middle

of the slide, is reserved for cases where there is

no human data although there may be animal data

that demonstrates a fetal risk. However, the

important point to make is that the risk-benefit

ratio is acceptable for the indicated use.

Category D applies to cases where there is

human fetal risk based on actual human studies or

on post-marketing data, but in these cases the

benefit outweighs the risk. Examples of these type

products would be products that are used to treat a

life-threatening type indication.

Last is pregnancy category X in which the

product is contraindicated for use during pregnancy

in pregnant women because there is a human and/or

animal series of data that indicate a fetal risk.

But in this case, it differs from the other

232

categories in that the risk-benefit ratio is

unacceptable. That is, the risk outweighs the

clinical benefit.

[Slide]

Since its approval for marketing in 1987,

Mevacor has been labeled as a pregnancy category X,

as are all the statins. The rationale for the

current pregnancy labeling is summarized on this

slide.

There are no well-controlled studies in

pregnant women for Mevacor. There are, however,

some post-marketing reports of fetal adverse

effects on live births. In these cases exposure

has been established and it appears to occur within

the first trimester. However, the caveat is that

it is limited data so the cause and effect cannot

be demonstrated. However, there clearly are

findings and this would certainly not allay our

concern.

The animal studies, which I will explore

in some detail, show fetal and neonatal adverse

effects in the absence of maternal toxicity. This

233

is an important distinction because it is felt that

the findings in the absence of maternal toxicity

are those that are potentially relevant because a

responsible physician is not going to dose up to

the point of maternal toxicity.

I should state that both CDER and Merck

agree that there is no benefit to temporarily

treating pregnant women. Therefore, we both agree

with the contraindication during pregnancy.

[Slide]

For those of you who may not be familiar

with developmental study designs, I will briefly

review these in this current slide. Standard

reproductive and developmental evaluations are done

in accordance with ICH guidelines S5A, which is a

guidance to industry. Generally, these study

designs fall into one of three categories. I also

want to point out that this is considered the

minimum for product registration and Merck has

clearly, over a 24-year period, submitted a

substantial number of these types of studies which

exceed the minimum.

For the purpose of discussion just to

describe these types of studies, the traditional

segment 1 study which you may be familiar with is

234

really a fertility/early embryonic developmental

study. It is performed usually in one species,

usually a rat. The exposure is performed prior to

and during mating in either males or females. In

females the exposure continues from mating through

implantation.

The segment 2 studies are set up to asses

embryo-fetal development. They are usually done in

two species, both rat and rabbit. In this case,

exposures are done during organogenesis.

The segment 3 studies, which are peri- and

postnatal developmental studies, are usually

performed in one species, usually the rat.

Exposure occurs from implantation to the end of

lactation.

[Slide]

This slide summarizes Merck's

interpretation of their reproductive and

developmental data. Specifically, they denote that

235

the developmental toxicity seen consists of rat

skeletal anomalies which occur at maternally toxic

oral doses, those doses that either equal or exceed

400 mg/kg/day. This is a very high exposure dose.

Moreover, they determined that the

skeletal anomalies are a direct function of fetal

nutritional deficits which are the result of

reduced maternal food consumption and maternal body

weight. These factors are a function of maternal

toxicity, specifically for forestomach

inflammation, which can become progressive leading

to hyperplasia of the squamous epithelium. Merck

hypothesizes that the forestomach inflammation is

due to a local up-regulation of HMG CoA reductase

in the rat forestomach. Moreover, the rat

forestomach is an organ specific to the rat.

Humans just don't have this organ.

They believe that the histopathology is

reversible by co-administration of mevalonate. I

should note that the actual studies that show HMG

CoA reductase up-regulation were performed in

hepatocytes, not in forestomach.

Merck feels that these particular skeletal

findings are probably not clinically relevant

because they occur in a rat specific organ, as I

236

mentioned, and they occur at a significant exposure

multiple compared to the proposed 20 mg clinical

OTC lovastatin dose. CDER doesn't necessarily

disagree with this interpretation of these findings

that are extremely high exposures, but we believe

that this interpretation is only part of the story.

[Slide]

One of the differences in interpretation

of the data involves the definition of maternal

toxicity. According to Merck, maternal toxicity

occurs at an exceedingly high dose, at or above 400

mg/kg/day given to rats by oral administration, and

it results in the forestomach hyperplasia that I

mentioned. But if you actually go back and look at

the data, you find that at exposures less than this

dose--so between 100 and 400 mg/kg/day--given to

rat dams by an oral route during pregnancy, you see

that there are maternal decreases in body weight

gain of roughly 10 percent and you see decreased

237

food consumption.

Moreover, when you look at the studies

that administered lovastatin to the rats during

pregnancy by a different route, by a subcutaneous

route in order to avoid the forestomach toxicity,

you still see maternal toxicity in that you still

see maternal mortality and you also see decreased

body weight gain.

This suggested to us that perhaps a more

conservative maternal no-effect level, no

observable adverse effect level, which is what

NOAEL is, could be established at an 80 mg/kg dose

which represented about a 60-fold exposure relative

to the proposed 20 mg clinical dose.

What we did is, having established this

NOAEL effect level, we went back and reviewed the

reproductive and developmental data from 1980 and

looked to see if there were any fetal or neonatal

findings at these doses and below. What we found

was that there were fetal and neonatal findings

that were observed in fertility, embryo-fetal

studies through postnatal developmental study

238

designs. The results of this analysis are briefly

summarized in your briefing document. In the

interest of time, I can't go through those

specifics. But the results are summarized on the

next slide.

[Slide]

This summarizes fetal and neonatal

findings at clinically relevant exposures. So, at

exposures in rats less than or equal to five times

the therapeutic exposure--and what I mean by

therapeutic exposure is the exposure that you would

achieve following a 20 mg clinical lovastatin

dose--you still see fetal findings. You see fetal

and pup mortality and you see fetal and pup

decreased body weights. In some of these studies

we have observed these findings at exposures

equivalent to the therapeutic exposure.

If you look at studies where higher doses

were used and greater exposures were achieved, you

begin to see the developmental delays which involve

changes in reflexes, such as the righting reflex,

the auditory startle response, and you see effects

239

in swimming and open field effects. You also see

some incomplete skeletal ossification.

If you go at still higher cephalosporins,

25 times, you begin to see these skeletal

malformations that I discussed previously. These

translate to increased supernumerary ribs and wavy

ribs and, in addition, you still see the incomplete

skeletal ossification. I want to emphasize that

all these findings occur in the absence of maternal

toxicity.

[Slide]

In addition to those studies, Merck has

also looked at co-administration of lovastatin in

the presence of the end products of HMG CoA

reductase, specifically, mevalonic acid

co-administration or cholesterol co-administration

with lovastatin. Our interpretation of these data

is that you do see attenuation of the more severe

fetal malformations, but you still see wavy ribs

and incomplete ossification present, and you still

see evidence of maternal toxicity. To us, the

results of these series of studies support that the

240

fetal toxicity is related to disruption of

cholesterol biosynthesis by lovastatin.

[Slide]

If I could summarize our interpretation of

these studies, it would be that fetal and neonatal

toxicity is seen in the absence of maternal

toxicity; and that the drug-related fetal and

neonatal toxicities include skeletal malformations,

mortality and developmental delays. Moreover, some

of these fetal findings occurred at exposures that

are similar to the clinical exposure, that is, the

proposed 20 mg lovastatin OTC dose. And, these

findings are potentially relevant to clinical risk

assessment. Moreover, our feeling was that the

pregnancy category designation is still valid.

[Slide]

A developmental no-effect level can be

established in various species, as shown on this

slide, for both rat, as you have seen, the rabbit

and the mouse. This is a level of exposure where

there are no fetal or neonatal findings observed,

and that is indicated in this column where the no

241

observable adverse effect level is indicated. This

exposure level is then expressed in this next

column, indicated by the safety margin column.

This exposure level is, again, expressed as a

multiple of the human exposure following a proposed

20 mg lovastatin OTC dose. The comparisons are

based on body surface area rather than actual

pharmacokinetic or AUC exposure data but they do

indicate that there is establishment of a

developmental no-effect level, which is comparable

across the species but, as you can see, the

exposure multiples are relatively low.

[Slide]

In 2004 Merck submitted to us new

postnatal neurodevelopmental data. This data was

actually requested by the agency to address data

gaps in the neurologic development based on

limitations in postnatal study design between the

species. For example, the major periods of

myelination occur in the rat postnatally,

specifically weeks two through four, but occur

during the second and third trimester in humans.

Our feeling and the advice of our internal

experts was that the postnatal developmental study

designs may not adequately evaluate this particular

242

event. Moreover, as you have seen briefly, the

prior studies had shown that developmental delays

occurred in prior postnatal studies. So, we

specifically requested a detailed

neurodevelopmental assessment and recommended

direct dosing of rats during the critical period of

neurologic development. We specified that we would

like to see evaluation of exposure, establishment

of a no-effect level, detailed brain histology, and

certainly adequate behavioral and functional

developmental assessments.

[Slide]

The study that we actually received in

2004 was a direct dosing neonatal rat study. The

dose selection for the higher dose tested in the

actual study was based upon a dose-range finding

study looking at acute dosing. The results of that

study suggested that at a dose of 20 mg/kg/day

there were findings such as a decrease of body

243

weight gain in these neonatal rats, and some

injection site alopecia and scabbing.

Based upon this, in the definitive study

the high dose was halved so that a 10 mg/kg/dose

was tested. The drug was given subcutaneously from

postnatal day 4 in these neonatal rats up to days

41 or 51, depending upon the type of evaluation

that was performed.

The results of these studies suggest to us

that there was a short-term learning retention

decrease. Specifically, there was an effect in the

passive avoidance test. Moreover, the functional

observational battery also showed an increase in

central nervous system activity in the same group.

We felt a no-effect level for this particular study

could be established at 5 mg/kg/day, which would

achieve a rough exposure of 20 times that of the

proposed clinical dose based on AUC.

I should point out that this 20-fold

sounds like a large exposure multiple relative to

the other postnatal studies that I described, but

you have to keep in mind that the study design for

244

this particular study is very different. This

study is a neonatal rat study in which the neonates

were directly dosed and exposures were based upon

known exposures in these neonates. In the previous

postnatal studies the mothers were the ones who

were directly dosed and so the exposures are based

upon maternal plasma exposures.

Moreover, the only way that the neonates

could be exposed in the earlier postnatal studies

would be through placental transfer--I should say

that is how the fetuses were exposed. The neonates

would be exposed only through drug that was

excreted in the milk.

[Slide]

So, our assessment of the new

neurodevelopmental data is that there are decreases

in short-term learning retention; increased

activity in the central nervous system, at least in

high dose females. And, these learning and

behavioral findings are consistent with the prior

postnatal evaluations. However, we felt, through

several discussions with the sponsor, that the

245

neurologic evaluation was somewhat minimal in that

the passive avoidance test, being the only measure

of cognitive function, was somewhat minimal. Our

reasoning for this was since various tasks could be

assisted by different neural systems a second

neurobehavioral test had been recommended,

specifically a swimming maze.

I should also point out that the

histopathology done in the study was focused on

neural tissues only. I believe it was brain,

tibial and sciatic nerves, and only in the high

dose treatment groups compared to controls.

Toxicology endpoints in other tissues were not

performed, and the neural anatomical and

biochemical evaluations according to protocol were

only going to be performed if there were lesions

that were observed in the high dose group, and

since they weren't the evaluations weren't done.

The other part of the assessment is that

the study design of this study is to evaluate acute

and not delayed developmental effects which were of

concern.

[Slide]

So, if I could summarize our

interpretation, although I didn't talk about this,

246

there is clearly an established statin mechanism of

action. The extensive developmental studies

submitted from 1980 to 2004 show consistent

findings with lovastatin exposure. These findings

include fetal mortality; decreased fetal weight;

skeletal malformations; and behavioral and learning

delays. The limited neurodevelopmental neonatal

rat study with the delayed learning effects is

consistent with the prior postnatal studies.

Some of these findings, as I mentioned,

occur in animals at exposures that are similar to

the therapeutic exposure, that is exposure that

could be achieved in humans following a 20 mg

lovastatin OTC dose. Moreover, this was reviewed

by our in-house panel of experts on the CDER

reproductive toxicology subgroup and there was

consensus.

Post-marketing reports of first trimester

fetal adverse effects although, as I mentioned,

247

represent very limited data which results in

failure to show cause and effect, certainly don't

allay the potential concern.

[Slide]

If I could conclude, based upon the

extensive animal data, a potential human fetal risk

exists following exposure to lovastatin during

pregnancy in women of childbearing potential. The

contraindication of statins, including lovastatin,

during pregnancy is valid. Thank you.

DR. WOOD: Thank you very much. Merck has

asked to respond to this and, in the interest of

fairness, I think we should let them do so.

Before we get to that, and I may have been

postprandial, help me understand what the data are

in humans. You sort of alluded to that but I

didn't actually hear that data, I don't think.

DR. DAVIS-BRUNO: I didn't present that

data--

DR. WOOD: That is why I didn't hear it!

DR. DAVIS-BRUNO: --because that is not my

expertise, although it is summarized in the

248

briefing document that has been presented to the

committee.

DR. WOOD: I understand that. Can you

summarize that for us?

DR. DAVIS-BRUNO: If I can get an overhead

I can.

DR. WOOD: Well, maybe while Merck is

presenting you can be thinking about that because

that is obviously key.

DR. HEMWALL: Thank you, Dr. Wood. As you

can see, this is a complicated issue. In fact, we

agree with the regulatory definition, such as it

is, that when there is no benefit to treat during

pregnancy the drug should remain labeled category

X. But I think we need to put a little perspective

on the data. Recognizing the complicated nature of

all of these different interpretations, we will

have just a few remarks by Dr. George Lankas who

supervised the conduct of most of these studies,

and then I will have some follow-up remarks after

him.

DR. LANKAS: Hello. I am George Lankas

249

and I am a toxicologist at Merck, and I have been

responsible for conducting many of the studies that

were just alluded to.

As Dr. Davis-Bruno mentioned, there has

been an extensive amount of preclinical

reproductive and developmental toxicity data that

has been generated with lovastatin over the years,

and there is certainly opportunity for reasonable

scientists to disagree in the interpretation of

many of these findings. But given the potential

significance of two certainly key findings that

were just mentioned, the developmental effects on

body weight and also the fetal death, I thought

that those findings warranted closer scrutiny. So,

what I would like to do is just briefly review for

the committee the differences in the approach of

how these data are analyzed and actually show an

example of the actual data and the difference in

interpretation. So, if I could have slide 766,

please?

[Slide]

This is my attempt to summarize for the

250

committee the differences in methodology with

respect to how these data are looked at based upon

reviewing the FDA briefing document. The FDA

method focuses on actual individual group mean

differences between treatment group data and

concurrent controls, and tends not to utilize

statistical analyses unless the statistical

analysis indicates that there is a significant p

value. The Merck method, the MRI method, relies on

a combination of looking at dose-response

relationships, that is, evidence of a dose-related

trend in the response that is under analysis, as

well as statistical significance and an evaluation

of both concurrent and historical control data.

The committee has to realize that for many of these

data there is tremendous variation in control data

in a given species. So, reliance just upon

concurrent control data can sometimes be

misleading.

In addition, when there are multiple data

available from different studies on a given

endpoint, we also look at reproducibility of those

251

findings as further evidence or confirmation of

whether there is a treatment-related effect.

[Slide]

On this slide I would like to summarize

the FDA's analysis of the data as indicated in the

briefing document that was supplied by FDA. This

is characterized by FDA's study number 2. This was

a rat study in which dosages of 2, 20 or 200

mg/kg/day were administered to rats, beginning 15

days prior to mating and then throughout mating and

then throughout the gestation period until

gestation day 20.

These are the doses here. The FDA's

review indicated that these are the exposure

multiples relative to the OTC dose of 20 mg. The

check mark indicates that there were findings that

were delineated by FDA as being drug related. Note

that at the highest dose there is nothing indicated

as being drug related, but at 20 mg, the mid-dose

group, there were findings of fetal death as well

as decreases in fetal body weight.

[Slide]

This slide actually shows the data on

which this interpretation is based. So, these are

the various groups in the study, control through

252

high dose, and these are the number of dead pups

that were evidenced in this study by control group.

You can look at the total number of pups across the

groups. It is a relatively high number. You will

note that there is really no evidence of any

dose-related effect when you look at the concurrent

control through the high dose of 200 mg/kg/day.

Just to add perspective, this is roughly 25- to

30-fold based on exposure multiples, the proposed

20 mg OTC dose. So, this would be characterized as

a relatively high dose.

So, the findings of fetal death are really

based upon a finding in the mid-dose of 20, which

is really due to the findings from one litter. One

dam lost the entire litter, almost the entire

litter, 8/14 pups. So, in our view, this does not

rise to the level of a drug-related effect and we

would discount this one litter as being evidence of

a treatment-related finding, particularly when

253

there was nothing in the high-dose group.

Similarly, if we look at the effects on

fetal body weight in these various treatment groups

by time--PND stands for postnatal day, these are

the days after birth on which these measurements

were taken. Please note that the statistical

analysis shows absolutely no evidence of any

statistically significant effect. I believe that

the effect that is being noted as possibly being

evidence of a drug-related effect is on postnatal

day zero or postnatal day seven, a period which

really doesn't indicate any evidence of trend with

respect to dose response.

So, our conclusion is that there was no

evidence of a drug-related effect on mortality or

on postnatal body weight not only in the 20 mg

group but the other treatment groups as well.

[Slide]

This is an attempt to summarize for the

committee what animal findings look like with

respect to other over-the-counter products and also

another lipid-lowering agent that is currently

254

prescription, fenofibrate. So, if we look at

cimetidine, fenofibrate, epinephrine--this is

actually ephedrine, and ibuprofin relative to

lovastatin and we look at the effect on these

various endpoints and look at the lowest effect

level, that is, the lowest dose at which the

reported effect has been observed, and then compare

that to the animal relative to the human dose

ratio, if this ratio is less than one it indicates

that there is absolutely no evidence of a safety

margin relative to the human recommended dosage.

So, for these various agents you can see that the

safety margins for lovastatin are well in line or

exceed the margins for these other products.

So, it is our conclusion, our firm

conclusion that the findings that are noted with

lovastatin are non-specific findings, not

indicative of a direct fetal toxic or teratogenic

effect and that lovastatin certainly has an

adequate safety margin relative to other

over-the-counter products.

DR. HEMWALL: We do have just a little bit

255

more here. I want to put this in some perspective.

First of all, my conclusion is that these studies

are really complicated and it is tough to ask the

committee to make some kind of judgment on what

they just saw, but I want to try to put this into a

little bit more context.

Let's go back to the pregnancy categories

that we were looking at and the definitions, and

let's remember--let's have the first slide--

[Slide]

--that our position is that lovastatin is

not a teratogen. There are certainly some findings

in animal studies that put it in a situation where

it has to be judged to either be category C or

category X, and it has been put into category X

because of the fact that the fetal risk that is

seen is enough to outweigh possible benefit, and we

have all established that we agree that there is no

benefit to treating a woman with a lipid-lowering

drug during the period of pregnancy. The very fact

that there are other drugs that have very similar

findings but are listed category C is because they

256

do have benefit. Drugs used in diabetes; drugs

used in asthma; drugs used in hypersecretory

conditions are all category C with very similar

findings, but that is because they have benefit

when given to a mother and a doctor is asked to

make that decision as to whether or not the risk

outweighs the benefit, and they are called category

C. In fact, a heartburn drug approved by NDAC just

a couple of years ago has a category C label with

animal findings and even sporadic reports of fetal

abnormalities in human exposures. Next slide,

please.

[Slide]

But let's take a look at what the human

exposures actually are. These are numbers from the

IMS database that show the number of women of

childbearing age that have been prescribed

lovastatin. To be exact, it is the number of

prescriptions that have gone to women of

childbearing age.

Let's just look at 2004, and you can see

the numbers are increasing. About 19 million

257

prescriptions were written in 2004 for a statin.

Of these, about 100,000 were women of 21-30 years;

480,000 were prescriptions for women of 31-40

years; and the numbers start to rise dramatically

as you get into the older age group but still

technically of childbearing age. Over two million

prescriptions were written for statins for women of

childbearing age in 2004, and there is a cumulative

number of prescriptions obviously written over the

years. Next slide, please.

[Slide]

In our own database we have, as you have

heard many times and will remember it after today,

the 27 million patient-years of exposure. We do

have 105 reports of pregnancy in our WAES database.

The majority of these are in the first trimester.

There are 67 cases where the actual report is

prospective. That means that we got the report

before the pregnancy went to term so we were able

to follow the pregnancy--or the reporter was able

to follow the pregnancy to term. Then, 38 reports

were retrospective. That is, once an anomaly was

258

found, often these reports come in and they are

more commonly seen. So, in those 38 reports we do

have 7 congenital abnormalities, and the specific

pattern of defects in those reports is very

diffuse. There is no pattern which would suggest

something is going on that would be representing a

mechanistic cause. Next slide.

[Slide]

So, our conclusions are that the reported

experience with lovastatin exposure during

pregnancy is limited, and that is because of the

labeling and that is appropriate and we would want

to reinforce that message in anything we do with an

OTC product to minimize the potential for women of

childbearing age to actually use the product. And,

there is no evidence that exposure during early

pregnancy is associated with any specific pattern

of congenial abnormalities when they do appear.

Also, just to take a quote directly out of

your background package that the FDA provided to

you, in their Office of Drug Safety Review: A

causal association between in utero statin exposure

259

and identified birth defects cannot be made based

on the current information. So, we are not talking

about a teratogen. This is not thalidomide; this

is not Accutane where true fetal toxicity is known.

We are talking about a drug that has a signal that

is consistent with a category C drug but, simply,

the history has been that there is no benefit for

treating women during pregnancy so, by definition

of the categories, that puts them in category X.

[Slide]

This is also looked at in a computerized,

well recognized teratogenic tracking system, called

the TERIS database. We have provided the actual

printout from the TERIS database to everybody at

the table here. This is something that accumulates

all the animal data and all the human data and puts

it into a computer-based system, and then it is

reviewed and there is consensus by a group of

clinical toxicologists. They group them into three

broad categories, either no risk, minimal risk or

unlikely, a small risk or risk undetermined. Next

slide, please.

[Slide]

In the TERIS database, and you can read it

in the handout you have, lovastatin is listed among

260

only 6.4 percent of drugs which are actually listed

as unlikely to pose teratogenic risk in human

pregnancy. About 90 percent of the drugs have not

enough information. They have actually viewed that

the lovastatin information is enough to support

that conclusion. They have also noted that the

non-minimal or unlikely category is equivalent to

the FDA use of the pregnancy category A or B. Last

slide.

[Slide]

So, just in summary, it is labeled

category X because of the lack of clinical benefit

and the potential risk that we have seen from these

animal studies. We are not disputing that there

are findings, and we can have our dueling experts

going back and forth about which is the level and

which is not the level, but there are findings that

are consistent with category C. There is no

evidence that we have seen in our databases that

261

exposure during early pregnancy is associated with

increased risk of any specific congenital anomaly,

and the TERIS database supports this, listing it as

unlikely. That is why we believe that the risk to

a mother who has an inadvertent exposure, however

much we try to minimize the frequency of that

event, is very low, especially compared to the

overall benefit to the large population of people

that should be getting this drug, lowering their

cholesterol and lowering their risk of

cardiovascular disease.

DR. WOOD: Karen, do you want to say

anything in addition to that?

DR. DAVIS-BRUNO: To address the Chair's

question about what the actual findings were in

those limited human experiences, this table that I

am going to present is also in your briefing

document.

DR. WOOD: That is fine. Just tell us

where it is and then keep going.

DR. DAVIS-BRUNO: It is at Tab 4, around

page 4 or page 3, in the beginning of my review.

DR. WOOD: Okay, keep going.

DR. DAVIS-BRUNO: Well, I am done with my

presentation, unless you want to entertain

262

questions.

DR. WOOD: Let's keep the questions until

the end and let's go straight on to the next

presentation, which is from Capt. Laura Shay.

Label Comprehension Study

CAPT. SHAY: Well, good afternoon.

[Slide]

This is switching gears quite a bit from

the last talk. My name is Capt. Laura Shay. I am

a consumer safety officer for the Division of

Over-the Counter Drug Products.

[Slide]

The purpose of my presentation this

afternoon is to provide a summary of my review of

the pivotal label comprehension study for Mevacor

OTC. First, I will provide a description of

basically what label comprehension studies are;

followed by a description of the Mevacor study

design. Finally, I will provide a summary of the

263

study results.

[Slide]

The purpose of a label comprehension study

is to evaluate whether or not consumers can

comprehend important communication objectives on

the label. It is important that both literate and

low literate populations are evaluated, and that a

diverse population is evaluated that is

representative of the United States population.

[Slide]

Generally, label comprehension studies are

performed prior to the behavioral or actual use

study. This is in order to optimize the label

before placing it into a naturalistic setting. It

is important to note that low comprehension may be

predictive of poor results in the actual use

setting. However, as has been mentioned

previously, high comprehension does not necessarily

guaranty success in the actual use setting.

[Slide]

For the pivotal label comprehension study

the primary objective was to evaluate consumer

264

comprehension of the label used in the CUSTOM

actual use study.

[Slide]

Secondary objectives included were to

determine how well respondents correctly respond to

questions designed to try to measure

self-selection; to evaluate low literacy

respondents; and to evaluate non-Caucasian

respondents.

[Slide]

The key communication objectives are

provided in your FDA background package under Tab

6, page 1. But I will provide more detail on them

as I present the results of the study.

[Slide]

It is important to note that in the Code

of Federal Regulations an OTC label must be likely

to be read and understood by the ordinary

individual, including individuals of low

comprehension, under customary conditions of

purchase and use.

[Slide]

So, how do we assess comprehension? There

is no defined numerical value for acceptable

comprehension. Ideally, we would like everyone to

265

understand everything on the label 100 percent.

However, realistically we understand this concept

is not possible. However, the more clinically

significant a communication objective is, the close

to 100 percent comprehension is desired. For

example, for the consumer's ability to understand

that they need to stop Mevacor OTC if they

experience unexplained muscle pain, we would like

to see high comprehension. For other communication

objectives we might accept a lower score. A good

comparison would be a driver's manual. After

someone reads a driver's manual you can test them

on their comprehension of the manual, and you would

like to see comprehension for understanding the

need to stop a car at a red light. If someone

doesn't comprehend well the need that you need to

park at least 10 ft from a fire hydrant and not 8

ft, this would not be viewed at the same level of

importance as the red light. In the process of

266

developing and testing a label judgments have to be

made on the areas that need to be fixed and what

areas can be left alone, even if they are not even

close to 100 percent.

[Slide]

Everyone at this point I think is familiar

with the label. This is the principal display

panel that was tested and also used in the CUSTOM

use study.

[Slide]

This is the drug facts label.

[Slide]

The study design was as follows:

Recruitment was done when subjects were selected if

they were found to be cholesterol-concerned

respondents. They were shown a concept board and

they were asked if they were interested in lowering

their cholesterol. If they were concerned or would

like to lower their cholesterol, they were asked to

participate in the study. And, they were paid

$20-$25 for participating and essentially to cover

the cost of their time.

[Slide]

The study was conducted in 25 shopping

malls across the country in a very diverse

267

population.

[Slide]

The total number of study cohorts was 696.

Of those, 203 tested at low literacy. The

definition for testing at low literacy--and they

used the REALM test which also was mentioned. That

stands for the Rapid Estimate of Adult Literacy in

Medicine test. That is if they test less than or

equal to an 8th grade reading level. And, 493 were

considered adequately literate; 207 were

non-Caucasian; and 489 were Caucasian.

[Slide]

The gender breakdown, 44 percent were

male. Of the males, 51 percent were greater than

or equal to age 45, which is the target population

for this product, and 56 percent were female and 35

percent of those were greater than or equal to age

55, the target population for this product.

[Slide]

The questionnaire design was testing one

label. They used structured interviews, and the

respondent was allowed to refer to the label

throughout the study. The questions were primarily

multiple choice, and there were many scenarios used

in order to test key communication objectives and

268

to test decision-making ability based on

information found on the label.

[Slide]

An example of one of the scenarios is one

for unexplained muscle pain: Diane has been taking

Mevacor OTC for several weeks. She didn't do any

unusual physical activity and isn't feeling sick,

but she has started to feel pain in her leg

muscles.

[Slide]

On the drug facts label there are two

areas that explain to consumers what they should do

if they develop unexplained muscle pain. Under

warnings it states "stop use and ask your doctor.

If you develop any unexplained muscle pain,

weakness or tenderness stop immediately. This can

269

be a sign of a rare but serious side effect."

Under directions, it is also stated a

second time. Unexplained muscle pain--:stop using

immediately and talk to your doctor if you develop

unexplained muscle pain, weakness or tenderness.

This can be a sign of a rare but serious side

effect."

[Slide]

According to the protocol, the answer

definitions were as follows, a correct answer would

be if a respondent's answer adhered to the label.

An acceptable answer is if a respondent's answer

did not specifically adhere to the label but would

not pose a safety risk.

[Slide]

The answer selection for the unexplained

muscle pain is the following, the choices they had

and the results are going to be listed right now:

They were told to stop using the drug. Must talk

to a doctor. That was considered correct. They

could select continue to use but must talk to a

doctor. This was considered acceptable. Stop

270

using; does not need to talk to a doctor--also

acceptable. Continue to use and does not need to

talk to a doctor--incorrect. And don't know would

be considered incorrect.

[Slide]

The breakdown of the scenario results

according to correct--and that would be, again,

just strictly adhering to the label, the results

were between 74-81 percent. When acceptable

answers were factored in the results were 98-99

percent.

[Slide]

Another scenario is for liver disease.

Barbara has liver disease.

[Slide]

On the drug facts label the issue of liver

disease is under one area in the warning section

and it states liver disease--"do not use if you

have liver disease."

[Slide]

The answer options for this

scenarios--this person should not use at

271

all--correct. Before using, this person needs to

talk to a doctor--acceptable. This person could

start using right away--incorrect; And, again,

don't know is considered incorrect.

[Slide]

The results of this scenario, for the

correct answers, adhering to the label, the range

was 65-71 percent. When acceptable was factored in

the range was 99-100 percent.

[Slide]

I will now present the study results.

There was little difference between the cohorts of

the low literacy, normal literacy, Caucasian and

non-Caucasian. Therefore, I will present only the

total representative sample, and I will only

present the correct answers, which were those

answers in which respondents strictly adhered to

the label.

[Slide]

Ninety-nine percent understood what the

product was used for; 99 percent, dosage and dosing

information; 95 percent, the need to consult with a

272

healthcare professional prior to use if on a

prescription drug. Ninety-two percent understood

the active ingredient; 87 percent, time frame for

cholesterol testing. Eighty-six percent understood

the need to have diet and exercise before taking

the medication; 82 percent, that evening was the

best time of day for dosing; and 78 percent, the

need to fast before cholesterol testing; and 50

percent, that the cholesterol will go up if Mevacor

OTC is stopped.

[Slide]

The percent of correct answers according

to the label for scenarios that indicate the need

to stop Mevacor OTC with multiple scenarios and the

range of correct answers were 47-90 percent. Of

most clinical significance was the unexplained

muscle pain at 79 percent.

[Slide]

The percent of correct answers according

to the label for self-selection scenarios was a

range of 37-81 percent, with an average of 54

percent. Of most clinical significance, allergy to

273

lovastatin 72 percent; and in the scenario they

listed a prior history of muscle pain on

cholesterol-lowering medicine and the correct

answer for that according to label for that was 42

percent.

[Slide]

The percent of correct answers according

to label listed under the warning section of the

label, "do not use if...," 74 percent for

pregnancy; 77 percent for breast feeding; 69

percent for liver disease.

[Slide]

The percent of correct answers for false

positives--and what these were was the sponsor did

a nice job of integrating scenarios that may not

necessarily be on the label but forced the

responder to have to think in a decision-making

manner, sort of common scenarios such as if you

developed a cold, you were taking Tums for

indigestion, you have poison ivy, you have gas from

food or constipation. The correct answers

according to label, the range was 64-72 percent.

274

Again if acceptable was factored in the range was

94-98 percent.

[Slide]

Self-selection was also looked at.

Respondents were asked if they could start Mevacor

OTC today. This was after they had a period of

time to look at the label and it was asked at the

very beginning of the study. This answer was then

compared to the self-reported medical history

questions and demographic data in order to validate

if the response was correct.

[Slide]

Of the 696 total respondents or total

representative sample, 461 reported that they could

not start Mevacor OTC today; 209 reported that they

could start Mevacor OTC today; and 26 respondents

were unsure.

[Slide]

The results, of the 461 that responded

that they could not start today, 100 percent of

them were correct. All 461 had a contraindication

on the label that they discussed in their

275

self-reported medical history. Out of the 209

respondents who reported they could start Mevacor

OTC today, three, or one percent, self-selected

correctly according to the label criteria. That

brings a total of 67 percent, or 464 out of the 696

total respondents that self-selected correctly

according to the label.

[Slide]

In summary, this was a well-designed study

in that it covered a diverse population and

included non-Caucasian and low literate subjects.

The questions were non-leading and well

constructed. And, the study was able to

distinguish varied levels of comprehension.

[Slide]

The areas of clinical significance that

adhered to the label strictly, for unexplained

muscle pain 70 percent; for breast feeding 77

percent; for pregnancy 74 percent; allergy to

lovastatin 72 percent; liver disease 69 percent;

and explained muscle pain 47 percent.

This point of unexplained muscle pain is

276

not a clinically significant issue but it does

point to the fact that respondents had a difficult

time understanding the difference between explained

and unexplained muscle pain. Although, again, not

clinically significant in that we would rather see

someone stop and ask a doctor if they are

uncertain, it does point to the complexity of this

label in that it attempts to convey medical

information to the consumer that is more

complicated than what is seen in current OTC

labeling.

[Slide]

In summary of the self-selection, the

total number who self-selected correctly according

to the label was 67 percent or 464. Of those who

said they could start Mevacor OTC today, one

percent or 3 out of 209.

[Slide]

Now, the issue of correct versus

acceptable, when acceptable answers were factored

in the answers increased most scores to greater

than 90 percent. In some situations factoring in

277

acceptable responses could actually be considered

correct if these issues or scenarios fell under the

sub bulletin in the label that states do not use;

ask a doctor of pharmacist, or under the sub bullet

do not use unless directed by your doctor.

However, the acceptable answers often contained

"ask the doctor" even when not indicated to do so

on the label. It is important to note that

respondents often had a greater than or equal to 50

percent chance, or a three out of five chance of

selecting either a correct or an acceptable answer.

The sponsor chose to use both correct and

acceptable answers to assess comprehension of this

label. This method potentially creates an

elevation of the scores, resulting in an

overestimate of a consumer's ability to comprehend

the label. Should the acceptable answers that

contain "ask a doctor," even when not directed to

do so on the label, be factored in? Did they truly

assess the ability to comprehend the label or are

they attempting to predict the behavior? Did the

respondents choose an answer that contains "ask the

278

doctor" rather than the answer "I don't know"

because it was more comfortable? These are

important questions to ponder.

Again, it is important to remember that

the label comprehension study cannot predict

consumer behavior. Even labels with high test

scores for comprehension can do poorly in the

actual use setting. As previously described, this

label was tested in the CUSTOM actual use study. A

review of this study will now be presented by Dr.

Daiva Shetty.

DR. WOOD: Just before you leave, on page

two of your briefing document and also on your

slides you get to the total number who answer a

question correctly by adding the numbers who

couldn't start with the numbers who could start

and, it seems to me these are not equal questions.

So, getting the question wrong that you could not

start and, therefore, not starting is a quite

different outcome from getting the question wrong

that you could start and starting. And, only one

percent of the people who could start got the

279

question right whereas a large number who could not

start got the question right and that is what gives

you this 67 percent answer. So, it seems to me,

that is like asking people if it is all right to

jump out of the plane and the people who did jump

out of the plane, only one percent of them got it

right because they had the parachute on--

[laughter]

--and, you know, the ones who said it

wasn't time to jump out of the plane, all of them

got it right so that was all right, we will just

add the two together. Well, I am not so sure that

is right. So, could you comment on that? I mean,

that seems to me an extraordinary addition to make.

CAPT. SHAY: You want me to comment on

that?

DR. WOOD: Yes, please. I mean, only one

percent of the people who jumped out of the plane

got it right.

CAPT. SHAY: True, but I think it is

important to look at the entire balance and, in all

fairness, when a person goes and selects a product

280

you also want to make sure that they are not

selecting appropriately if they shouldn't. So, we

always factor that into the whole decision-making

process. But I agree with your scenario in that of

the 209 who did self-select correctly and the one

percent, or three, that got it right--that is of

concern.

DR. WOOD: So, I am reading that right?

All right.

DR. GANLEY: Alastair, could I just add to

that a little bit?

DR. WOOD: Sure.

DR. GANLEY: I think the analogous

situation is when you look at the actual use study

and you have the purchasers and non-purchasers.

Those non-purchasers, they did have to make a

decision whether to select to use the product and

they chose not to use it for various reasons. And,

many of the answers there were correct answers.

So, you can't really ignore that.

DR. WOOD: No, I am not ignoring it.

DR. GANLEY: That is why we have broken it

281

up like that and not just given you 67 percent.

DR. WOOD: But I just wanted everybody to

be sure they understood where that 67 percent came

from. Let's move along to the next talk.

CUSTOM - Actual Use Study

DR. SHETTY: Good afternoon.

[Slide]

My name is Daiva Shetty. I am a medical

officer in the Division of Over-the-Counter Drug

Products.

[Slide]

My presentation today will briefly cover

some aspects of actual use studies; actual use

issues that are important to address for Mevacor

over-the-counter marketing; and the results of the

actual use study submitted to support the

prescription to over-the-counter switch of Mevacor.

My presentation and the results will focus on the

analyses that strictly adhere to the label

criteria.

This morning Merck presented multiple

analyses that looked at ways to view the data.

282

Some of them were prespecified and some of them

were not prespecified. Most of them assess data

from the benefit to the population point of view.

[Slide]

Before presenting data from the CUSTOM

study, I would like to mention a few words about

actual use studies in general. Actual use studies

attempt to simulate over-the-counter use.

Recruitment is usually done through print and

broadcast media directed toward the general

over-the-counter population targeted for use of the

drug. Study sites are usually located in areas

where consumers would seek to purchase

over-the-counter medications, such as pharmacies

and grocery stores. The studies have very few

exclusion criteria and ideally should not have

recruitment pre-screening and minimum interactions

between the participants and the study personnel.

As much as they try to mimic over-the-counter use,

these studies are not perfect. There are

procedures, such as informed consent, information

gathering and diaries that always involve

283

interactions between the subjects and the study

personnel, and participants usually are compensated

for their participation in those studies.

[Slide]

The objectives of an actual use study

depend on the specific product and concerns related

to that product, such as self-diagnosis, which

refers to a consumer's ability to diagnose the

condition for which the over-the-counter product is

indicated; self-selection, which refers to a

consumer decision to use the drug or not to use it.

De-selection refers to a consumer's decision to

stop using the drug in cases such as not achieving

a benefit or development of an adverse reaction to

the drug. They also assess compliance, the dosing

and duration of use; off-label use; safety and

sometimes efficacy in over-the-counter use

population.

[Slide]

In the actual use study there are several

important behavioral issues for the nonprescription

Mevacor marketing. First of all, are consumers

284

able to self-diagnose hypercholesterolemia? Did

they know their own cholesterol values? And, did

they understand serum cholesterol values? Are they

able to identify risk factors for coronary heart

disease? And, do they understand how many of those

risk factors they should have or should not have to

qualify for the treatment? Are consumers able to

self-select appropriately based on the label

eligibility and the contraindications for use?

[Slide]

Are consumers able to self-treat

hypercholesterolemia? Are they able to follow

label directions for dosing and duration of use?

Do they follow directions for when to get follow-up

cholesterol tests or when to see a physician? Do

they understand the treatment goal? And, are they

able to identify risks during therapy and

de-select? For example if they develop muscle pain

or start new medication that may have a drug

interaction with Mevacor, or do not achieve goal

cholesterol levels, would they stop using the

product?

[Slide]

Now I will switch my presentation to the

data of the actual use study submitted to support

285

this application. The study, as you have already

heard, was called CUSTOM, Consumer Use Study of OTC

Mevacor.

[Slide]

I will start from the label used in the

CUSTOM study and tested in the label comprehension

study which is identical to the proposed label for

over-the-counter marketing. According to the

proposed label, there are four conditions that

determine correctness of the self-selection. The

order that consumers have to go through in their

thought process when looking at the label is as

follows: To be eligible for treatment with

Mevacor, the consumer must be a man at least 45

years of age or a woman at least 55 years of age;

must have LDL cholesterol between 130-170 mg/dL;

must have at least one of the following risk

factors for coronary heart disease, smoking, low

HDL cholesterol, family history of coronary heart

286

disease or high blood pressure, and also must be

free of conditions that may put him or her at

increased risk from using the product.

[Slide]

The study did not evaluate self-selection

as the primary endpoint. Rather, it assessed the

decision to purchase Mevacor. It is obvious that

purchasing the product can be construed as

self-selecting a product. A total of 3316 subjects

participated in the decision to purchase Mevacor

and 1205 decided to buy the product and 2111 did

not. The majority of both those who purchased and

those who did not purchase stated that they needed

more information to make a decision to buy or to

use the product. The most common reason among

purchasers needing more information was to obtain

their cholesterol numbers. Non-purchasers commonly

cited a need for personal health information or to

talk to a physician. The reasons for not

purchasing the product were evaluated. We believe

that the majority of non-purchasers may have made a

correct decision not to use the product.

[Slide]

In the next few slides I will show the

self-selection decision results based on the four

287

previously mentioned label criteria, age,

cholesterol levels, risk factors and the warnings

listed on the label. It does not include the

physician override concept. Since the raw data

were submitted late into the review process, the

numbers I will present today will differ a little

bit from what you have in your background packages.

There were a total of 1061 subjects in the

study who not only purchased but also used the

product. Two were excluded because of protocol

violations. Of all the users, 797 subjects met the

age criteria. That means that they were men at

least 45 years of age or women at least 55 years of

age. Of those who met the age criteria, 281 had

LDL cholesterol levels between 130-170. Of these,

206 had at least one risk factor for coronary heart

disease. The majority of them were men. Only 69,

out of 430 women were in this group meeting the

first three labeled criteria.

[Slide]

A further three subjects with underlying

liver disease, which is contraindicated in the

contraindications for use, were excluded and 18

subjects with a history of muscle pain or weakness

from using statins, and we are left with 185

288

subjects.

[Slide]

Then, there were 22 subjects who had only

one risk factor for coronary heart disease, in

addition to age, and a high HDL level above 60

which did not qualify them for treatment. Finally,

there were 53 users with high triglyceride levels,

over 200. The final numbers of correct

self-selection according to the strict label

eligibility criteria were 110 users, 33 women and

77 men, which is 10 percent of all the user

population. This does not include the physician

consultation.

[Slide]

It is important to look at the

demographics of the users. Among the 1061 subjects

289

who purchased and used the drug, there were 430

women. Of the 430 women who used the drug, 37.4

percent were less than 55 years of age, below the

targeted age by the label. The breakdown of women

users by age was as follows: 11 percent were less

than 45 and another 26 percent were between 45-54.

[Slide]

The actual use study suggests that women

of childbearing potential may select to use the

product. Over 20 percent of all women users were

less than 50 years of age. Consequently, because

during the first trimester of pregnancy women may

not realize that they are pregnant, it is important

to understand the risk to the fetus if women of

childbearing potential are going to use the product

in an over-the-counter setting and determine what

mechanisms could decrease that risk.

[Slide]

Now I would like to show the study results

on whether the users knew their LDL cholesterol

value at the time of purchase. The knowledge of

cholesterol value becomes important in an

290

over-the-counter setting especially if there is not

access to testing.

The rows in this table represent user

self-reported cholesterol values and the columns

show the results of LDL cholesterol at baseline.

Highlighted in yellow are the numbers of subjects

who knew and correctly identified their LDL

cholesterol. Around two-thirds of those who

thought they knew their LDL cholesterol correctly

identified it. It comprises 47.7 of all user

population.

It is important to note that over a third

of all users did not know their LDL cholesterol

value or their values were missing. Given that the

label states that you should know your cholesterol,

why would these subjects purchase Mevacor without

knowing their cholesterol? There could be two

reasons. First, they could get a physician

override, and I don't have data on which of those

318 plus 27 subjects consulted their physician.

Or, they could have purchased a test at the site.

Everybody in the study had an opportunity to buy a

291

test at the time of purchase. However, out of 318

who did not know their cholesterol, 67 decided to

buy a cholesterol test on site in order to find out

their cholesterol.

[Slide]

Another important fact that could be

learned from this table is that a significant

number of users had a baseline LDL cholesterol

below the targeted level. That means that they may

not need to be treated. Even though the

correlation between the self-reported and measured

LDL cholesterol values was high in the subgroup, 87

out of 122, knowing that their cholesterol is low,

chose to use Mevacor; 168 out of 265 subjects who

had higher than targeted LDL cholesterol also

incorrectly chose to use Mevacor.

[Slide]

This is the summary of consumer knowledge

of their LDL cholesterol values based on the data

from the previous table, 30 percent of the users

did not know their LDL cholesterol and chose to use

product; 47 percent of all users actually correctly

292

identified their LDL cholesterol value; 71 percent

of users who correctly identified their cholesterol

is less than 130 chose to use Mevacor; and 75

percent of those who correctly identified their

cholesterol above 170 also chose to use Mevacor.

[Slide]

The sponsor analyzed the self-selection in

more than one way. One of those self-selection

assessments was based on the number of risk factors

for coronary heart disease, ignoring whether the

user cholesterol values were within the labeled

range of 130-170. The results of this study showed

that 42.7 percent of users did not have at least

two risk factors and used the product even though

they did not meet the label criteria.

[Slide]

Now I would like to explain how the

sponsor assessed the correctness of self-selection

and why our results are so different. The original

definition in the study protocol defined correct

self-selection as according to label, or AL, which

represented a decision that is entirely consistent

293

with the product label. Or, if not according to

label, the consumer achieves LDL cholesterol goal

after six weeks of treatment.

In the middle of the ongoing study the

sponsor redefined the categories and the major

difference that was introduced for assessment of

self-selection is the physician override concept,

which means that if a consumer failed

self-selection for any reason but stated that their

physician approved the use of Mevacor, they were

classified as correct self-selectors.

There is nothing wrong if people consult

their physicians to make a better decision for

self-treatment, however, in this study the contact

with a physician or the information discussed was

not verified and we don't know why the majority of

users in the study failed the label criteria and

were approved by their physicians despite the risks

or no benefits for the treatment.

[Slide]

The sponsor also introduced two additional

categories for assessment of correctness of

294

self-selection. The first one was called "closely

adhered to the label" and included users who did

not meet one or more of the criteria for age, risk

factor profile, and had LDL and HDL values outside

the targeted range for treatment. But because they

knew their lipid profile; did not have elevated

triglycerides; did not substitute Mevacor for their

prescription lipid-lowering medication; and did not

have diabetes, heart disease or stroke, they all

were assessed as correct self-selectors.

[Slide]

In addition, the sponsor reevaluated

subjects who failed the previously mentioned

definition, "closely adhered to label" benefit

criteria, and looked at the subject's 10-year risk

profile for myocardial infarction or coronary

death. This approach allowed them to reclassify

the users who failed self-selection according to

the label if they did not know their lipid profile,

if they had elevated triglycerides, substituted

Mevacor for their prescription lipid-lowering

medication, or had diabetes, heart disease or

295

stroke but were eligible for study therapy by ATP

III guidelines based on the calculated more than 10

percent 10-year risk for myocardial infarction of

coronary death.

[Slide]

These are the sponsor's results of the

correct self-selection, 484 self-selected correctly

according to the label or medically acceptable for

self-management definition; 68 of those

self-selected on their own without a physician's

input. An additional 202 subjects who closely

adhered to the label were added to the correct

self-selection group. Finally, the sponsor states

that although 357 did not adhere to the label

benefit criteria, 258 of this cohort were eligible

for statin therapy by ATP III guidelines, thus

raising the correct self-selection rate to 89

percent or 944 subjects.

These analyses are not based on subject

self-selection decision but, rather, on the

retrospective analysis of their baseline

characteristics. When consumers are picking up the

296

package from the shelf they should be able to make

the right decision by reading the label.

[Slide]

There are several relative

contraindications for the use of Mevacor listed on

the proposed label. Of the 1061 users, 55.5

percent had at least one or more contraindication

specified on the label. In addition, 2.2 percent

subjects' data was not known due to missing

information. This brings the number to 42.3

percent of users who did not have any relative

contraindications for using Mevacor. The majority

of those users with relative contraindications were

classified by the sponsor as correct self-selectors

because they stated that they spoke to their

physician. Even if we assume that some

participants in fact discussed their particular

risk condition with their personal physician, a

significant proportion of users with those

contraindications remain who did not get physician

clearance.

[Slide]

A listing of these non-clearance users is

shown on this slide and 37.5 percent of those who

substituted prescription lipid-lowering medication

297

with OTC Mevacor did not consult the use of Mevacor

with their physician; 64.5 percent of those with

high LDL or high triglyceride levels used Mevacor

without physician clearance; 37.5 percent of those

taking potentially interacting drugs; 41 percent of

diabetes; 41.5 percent of subjects with coronary

heart disease; 51.6 percent with a history of

stroke; and 61.6 percent of subjects with a history

of previous muscle pain while taking statins also

used Mevacor without consulting with their

physician.

[Slide]

Another consumer behavior aspect that was

assessed in the study is the self-management or

compliance with treatment and de-selection. Over

the next two slides I will show you how users in

the CUSTOM study behaved after the initiation of

therapy.

Thirty-seven percent, or 393 subjects did

298

not get any follow-up cholesterol test after they

started using Mevacor, and the majority of them,

277, continued therapy; 63 percent, or 666, had at

least one follow-up cholesterol test.

[Slide]

Of those who had at least one follow-up

cholesterol test, 7 discontinued the treatment and

659 continued on therapy. Of those who continued

on therapy, 375 were at goal for LDL cholesterol

goal on their follow-up test; 160 subjects were not

compliant with their label treatment because they

were not at goal, and their cholesterol was above

130 or their follow-up cholesterol values were

missing and they continued on therapy. The rest

complied with the label treatment criteria

according to the sponsor because they either

continued with physician override or discontinued

because they were not at goal.

[Slide]

By the end of the six-month study a lipid

test was not optional but required by the protocol.

There were 548 subjects among the 878 tested with

299

LDL cholesterol below 130 mg/dL. However of those,

160 subjects had LDL cholesterol less than 130 at

baseline and for 39 subjects baseline LDL

cholesterol values were unknown. So, we don't know

what benefit, if any, these 199 subjects received

from the therapy. There were 349 with LDL

cholesterol values above 130 at baseline who

achieved goal by the end of six months of the

study.

Since there were some questions about the

compliance and how consumers in the study complied

with the treatment, I want to mention that the

median number of tablets that the users purchases

in the study was 122, which is approximately a

four-month supply for the treatment.

[Slide]

Despite many self-selection errors, there

were no safety signals reported during the study

and 17 percent of all users reported at least one

drug-related adverse experience and only one of

those was assessed as a serious event. That was an

allergic reaction to lovastatin. No other serious

300

drug-related adverse events were observed during

the study.

[Slide]

In summary, based on the information I

have presented, the actual use study showed that

the majority of the participants, those who

purchased and those who did not purchase Mevacor,

needed more information to make a decision.

Although approximately one-half of the users

correctly identified their LDL cholesterol,

approximately one-third of all users did not know

their LDL cholesterol values and chose to use

Mevacor.

[Slide]

There were some self-selection errors and

37 percent of women users were less than 55 years

of age; 26 percent of users met the age and

baseline LDL cholesterol range; 19 percent of users

met the age, LDL cholesterol and the risk factor

for coronary heart disease criteria. Based on our

assessment 10 percent of all users self-selected

correctly by the strict label eligibility criteria

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without a physician override. It is not clear

whether the complicated paradigm of treatment of

high cholesterol, or the label used in the study,

or both led to such poor self-selection results.

[Slide]

Forty-two percent of the users did not

meet the label eligibility criteria for the number

of risk factors for coronary heart disease. More

than half of the users had at least one relative

contraindication for the treatment with Mevacor.

[Slide]

There was relatively good compliance with

follow-up cholesterol tests, 63 percent; 35.6

percent of users achieved the target LDL

cholesterol goal of less than 130 at follow-up

testing. Data was not presented, as the sponsor

already mentioned--those who used Mevacor had

lowered their cholesterol approximately 21 percent

and 25 percent lowering in those who had fasting

cholesterol values. Even though testing at the end

of six months showed that over half of all users

had LDL cholesterol less than 130, one-third of

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them started at a level below 130 or their baseline

values were missing.

[Slide]

There were no serious safety signals

observed during the study, but if Mevacor becomes

available over-the-counter, based on the study

results, it is likely to be used by women of

childbearing potential, consumers with

contraindicated conditions, consumers with no risk

or low risk for coronary heart disease, and

consumers at high risk for coronary heart disease

who can potentially be under-treated. This ends my

presentation. Thank you for your attention.

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

take a break.

[Brief recess]

DR. WOOD: Dr. Koenig will now talk about

simvastatin use in the United Kingdom.

Nonprescription Simvastatin in the United Kingdom

DR. KOENIG: Good afternoon.

[Slide]

I am Michael Koenig, an interdisciplinary

303

scientist in the Division of Over-the-Counter Drug

Products.

Over the next 15 minutes or so I am going

to be providing some additional information about

what you have heard referred to earlier today as

OTC simvastatin in the United Kingdom. This is

currently the only statin available without a

prescription anywhere in the world. Simvastatin in

10 mg tablets has been marketed in the United

Kingdom as Zocor Heart-Pro since July of last year,

just a little under six months.

The information that I will be presenting

comes from the Internet and has been vetted by

colleagues at the British Medicines and Healthcare

Products Regulatory Agency.

[Slide]

My presentation can be divided into three

parts. First, I will describe how medicines are

classified in the United Kingdom. Second, I will

outline the process by which medicines can be

reclassified or switched between classes, which is

the process that we are going through here today.

304

This is part of that same type of process. Third,

I will bring up some of the issues that were

considered in the United Kingdom in considering

specifically the switch of simvastatin from

prescription to nonprescription status.

[Slide]

As in the United States, medicines in the

United Kingdom can be broadly classified into two

categories, prescription and nonprescription.

Prescription medicines are also known as

prescription only medicines, or POM medicines, and

they are in this class because of safety concerns.

The British feel that the medicines in the

prescription only medicine class present a direct

or indirect danger to human health if they are not

used under a doctor's supervision. Additionally,

these medicines may contain a substance or

substances requiring further investigation or they

require injection. All new medicines, and by that

I really mean all new chemical entity-containing

medicines, are initially placed in this class,

prescription only medicines.

[Slide]

Unlike in the United States, the

nonprescription classification of medicines can be

305

further broken down into two different subclasses.

The first of these that I am going to talk about

are those in the pharmacy, or P class of medicines.

These are available in pharmacies and only in

pharmacies, and they are administered under the

supervision of a pharmacist or the pharmacy staff

who have been trained to work with this medicine.

In the United States we would refer to this type of

medicine as behind-the-counter if we had such a

class but we currently do not. There is no legal

behind-the-counter classification. Simvastatin

falls in the pharmacy class of nonprescription

medications.

More like our OTC drugs are those listed

on the general sales list. These are available on

pharmacy shelves, open pharmacy shelves. They do

not require the assistance of pharmacy staff. They

are also found in supermarkets, and they include

medications such as analgesics and cough-cold

306

medications. As I indicated, the comparable class

in the United States is what we refer to as OTC or

over-the-counter drugs.

At this point I would like to point out

what you may have seen in the literature, and you

have already heard referred to this morning. You

have heard simvastatin referred to as OTC

simvastatin. All nonprescription drugs, that is

both classes, pharmacy and GSL, are considered and

are sometimes referred to as OTC medications. So,

there is that distinction that I wanted to bring

out.

[Slide]

Let me now talk about the reclassification

process itself, or the switch from one

classification to another. I am going to focus

specifically on the reclassification from

prescription only to pharmacy type of medicine

because that is the one that is involved with

simvastatiin. It is also possible to reclassify

medicines from pharmacy to GSL but medicines in the

United Kingdom do not jump directly from

307

prescription only to what we would consider OTC to

GSL.

The first thing that goes into the

application, as you would expect perhaps because it

is included in any NDA, new drug application for a

switch in this country, is the safety profile for

the drug. This includes reports of adverse

reactions; the results of post-marketing

surveillance studies; published literature

supporting the reclassification; and safety reviews

that may be available. Additionally, the

application includes patient information which is

the proposed labeling for the product. In the case

of a medicine being considered for switch to the

pharmacy class, the applicant must show how the

pharmacists and their staff are going to be

trained. Finally, the application includes a

detailed evaluation by a clinical expert and, of

course, since the application comes from the

sponsor the clinical expert is provided by the

sponsor.

[Slide]

The process itself can really be broken

down into five steps: First, the application

containing the information I have just talked about

308

is submitted to the Medicines and Healthcare

Products Regulatory Agency, or MHRA, a body that is

directly comparable to our FDA. The MHRA takes

this application in for review.

In the case of simvastatin and most other

switches from prescription only to pharmacy, the

MHRA likes to include the Committee on Safety of

Medicines, or CSM. This is analogous to you, to

the advisory committee members. These are experts

from around the United Kingdom who come together to

advise the MHRA on what they think, or contribute

their thoughts on the advisability of making the

switch.

Upon completion of the review, a

consultation letter is prepared which contains the

findings and tentative conclusions of the MHRA in

conjunction with the CSM, the Committee on Safety

of Medicines. This is then sent out to the

different health agencies for comment and for their

309

response. Whether the MHRA is leaning toward a

switch or against a switch, the information goes

out for public comment, and that is probably not

terribly different from what we will be having

tomorrow morning when we have the open hearing--the

same type of public input. This meeting is public

as well.

The responses are received back at the

MHRA. In this case the respondents were given 60

days to respond. They are then reviewed to

determine whether or not any new issues have come

up that the MHRA feels must be addressed. Then, in

the final step, the MHRA takes some sort of action,

either approving the switch or not approving it.

In the event that it is not approved there is the

right of appeal.

[Slide]

In the specific case of Zocor Heart-Pro,

this medicine was reclassified as a nonprescription

pharmacy type medicine in July, as I said, of 2004.

I would just like to briefly go over some of the

labeling. You have heard extensive talks about the

310

labeling both from the sponsor and from my

colleagues in the FDA. But let's look at the

labeling briefly for Zocor Heart-Pro, and I will be

going into some more detail on this a little later

in my talk.

This labeling is available in your Merck

background package right at the very end. For this

particular label the display panel is on page 343

of the Merck background package. You can see that,

just as labeling in this country, the labeling

indicates the proprietary name, Zocor Heart-Pro, as

well as the active ingredient.

What I wanted you to see is the primary

indication. In the United Kingdom Zocor is

marketed to reduce the risk of a heart attack. On

the back of the package there is the same sort of

information that you might find in this country,

although not in drug facts format. I want to point

out that Zocor Heart-Pro is for people who have a

moderate risk of coronary heart disease. So, I

believe that is the same indication that Merck is

seeking.

But in the United Kingdom patients are

advised or would-be purchasers are advised that the

pharmacist can advise them further and help them to

311

identify their risk level. Merck has already said

that will be the case with Mevacor. Here it is

actually a requirement. That is a specific

designated nonprescription class.

[Slide]

Additional labeling that consumers are

exposed to includes the questionnaire which must be

filled out in the pharmacy itself and is assessed

by the pharmacist or his staff or her staff to

determine whether the patient qualifies to receive

this medication.

[Slide]

Then, if they are able to obtain the

medicine, once they get home and open their package

detailed patient information is provided in this

patient information leaflet, and I will be

referring to this in somewhat more detail just a

little bit later on.

[Slide]

I would now like to get to the real meat

of what I hope to present to you today, and I would

like you to consider some of the issues that were

considered in the United Kingdom when they were

thinking about switching simvastatin to a pharmacy

status.

312

[Slide]

The public consultation letter, as I said,

contained all of the issues considered by the MHRA.

I have just picked six of these for a little deeper

presentation to you, a little bit deeper

discussion. The MHRA considered the potential for

myopathy and rhabdomyolysis. They also looked at

the potential for liver toxicity in consumers who

would be taking this product. They were concerned

about possibly use by pregnant women--if this

sounds familiar, it should. They were concerned

about whether or not consumers could adequately

self-diagnose that they were at moderate risk of a

heart attack, again with the assistance of a

pharmacist. They addressed the issue of whether

consumers even needed to know their LDL cholesterol

313

numbers or not. And, for this medication which is,

again, a pharmacy medicine, the MHRA considered the

adequacy of training materials provided to the

pharmacy staff.

[Slide]

With regard to the potential for myopathy

or rhabdomyolysis, the MHRA felt that this was a

sufficiently rare condition that they were not

particularly concerned about it, especially since

they considered the warnings on the labeling to be

adequate.

So, now if I take you back to that patient

information leaflet which is included in the

package, there are four things I would like to

point out here that all deal with myopathy and

rhabdomyolysis on the labeling. First, consumers

are advised not to take these tablets if they have

had muscle problems in the past after taking a

cholesterol-lowering medicine.

Secondly, consumers are advised to stop

taking the tablets immediately and check with their

doctor if they develop generalized muscle pain,

314

tenderness or weakness unless it is an explained

pain. That is, unless it is clearly the result of

flu, unaccustomed exercise, recent strain or

injury.

Thirdly, consumers are advised that they

should not be taking certain medications

concurrently, those being cyclosporin or other

prescription cholesterol-lowering medicines, as

these may cause problems if they are taking Zocor

at the same time.

Finally, and this is not on the labeling

in this country, the British pointed out that

consumers should not drink huge quantities of

grapefruit juice, more than a liter a day; 250 ml

was fine.

[Slide]

Now, regarding the potential for liver

toxicity, the MHRA concluded that this was an

extremely rare condition and that routine testing

of liver function was not required. Again, they

felt that the warnings included in the labeling

were adequate.

[Slide]

Again looking at the patient information

leaflet, we see the following three items: First,

315

consumers are told not to take these tablets if

they know they have liver disease or they have been

told they have had abnormal liver function blood

tests in the past. Secondly, do not take these

tablets if you drink excessive amounts of alcohol.

Third, stop taking these tablets and see your

doctor if you develop the symptoms of

hepatotoxicity--it doesn't say hepatotoxicity but

yes.

[Slide]

What about the possible use by pregnant

women? This has come up today I think. It was not

a concern to the folks at the MHRA. They pointed

out that the labeling clearly specifies, right at

the very outset, that it is only to be used by

women by 55 and over. Furthermore, again they felt

that the warnings in the labeling were adequate.

Again, if I could refer to the patient

information leaflet, there is this directive: do

316

not take these tablets if you could become

pregnant, are pregnant, are planning to become

pregnant or are breast feeding.

[Slide]

What about the consumer's ability to

self-diagnose that they are at moderate risk of a

heart attack? The MHRA concluded that with

pharmacists' assistance patients should readily be

able to identify whether or not they are at

moderate risk based on age and the risk factors.

This is included in the questionnaire which the

pharmacist goes over with the would-be purchaser,

as well as in the patient information leaflet.

[Slide]

On the questionnaire, right at the top,

patients are asked if they are of a certain age. I

would just like to point out because this came out

earlier today too, females ages 55-70, and if you

are female, have you reached menopause? Yes/no?

They are also asked about four risk

factors, and these are similar but not identical to

the four risk factors on Mevacor. Smoking is the

317

same. Family history of early heart disease I

think is very similar to what is on the Mevacor

label. But not on the Mevacor label, and of

concern to the British regulatory agency, was

whether the consumers were overweight and whether

or not they were of a family origin from South

Asia.

[Slide]

The same information is on the patient

information leaflet. You are likely to be at

moderate risk based on age criteria as well as

those same risk factors. So, there is plenty of

exposure to determine if they are at risk for

coronary heart disease. This, by the way, as in

the United States, is the leading killer of adults

in the United Kingdom, coronary heart disease.

[Slide]

What about do consumers need to know their

LDL cholesterol levels? The MHRA pointed out that

reducing the level of LDL cholesterol or bad

cholesterol reduces the risk of a heart attack, and

you have heard that described already today.

318

Therefore, the MHRA felt that there was no specific

requirement to know initial LDL cholesterol levels

or to monitor these levels after starting.

Consumers that are found to be at a higher

risk--and this is based on the answers they give to

that questionnaire--would be identified by the

pharmacy staff and would be given opportunities to

determine their LDL cholesterol levels. These

people could then be referred to a doctor for

further studies.

[Slide]

Finally, what about the MHRA's feeling on

the adequacy of pharmacy staff training? It

doesn't really apply in this case but to complete

the major issues. The MHRA felt that this had been

prepared in consultation with national pharmacy

bodies and was adequate; would be distributed to

pharmacists and medicine counter assistants

throughout the United Kingdom; and the education

specifically included understanding of

pathophysiology of coronary heart disease and major

risk factors; contraindications, precautions, and

319

possible adverse effects of taking Zocor, as well

as alternative interventions including, for

example, lifestyle changes--diet and exercise.

[Slide]

The consultation letter went out in

November of 2003 and was sent to over 250 different

health service agencies. Of those, they received

100 responses. Most of these came from national

health service trust organizations, but they also

got significant input from pharmacy bodies, royal

medication colleges, medication bodies and

academia. Additionally, there was input from

industry and from patients.

[Slide]

Well, what did people think? Of those 100

responses, 9 percent said unequivocally yes, we

feel this should be switched to pharmacy status; 24

percent said yes, they felt it should be switched

but they had issues they felt warranted further

consideration; 21 percent said neither yes nor no

but stated that they had issues that they felt

should be addressed; 11 percent responded with no

320

comment; and 35 percent said no, it should not,

either statins in general nor Zocor in particular

should be switched to pharmacy status.

[Slide]

I will just briefly and quickly go through

the major concerns raised in response to that

consultation letter. At least 50 of the

respondents indicated that they felt the dose of

Zocor 10 mg was too low to be effective, and

pointed out that there were no clinical trials at

this dose so it was not clear how the MHRA had

reached a conclusion that it was efficacious.

At least 27 felt that, although the MHRA

did not feel this way, there was a need for

cholesterol testing, arguing that since this is an

asymptomatic disease, a chronic asymptomatic

disease, how could people know if it was effective

if they had no way of seeing anything or measuring

anything?

At least 21 felt that there was a need for

liver function testing, something that you will

remember the MHRA did not feel is necessary. The

321

argument was that preclinical only medicines

require liver function testing so it was not clear

to these respondents why it shouldn't be required

for pharmacy class medicines.

At least 21 respondents raised the issue

of the potential for ignoring lifestyle changes.

In other words, people might forego changes in

their diet or exercise regimens in favor of taking

Zocor Heart-Pro.

Another 21 brought up the issue of the

cost of OTC statins. That is not an issue that we

worry about in the FDA but it was an issue that

came up over there. Zocor costs about 12-15 pounds

per package. That is a 28-day supply, taken once a

day, usually in the evening. That equates to about

$24-30 and that is about $360 a year. So, there

were concerns that there would be a disparity

between the ability of those who could afford it to

buy it and those who really couldn't afford to buy

it.

[Slide]

At least 16 raised the issue of the burden

322

on the pharmacist and the pharmacy staff and the

training that would be required. We felt that

either the training wasn't completely adequate or

they felt that training and the time spent

counseling potential purchasers would be too great

a burden on the pharmacist.

Another 16 were concerned about record

keeping and patient management. The feeling here

was that since the pharmacy had one set of records

and the doctors had another set of records there

might be a disconnect between the two and the left

hand doesn't know what the right hand is doing. So

that was an issue.

Ten felt that interactions with other

medications warranted further consideration, and 10

felt that the side effects, for example the

rhabdomyolysis and the liver toxicity, merited

further consideration as well.

[Slide]

In summary, as I said, this was

reclassified as a pharmacy medication in July of

last year because the medicine does not produce, in

323

the view of the MHRA, a direct or indirect danger

to consumer health without medical supervision, but

only if it is given with the advice of a pharmacist

and supported by a comprehensive pharmacy training

package. Again, this type of behind-the-counter

classification does not currently exist in this

country. There is no legal basis for it at

present. Thank you.

Questions from the Committee

DR. WOOD: Thanks to all the presenters

for sticking to time. I guess now is the period

for the committee to ask questions and we will

entertain questions. DR. WOOLF: A couple of

questions. The system in Great Britain has been in

place for six months. Do we have any idea, in this

short period of time, how well it has worked?

DR. WOOD: The question was it has been in

place for six months in the U.K., how well has it

worked?

DR. HEMWALL: Yes, as you noted, it has

only been on the market for six months in the U.K.

We don't have a good handle on how well it is

324

working yet. I do have Dr. Steve Mann, who

actually was the person who took the application

through the MHRA, here and he can answer a lot of

your questions about this. Maybe you have a

comment now, Steve?

DR. MANN: Thank you. Firstly, I want to

thank Dr. Koenig for what I thought was a fair

characterization of the process in the U.K. As Ed

said, it is a little early to judge exactly how

well this is working, although we are committed to

monitoring how the system works.

We did pilot the questionnaire that is

used in pharmacies before or actually during the

process of the application and showed that it works

well, with pharmacists being able to use it

adequately, and actually, a fair proportion of

people being able to fill in the questionnaire

without any pharmacy help.

Perhaps the only comment I would make on

the process is that the Committee on Safety of

Medicines was heavily involved in approving this.

It is not just the MHRA. The Committee on Safety

325

of Medicines, as Dr. Koenig pointed out, is an

independent body of advisers to the government.

The only comment I would take slight issue

with is we do encourage people to test their

cholesterol. It is just simply not mandatory for

them to know their cholesterol level going in. The

view of our experts and of the Committee on Safety

of Medicines was that if people have a risk level

that justifies treatment, whatever their starting

LDL cholesterol level, there is evidence that they

will benefit, and that it is important to know that

their cholesterol is reducing, and that they don't

have a high level on treatment. That really is the

place of cholesterol testing is the current view in

the U.K. I hope that was helpful.

DR. WOOLF: The second question is for the

FDA. On page 2 at Tab 4 of our briefing document

it states that there were 195 cases of women who

were pregnant who received a statin. We only have

the data on the 25 who had lovastatin. Do we have

the information for the remaining 170 who took a

different statin and what was the outcome in those

326

pregnancies?

DR. DAVIS-BRUNO: That particular data was

obtained from an Office of Drug Safety consult that

we requested. I don't know of Jocelyn Swann is

here but she is the one who actually did the

consult and could specifically address that

question. I don't have slides on the other

statins.

DR. WOOD: Well, while you are up there,

if my recollection is right, Merck said there were

seven fetal abnormalities in your database, and on

page 2 and 3 of your Tab 4, are these overlapping

or are these additive, or what is the story there?

DR. DAVIS-BRUNO: If you are referring to

the pharmacology/toxicology briefing document, that

table with clinical findings--

DR. WOOD: I am referring to Tab 4.

DR. DAVIS-BRUNO: Right. Those particular

human findings are relevant only to lovastatin.

DR. WOOD: No, no, I understand. These

are the numbers from the AERS database.

DR. DAVIS-BRUNO: Correct.

DR. WOOD: And in the Merck database there

are seven, they said. I was surprised, first of

all, that the seven didn't seen to be reported to

327

the AERS database and the question was did these

seven that they have include these five, or are

there really 12, or what are the numbers? I

thought they had an obligation to report all the

numbers, so how come there are less?

DR. LEVINE: I am Jack Levine, with Merck.

The five that are there are included in our

seven--those six are included in our seven.

DR. WOOD: Okay, and what is the seventh?

DR. LEVINE: There was one aborted fetus

that the FDA refers to, and we have two where there

is actually a question of whether they are the same

case.

DR. WOOD: All right. So, the total

universe is seven including 1/2.

DR. LEVINE: Correct.

DR. WOOD: Thanks. Dr. Parker?

DR. PARKER: It seems that there was some

valuable information obtained from the label

328

comprehension study, as well as the use study,

about the bottom line of people who would use this

drug, their ability to understand what they need to

know. I am wondering if the insights gained from

the label comprehension study, however you slice

the pie, were used to modify the label for the use

study. In other words, what is the exact timing of

the label comprehension study and the use study,

and whether or not the results from the label

comprehension were used to make the label better in

the use study?

DR. HEMWALL: As you saw in one of the

slides that Jerry Hansen showed, we did research

for about three years, and the total amount of

research going even further back that that was with

about 30,000 consumers, studying every possible

element of the label in focus groups and in pilot

label comprehension studies. So, once we had the

label that we were confident was well understood,

we did the studies, the CUSTOM study and the label

comprehension study simultaneously, knowing

full-well that the next study would be one with

329

input from this committee and from the FDA, having

reviewed and commented upon the results of not only

the label comprehension study but the CUSTOM study,

to help further refine that.

DR. WOOD: Mary?

DR. TINETTI: I have a few questions

related, first of all, to label comprehension, and

this would be both for the FDA and Merck. First of

all, I was sort of interested that it had an 8th

grade comprehension level. I wonder if anybody

knows what the median comprehension level for the

older population is. I guess the last I heard, it

was closer to 5th grade. I am curious. In this

population there is only 35 percent for women, for

example, who are over 55 and probably few of those

are over 70. My concern is that there is a large

number of those people who are going to have many

of either the contraindications or most likely the

indications for discussing it with their

physicians. So, I wonder if there was any

sub-study looking specifically at that population,

and whether the people we are most concerned about

330

understand the label, and could they, indeed, do

it.

I am also concerned about the size of the

print for the older population. Finally, I was

sort of curious. It sounded as if people

understood that if you stopped the medicine your

cholesterol would go back up. But do they really

understand the question that we are interested in,

that once you start this medicine you are only

going to get better if you take it forever and

taking it in fits and starts is not going to be

particularly helpful. I wonder if there were any

questions related to that and, if not, what do we

think the repercussions of not having that

information are.

CAPT. SHAY: There were no questions in

the label comprehension study that addressed that

but, I agree, that would have been an important

element to come out in the study.

DR. WOOD: Let's go on to Dr. Follman.

DR. FOLLMAN: I wanted to talk a little

more about pregnancy. In the sponsor's analysis

331

that they showed on the screen a little while ago,

my recollection was that they talked about 67

reports of statin use during pregnancy and that

nothing happened as a result of this, no toxicities

or problems, or anything. But in their briefing

document they talk about these 67 and note that in

34 of these pregnancies that were reported during

statin use outcome data was available, and in this

table they note that three of these 34 with known

outcome data ended in elective abortion; one in a

spontaneous abortion and one in fetal death.

So, I wanted to, I guess, set the record

straight in terms of what they said earlier that,

in fact, there were some untoward events during

those pregnancies.

I also have a couple of comments about the

analysis of the mice data. One was that the

sponsor's analysis sort of disparaged what the FDA

did and noted that one of the litters had, I think,

8/8 fetal abnormalities. So, all of the

abnormalities were in one litter and that seemed to

be sort of over-counting. I don't know exactly

332

what statistical analysis the FDA did but there are

certainly analyses that I trust the FDA did which

take into account the fact that outcomes in a

litter are likely to be similar. So, just the fact

that you used litters in your analysis doesn't

necessarily mean that it is incorrect.

Another point I wanted to make was that in

the weight loss analysis they had a table which

showed various outcomes in the control group and

then weights at different times for the three

different doses of statin, and they said these were

all non-significant. But if you look at them, in

each instance, except for one of the 12 I believe,

the weight was less in the lovastatin-fed mice than

it was in the control group. So, to me, if you

would combine that it would suggest something more

consistent with what the FDA said, which was that

there was concern about weight loss with

lovastatin.

Finally, there was some comment about

disparaging the use of concurrent controls and that

historical controls would be better. I have never

333

heard that argument before; it is kind of

mystifying to me.

DR. WOOD: Does the sponsor want to

respond to that as these were in their

presentation? No? All right.

DR. DAVIS-BRUNO: Can I just clarify? I

just want to make sure that it is clear that the

FDA looks at both concurrent controls and also

historical control data when we do our analysis.

DR. WOOD: Okay. Dr. Watts?

DR. WATTS: I would like to hear from

Merck. You have one of your products now approved

at the pharmacy level for use in the U.K. and you

are asking us to approve or recommend approval of a

different drug in the same class for use in the

U.S. I wonder why you picked simvastatin to use in

the U.K. and lovastatin to use in the U.S.

DR. HEMWALL: There is a fairly simple

answer. Lovastatin was never approved for

prescription marketing in the U.K. so simvastatin

was our only option for switching in the U.K.

DR. WATTS: But why not simvastatin here?

DR. HEMWALL: Well, as you have heard

today, we have done an awful lot of work on

lovastatin, including additional investigative

334

animal work, and this has been our project I think

since about 1997. It would have been difficult to

switch in midstream to simvastatin. Secondly, in

keeping with the data-driven determinations that

are made by this committee and the FDA, lovastatin

is directly tied to a study, AFCAPS, which showed

risk reduction in the primary prevention target

population that we are considering for OTC.

Simvastatin has many excellent long-term studies

but they are in different risk level populations

although the HPS study was certainly a basis for

approval in the U.K. without needing to know one's

cholesterol level.

DR. WOOD: While we are talking about the

comparison between the two, you obviously went with

an approval in the U.K. without an LDL measurement,

and you are going here with an LDL measurement. Do

you want to comment on why you made that

distinction?

DR. HEMWALL: I think I will ask Dr. Mann

to comment on the thinking that was considered in

the U.K. In the U.S., of course, we are trying to

be as consistent as possible with the NCEP

guidelines.

DR. MANN: Yes, if I could comment, in the

335

U.K. we faced a very different situation I think to

what prevails in the U.S., in that there has not,

in the U.K., been an extensive cholesterol

awareness campaign over many years, and I think it

is fair to say that the level of consumer knowledge

about cholesterol risk factors for coronary heart

disease and the connection between the two is not

very high in the United Kingdom. We were faced

really with a quite different setting I think from

what prevails here.

Our expert panel and the Committee on

Safety of Medicines concurred with this view and

felt that the current state of knowledge about

cholesterol dictated that intervention should be

based on someone's absolute risk of coronary heart

disease and, if that risk justified intervention,

336

then the person would benefit from reduction of

cholesterol whatever the starting level of LDL-C.

I think you saw earlier today that Dr. Pasternak

presented those data, suggesting really that the

benefit is there throughout the line of what the

starting cholesterol LDL-C is.

It is also the case in the United Kingdom,

and I think it is probably true to a similar degree

in the United States, that with these age and

gender categories there are very few people who

have what is characterized as a desirable LDL-C

level and, on that basis, it was felt that not

having to know the LDL-C at the start of treatment

would discourage fewer people in the United Kingdom

from taking part because really the knowledge of

those numbers didn't exist. But knowing what their

LDL-C was on treatment is something that would be

encouraged both to motivate and to continue but

also to pick up those who are inadequately treated.

DR. WOOD: Dr. Fincham?

DR. FINCHAM: I would like to preface my

question with just perhaps a comparison between

337

pharmacy in the U.K. as opposed to pharmacy in the

U.S. If you look at the sheer numbers of

pharmacies in the United States, there are probably

four times as many pharmacies in the U.S. as there

are in the U.K. But, yet, because of the

population difference, if you look at it as a

pharmacy per unit of population, residents of U.K.

have probably twice the opportunity to see a

pharmacist perhaps as we do in the U.S. Plus, the

types of pharmacies that you see in the U.K. are

vastly different from what you see in the United

States, and there is some penetration of chains

much more recently into the U.K., and certainly it

is dominant in the United States. So, the size of

the pharmacies is perhaps different. Thank you for

allowing me to say that.

The question is it appears, when looking

at the training materials either for consumers or

for consumers and pharmacists, that the process in

the U.K. seems to be driven through a pharmacy by a

pharmacist or a trained technician to aid the

consumer, whereas, in the United States what has

338

been proposed, or at least what I have seen in the

documentation, indicates that it is much more of a

consumer-driven process within a pharmacy and, by

the way, you can ask a pharmacist in the United

States should you need to. And, I would just like

to have an answer to the question why is there a

difference in how this is being marketed to

consumers through pharmacies in the different

countries.

MR. HANSEN: Maybe I will have Steve

comment on access to pharmacists in the U.K. versus

the U.S. My understanding, after being over there

several times, is that it is pretty similar to the

U.S. in that two major chains do have about 50

percent of the market share--but I will let Steve

confirm that--and the rest are independents, which

is similar to what you see in the United States--

DR. FINCHAM: However, one of those

pharmacies traditionally has been a major player,

and it is Boots, and Boots has always had smaller

pharmacies as the norm as opposed to the opposite.

DR. HANSEN: Yes, it is not true anymore.

339

They look more like a CVS or a Walgreens than they

do the old Boots that you remember. In fact, they

even have a dentist's office in a lot of them. So,

they have expanded over the past few years. I was

actually surprised. So, we can debate whether they

look the same or not the same.

But I think the key question is why the

difference; why aren't we putting it behind the

counter here and putting it behind the counter in

the U.K.? And, the key difference, as Dr. Koenig

from FDA said, is that there is no third class,

legislative third class in the United States.

DR. FINCHAM: That is a great answer but I

don't think it answers my question. The question

is that driving the product for consumer use

appears to be vastly different between the two

models. My point is that in the U.K. you are

driving it through consumers to go through the

pharmacist in a pharmacy, whereas here, at least in

what has been proposed and what is on the boards,

etc., it appears that this is driven by the

consumer in the pharmacy who may or may not have a

340

consultation with the pharmacist.

MR. HANSEN: Yes, I think the difference

is the hallmark of our program, that the consumer

can do it on their own here, in the United States,

because you have to consider worst case, that they

are not going to talk to the doctor; they are not

going to talk to the pharmacist and, therefore, we

developed a system for them to do it on their own.

That is number one.

Secondly, understanding the type of

consumer who is interested in using this, we know

that most of them see their doctor on a regular

basis. Most of them consult with a pharmacist.

So, we want to make sure we facilitate that and we

want to make sure that they do have that option in

a pharmacy so that it is there. It is not

mandatory. It is not behind the counter because

there is no legislation for that, however, we do

want to make it easy for consumers to avail

themselves of that as well.

DR. WOOD: Also, I would not oversell what

actually happens in a U.K. pharmacy when they are

341

behind the counter.

MR. HANSEN: I was going to stay away from

that!

[Laughter]

DR. WOOD: Right, you may be reluctant to

say that what happens is the consumer goes up to

the girls who stands behind the counter and says

they would like that, and the sales person waves it

at the pharmacist who says okay, and then it gets

issued. Is that fair?

DR. MANN: I think it is probably fair for

acute symptomatic treatments. They take it much

more seriously with the newer medicines that are

becoming available, and I think simvastatin is

probably the first of a new class and is very much

recognized as having to have a different approach.

One thing I would add to what Jerry said

is that access to healthcare professionals in the

U.K. drives to a large extent how people get their

medical care, and primary care doctors are under a

huge amount of pressure in the U.K. just by virtue

of the numbers. So, people are used to accessing

342

care in pharmacies. However, the model that is

applied in pharmacies in the U.K., particularly for

simvastatin, is relatively simple and certainly our

experience with piloting the questionnaire is that

many consumers can do that without pharmacy

assistance although the pharmacist is always there

at the point of sale.

DR. FINCHAM: But there are really some

sophisticated materials that are provided in the

U.K., a pharmacist training guide, medicine counter

assistance training guide, Zocor Heart-Pro consumer

questionnaire pad, concise guide to when to

recommend, BMI height/weight chart, customer

counter leaflets--

DR. KOENIG: If I could just add

something, I pointed out, I thought, during my talk

that the reason this is a pharmacy medicine is that

you can't go directly from prescription to GSL, or

what we would call OTC, in the United Kingdom. You

go sequentially and usually you stay in each class

at least five years so that a sufficient safety

record can be built up. So, simvastatin doesn't

343

have the option of being sold as we would do it in

this country; it has to be sold as a pharmacy

medication under those regulations.

MR. HANSEN: The only point I was going to

make is that exactly the same materials, at least

as they apply to the United States, would be

available here. In fact, a lot of the materials

used in the U.K. were actually adopted from the

U.S. because we have been working on the program

longer here than they have in the U.K.

DR. WOOD: Neal?

DR. BENOWITZ: I wanted to just follow-up

on some of the differences between the U.K. and the

U.S. trials. First, I just wanted to be sure that

we had data on primary prevention, that lowering

cholesterol below--or treating someone with

cholesterol below 130 is still a benefit because we

saw that a lot of people who are going to be taking

this drug will have cholesterols that don't meet

the entry criteria. I would like to know is it in

fact of shown benefit in primary prevention.

A second thing I am curious about is why

344

the U.K. criteria did not include hypertension

which is one of the major cardiovascular risk

factors. Was there some concern about why

hypertension should not be one of the indications

for use in the U.K.?

DR. WOOD: Tony?

DR. GOTTO: Tony Gotto. The log linear

plot of LDL was relative risk reduction showing an

intercept of 1 and LDL of approximately 40 mg/dL

where risk was not increased. There is nothing

magic about 130. The sponsor has very carefully

tried to make these recommendations consistent with

the NCEP guidelines to avoid causing further

confusion in the case of the person who is trying

to follow the directions or the physician. So,

they are very consistent with the guidelines but

there is nothing magic about 130.

In fact, the recommendations of the

National Cholesterol Education Program, ATP III

guidelines were that the optimal LDL level for all

patients is less than 100. I realize that in the

CUSTOM study there were people with LDLs less than

345

130, a third or so, who followed the program, but

it is very unlikely that you would do harm and, in

fact, some people with levels in that range will

get down to the optimal level. Only 23 percent of

the adult population in the U.S., based on the

current NHANES data, have an LDL under 100. So, it

is very unlikely that you will get down to very low

LDL levels.

As has been said before, there has been

much less cholesterol education in the U.K. and a

great deal of impetus for the Zocor OTC there, I

believe, came from the Heart Protection Study where

the investigators very strongly believed that you

treat risk levels, not cholesterol levels. As they

said in the presentation when HPS was presented at

the American Heart Association, if a patient is in

a high risk category we give 40 mg of Zocor

regardless of what their LDL level is because it is

too high for them. The OTC program in the U.K. and

in the United States is aimed at a moderate risk

category. So, based on the prevailing conditions,

lack of cholesterol measurements and education in

346

the U.K., they have gone a different route but here

we have been very closely tied to the numbers,

spending huge amounts of time and funds trying to

educate the public and physicians about the

guidelines. So, there certainly is benefit in

trying to have the guidelines as closely as

possible in sync with what is being recommended to

avoid confusing the public and the doctors.

DR. WOOD: Tony, before you sit down, what

you are saying has great importance for

interpreting the labeling studies because the HPS

study and other studies really suggest that most

people in the groups that are under study here will

benefit. So, the studies of label comprehension

and so on, my sense is, don't allow people to be

treated who wouldn't derive some benefit based on

most of the studies. Is that correct? Do you want

to develop that a bit because that is relevant to

understanding these studies and whether they

matter.

DR. GROTTO: Well, I think there is no

question that the patients are people who would

347

fall into this category with LDL between 130 and

170 with the age criteria and additional risk

factors. These were the patients that we studied

in AFCAPS/TexCAPS. Only 17 percent of those

patients would have qualified for statin treatment

by the guidelines at that time. We saw no

diminution in treatment. We were aiming at trying

to get LDLs down as low as 110 and the mean was 115

in the group on lovastatin. But we saw no

breakdown or no diminution in benefit going down to

the lower levels. The relative risk or the

absolute risk is related to the LDL level so you

have to treat more patients, obviously, at the

lower risk range in order to see benefit. But it

was a very robust result and indication for primary

prevention was given based on a single study. So,

I think going by the data that are available from

clinical trials, patients below 130 would benefit.

DR. WOOD: My point was also that if you

have patients who haven't had an LDL measured and

who fit the other criteria for risk, the proportion

of patients who won't benefit in that group is

348

relatively small. Isn't that right?

DR. GROTTO: That is absolutely correct.

DR. WOOD: So, that is relevant to

interpreting the apparent disparity in the labeling

studies.

DR. GROTTO: Yes. I completely agree.

That is a good point. Thank you.

DR. WOOD: Frank?

DR. DAVIDOFF: Yes, I have a question

about the issue of cost in the U.K. because, as we

have heard a number of times, cost is not

considered by the FDA in its decisions here. But

the British system of financing medical care is

obviously very different since the NHS pays for

virtually all healthcare in the U.K. including

medications.

I notice that there were editorials both

in the British Medical Journal and in the Lancet

apropos the decision to go to over-the-counter

statins, which took up the issue of cost as a very

major one. The BMJ more specifically pointed out

that if all those patients who were at moderate

349

risk were actually treated with statins, and most

of them currently are not, it would actually

consume 10 percent of the total NHS budget.

The arguments can go either way because it

was also pointed out by Lancet that going

over-the-counter would mean that those people who

could afford to pay what it cost to buy the

over-the-counter drug would do so and those who

couldn't would not, and that this would actually

increase the disparities in health care.

So, my question is whether in the

regulatory process, approval process, in the U.K.

cost is actually formally considered because it

clearly, from the NHS point of view, could make a

huge difference in making the decision to go

over-the-counter.

DR. MANN: It is not explicitly a

criterion for whether something goes

over-the-counter or not. However, it clearly has a

considerable impact on how people behave. The

joint British societies that issue our guidelines

on treatments of coronary heart disease have always

350

recognized that levels of risk, more moderate

levels of risk--that there is very good evidence

that treating them is beneficial. That has been in

the guidelines since 1998. But the thresholds for

treatment under the NHS are governed entirely by

socioeconomic factors. The new joint British

guidelines which are shortly to be issued and have

already appeared in some abbreviated formats do

suggest treating at lower levels of risk, going

down to 15 percent, or broadly the equivalent to 15

percent 10-year coronary risk. So, there is a

shift gradually downwards within the National

Health Service as resources allow--I think those

are the weasel words to be used.

I think the recognition here is that the

OTC approach is entirely complementary to what is

available on the National Health Service, and that

people should have the option to take that should

they wish to. Obviously, people then have choices

whether to spend their money on healthy lifestyles

or reducing their cholesterol.

DR. WOOD: Dr. Neill?

DR. NEILL: Earlier this morning Dr.

Ganley discussed what constituted the OTC and we

reviewed a little bit of that today in terms of the

351

fact that this is a consideration that includes a

condition that meets few or none of the classic OTC

conditions. In a prior NDAC meeting, in discussion

of non-sedating antihistamines, it was interesting

to listen to a company have to answer why a

medicine should not be made OTC since it was safe

and effective, and I believe it is still the case

that it is incumbent upon the FDA to make something

available in the OTC setting if it is for an OTC

condition and if it is safe and effective for use

in the OTC setting. In other words, a company

cannot simply decide to make it prescription if all

of those things are met because they would like to.

Rather, the FDA may compel them. And, it is my

understanding that that in part informed the

discussions between health plans in California and

the manufacturers of some of the non-sedating

antihistamines.

So, with that background in mind and given

352

that we are talking about a new OTC condition that

you already have approved in the U.K. a different

product from your company, I am anxious to hear, if

you are willing to reveal, how you would respond to

a health plan provocation to encourage you to take

other safe and effective statins OTC at some dose,

number one and, number two, perhaps for FDA, to

what extent is it in the public interest to make

these over-the-counter statins available across

product lines and across companies if, in fact, we

reach a decision--and I don't know what will happen

tomorrow--that this is an OTC type condition and we

are okay with that, and that this is a safe and

effective medication.

I am confident that we could sit here for

months discussing the individual dose for

Zocor--list all the statins--and we could discuss

how or whether they were safe and effective. But

that is a dichotomy that I think requires some

explaining. In other words, if the default is that

these must be OTC, why aren't they?

DR. WOOD: At the risk of sounding

353

cynical, it usually happens when the patent

expires.

DR. HEMWALL: I am not sure if that is a

question that has a straightforward answer. It

sets forth a number of hypothetical situations. I

think that we have been trying to develop the data

to convince the Food and Drug Administration and

your committee that a product like this should be

OTC for about seven or eight years.

DR. NEILL: We should approve Zocor as

well, and you should be compelled because the issue

here for me, in my mind, is that this is an issue

of compulsion. It is the FDA's duty to make these

medications OTC. That is the default. The only

reason to have them Rx is if they are not safe and

effective.

DR. WOOD: Hang on, hang on. We are here

to discuss Mevacor and that is probably more than

we can cope with before five o'clock. So, although

these are all very reasonable and interesting

points to discuss in the bar on Friday night, I

think we need to focus on Mevacor right now and

354

just stick to that. I don't mean to cut you off

but I think I have bitten off as much as I can chew

with that right now. Your point is noted. Leslie?

DR. CLAPP: I have a brief observation to

share with Merck about the packaging, and that is,

as my eyes mature I have increasing difficulty

seeing small print. But additionally, the script

that is in red on the label that is supposed to be

more important is very fuzzy and blurry. The only

one I can see in terms of red is "test at two

weeks." So, if you can consider emboldening the

red script, perhaps it will be easier for aging

eyes to see. That is just an observation.

But now I have more of a question for the

FDA. I would like to have some clarity about

pregnancy category labeling. As was stated

previously, Mevacor is pregnancy category X and the

components that seemed to go into that

determination is the clinical benefit of a

medication, as well as the human and animal fetal

risk. I don't know if there is any weighting that

has been done in terms of a perspective from the

355

FDA as to category X for Mevacor, but I heard some

comparisons from Merck as to those medications that

were category C. I am wondering if the perspective

we might be encouraged to feel is that Mevacor

could be a category C because of the lack of

risk--I think that is what Merck is touting as a

fact, that there is very little or negligible risk.

Whereas, the final statement on Dr. Davis-Bruno's

presentation certainly does mention that, based on

extensive animal data, potential human risk does

exist following exposure to lovastatin during

pregnancy. So, I am not sure if there is a

weighting that the FDA has to risk for the

medication from the human and animal fetal

component versus the benefit to the mother or the

woman of childbearing age taking the medication.

The other question I do have is are there

any other OTC medicines that are category X?

DR. MEYER: I will take the first part of

that question. I guess, to make it clear, under

the wording of the regulations as they stand for

the pregnancy categories, if one is to advise that

356

the drug not be used in pregnancy because the risks

outweigh the benefits, then it is a category X and

you can get to that calculus because of large risks

in the face of benefits, or you can get to that

with a smaller risk in the face of no perceived

benefits.

I think that you have heard from the

sponsor, and I am not sure we would very loudly

disagree with it, that that is more the case with

lovastatin, that we are in a situation where the

animal data suggests there are in fact some risks.

The human data don't really answer it at this

point. So, the temporary or short-term treatment

of the mother during her pregnancy does not

outweigh the potential that we feel the animal data

suggests might exist for the fetus. The decision

about the category obviously was made some time ago

and data continue to accrue both with the

post-marketing experience and otherwise.

I would urge the committee not to focus a

whole lot on whether it is category X or not. I

would ask you to consider the data that we have

357

presented and that the sponsor presented and look

at whether you think that represents a significant

risk and, if so, does the labeling that the sponsor

has undertaken help minimize that risk? That is

really the question because when you get to the OTC

setting pregnancy categories have no relevance.

DR. CLAPP: Yet I do just wonder whether

or not there are any over-the-counter medicines

that have been switched, that were category X as

prescription medications that are over-the-counter

now.

DR. ROSEBRAUGH: We have considered

category X drugs. We have drugs that are OTC that

do have teratogenic effects. The poster child is

probably nicotine replacement.

DR. WOOD: Dr. Parker?

DR. PARKER: I just wondered if you could

comment on the Zocor warning about alcohol use and

the fact that that is not there for Mevacor. Did I

miss that?

DR. HEMWALL: That is simply a matter that

that was something that was requested by the U.K.

358

It seemed like sound judgment to warn against

alcohol use, and certainly we would consider that

for the U.S. as well, but it is not because there

is any evidence that people with alcoholic liver

disease are at any greater risk. But, again, it is

meant to be more of a safety net and to keep the

risk to a minimum.

DR. PARKER: I guess that was a part of

the discussion that went on at the time.

DR. HEMWALL: In the U.K.?

DR. PARKER: Yes.

DR. MANN: In the U.K. we submitted this

to the expert opinion about the need for liver

monitoring and concluded that it was not necessary

and probably unhelpful. However, we started with a

Zocor label that said that people with preexisting

liver disease should not receive the drug, and we

really didn't feel we had evidence to say that we

shouldn't do that. Therefore, we have excluded

people with known liver disease and I think that is

just a precautionary principle. On that same

basis, people who have used alcohol and therefore,

359

potentially at least, have the risk of liver

disease were also excluded, again, on a

precautionary principle, not on the basis of any

great data that those people are at special risk.

DR. PARKER: Could I just ask do we have

from CUSTOM alcohol use? Was that a variable that

was captured?

DR. HEMWALL: No, we do not.

DR. WOOD: Does the Tylenol label have an

exclusion for liver disease?

DR. GANLEY: I would have to check on it

but I am not sure that it does right now. I don't

believe it does.

DR. WOOD: It would be worth knowing

because it is relevant to this.

DR. GANLEY: It has an alcohol warning.

DR. WOOD: I actually was asking for prior

liver disease. Jack?

DR. FINCHAM: I know we are not supposed

to talk about cost but it is hard not to think

about it in the context of at least the tradition

in the United States. When a drug is switched

360

insurance coverage ceases whether it is managed

care or whether it is Medicaid or soon to be

Medicare. In the U.K. previously, at least

according to pharmacy informatics organization, the

consumer paid in effect a third co-pay for a

month's supply of simvastatin, an equivalent of $10

for a $30 prescription. Now they pay between $19

and $30 and the government doesn't pay anything.

There can be no question that these drugs are

important to take. I just wonder what the result

will be, and this may be a rhetorical question but

I just wonder what the result will be when this

burden is forced more and more on consumers, not as

an opportunity to help themselves but, yet again,

another decision that they have to make relative to

how they spend limited resources.

DR. WOOD: Do you have that question to

address to somebody?

DR. FINCHAM: I don't have the answer to

it. If somebody else in the room does, I would

sure like to hear it. I think it is a concern that

is not addressed in any of our materials, nor

361

should it be.

DR. WOOD: Dr. Snodgrass?

DR. SNODGRASS: Just a couple of brief

comments around the birth defects, the fetal

adverse effects issue. One has to do with sharing

medications. If Susie buys it and shares it with

Sally and Sally turns out to be pregnant is an

issue. The comparison I will make is not,

obviously, a very good one at some levels but it is

a real one. Many years ago, before the current

procedure for Accutane in a physician's office to

fill out the long forms, Ed Lammer, in California,

had shown by epidemiologic data that there were at

least 1000 malformed infants in the United

States--this is well over 10, 15 years ago--with a

drug that had been marketed with a black box

warning about teratogenicity, realizing that it is

a very well characterized potent teratogen. So,

that occurred under prescription circumstances with

a black box warning.

The other comment is about the folate

receptor in in vitro studies. When you lower

362

lipids around that receptor it doesn't work as

well. It doesn't take up folate; it doesn't

respond as well, and we know the relationship

between folate and neural tube defects.

DR. WOOD: We have gone round and round on

this pregnancy issue so maybe we should try to

reach some sort of closure on that. If I can

summarize where we are, nobody disagrees that it

shouldn't be taken by pregnant women. So, the

question really evolves into--were this to be

approved and we are not there--have we got

sufficient confidence in the methodology to prevent

it being taken by pregnant women? That seems to me

the issue rather than debating the biology, which I

suspect we have neither heard enough about to

really deal with adequately today, nor do we have

sufficient time to do that. Is that fair? I mean,

are people comfortable with that? If people have

further comments, let's deal with that issue and

then put it away. Neal, is your comment on this

issue?

DR. BENOWITZ: Yes. Let me say that I

363

don't think you can make it quite that simple

because if we are talking about Accutane, then we

want to be very, very, very sure that no pregnant

woman takes it. If we are talking about a low

theoretical risk, then you might be more willing to

have a little bit of an error. So, I do think

there is a quantitative issue here.

DR. WOOD: Do you want to address what you

think the quantity looks like? I mean, are you

suggesting you think this is Accutane?

DR. BENOWITZ: No.

DR. WOOD: Okay, good. So, help us

understand that. I mean, where do you think this

fits in the quantitative level?

DR. BENOWITZ: I certainly can't answer

that. To me, it looks like it is low in terms of

evidence in human exposure levels but I wouldn't

want to have a woman take it if she is pregnant if

I could help it.

DR. WOOD: Right, I think we would all

agree nobody wants this to be taken by pregnant

women, but that would be true of most drugs that

364

don't have a benefit in pregnant women. So, the

issue then is can we avoid it and how do we avoid

it being taken by pregnant women? You are raising

a new issue--well, tell me what the new issue is.

DR. BENOWITZ: No, it is not a new issue.

It is how large is the risk. If a pregnant woman

absolutely takes it and the risk is really

substantial, then you want to make sure absolutely

and do everything possible to make sure no pregnant

woman ever takes the drug. If it is a theoretical

risk or very obscure risk, then if there are some

exposures it is not going to be of as much

consequence for the population so we may be a

little bit more willing to say let's have a little

bit of leeway. Now, I don't have the parameters

for that in terms of numbers for risk. It seems to

me that the risk in humans has not been

demonstrated at something equivalent to a 20 mg

dose. That is not to say it couldn't happen in

some case. But I think it is important in terms of

how strong the barriers have to be to prevent any

woman who could possibly get pregnant from getting

365

the drug.

DR. WOOD: Does the company want to

respond to that issue? Oh, I am sorry, we will let

Dr. Makris talk first.

DR. MAKRIS: Thank you, just a few

thoughts. It seems that there is pretty much

agreement I think between FDA and the sponsor that

what has been seen so far in human incidence data

really doesn't indicate that there is a real

concern for birth defects when there has been

accidental or unintentional exposure. So, there is

agreement on that.

It seems that there are some disagreements

in terms of how to characterize the animal data,

developmental data and having sat on a number of

peer review committees, I know that if you put

three toxicologist in a room you get seven

opinions--

[Laughter]

--about how to interpret the data.

Usually you have to go back to the individual

animal data and look at it a whole lot more

366

carefully to be able to weed things out, and I

don't know that that is really an issue here or

something that we need to be addressing.

But there is something that I do see in

the data that was presented that, you know, raised

some concerns with me. It had to do with some of

the functional assessments that were done. I

believe it was the seg. 3 study that characterized

a number of functional deficits in the pups and a

number of different parameters. And, there was a

follow-up study done that was a neurodevelopmental

study that dosed from postnatal day 4 through

somewhere around 41 or 50 of age, and did a number

of additional tests. The evaluation of that study

by FDA indicted that there were still some concerns

or that they felt that the endpoints that were

assessed in that study weren't enough to truly

characterize what they were getting at.

But even that being said, I think that the

original functional assessments that were done that

raised the concern were not addressed in quite the

same way in that second study because it was

367

looking at different stages of development. It is

possible that the functional deficits seen in the

first study may have come from in utero exposure;

may have come from postnatal exposures, and you

can't determine that from these types of studies.

The follow-up study that was done was

essentially trying to mimic human exposures in late

gestation and early postnatal and maybe even

through almost adolescence. But the early in utero

exposures were not captured in that study and that

seems to be what some of the concerns are here,

what happens when a woman who just finds out she is

pregnant is taking the drug and those early

gestational exposures are the ones of concern. So,

they haven't, I think, been characterized fully.

So, there are some uncertainties I think in terms

of whether or not there might be developmental

exposures that could result in some kind of

functional outcome in the fetus or child.

So, I am not sure that there is any way to

address that with the data that have actually been

collected, and there is nothing that I see in any

368

of the human or epidemiological data that would

suggest that maybe that is an outcome, but I think

we need to at least recognize that lack of

information.

DR. LANKAS: I would just like to make a

brief comment relative to your comment, and that is

that the neonatal toxicity study where the animals

were treated beginning on postnatal day 4 was done

expressly to, hopefully, try to ally some of the

concerns that FDA had raised that a statin-like

drug could affect myelination as a function of its

effect on lipid metabolism. As Dr. Davis-Bruno

pointed out, rats are quite different

developmentally than humans with respect to the

time of myelination. So, the specific study was

done to address the issue of when myelination

occurs the exposure to lovastatin was initiated,

and in the rat it is during early postnatal

development and in humans it is basically during

the latter part of pregnancy, during the second and

third trimester. So, that was the reason for that

study design.

Again, there are differences in

interpretation but I think Dr. Davis-Bruno's

characterization, a conservative one, indicated

369

that there was a clear no-effect level at the

middle dose group of 5 mg/kg which, in terms of an

exposure, would far exceed any exposure that a

human fetus would receive because we were dosing

the pup directly as opposed to any in utero

exposure or lactational exposure.

DR. MAKRIS: Yes, I understand that and

the study was not designed specifically to follow

up the effects that had been seen in the previous

study. It did have a completely different intent

and was designed to assess that.

DR. WOOD: I think Neal Benowitz's

question still needs to be addressed. Are you

going to do that?

DR. HEMWALL: Yes, if I can remember back

to the beginning of the discussion, you are

concerned about some of the behavior in CUSTOM.

There were 12 women who were pregnant or breast

feeding that came to the study site and evaluated

370

whether or not to use Mevacor OTC. All 12 of those

women elected not to use it, and there were no

pregnant women that took the product.

DR. BENOWITZ: What I was talking about

really was the number of women of childbearing age

who took it and, obviously, could have become

pregnant without knowing it.

DR. HEMWALL: Yes, that is correct. I

think what we want to be able to do is be stronger

in the labeling about the potential for

childbearing. Again, we don't believe that there

is a significant risk at all, but we do want to

minimize as much as possible the use of the product

by women who are of childbearing age, and labeling

that has been used for other products that have the

same problem, such as nicotine replacement which is

obviously used by women of childbearing

potential--we would extend that to Mevacor and work

with the agency or with committee recommendations

on the best language.

DR. WOOD: I thought, Neal, you also had

the question about getting some quantitative

371

measure of the risk in humans.

DR. BENOWITZ: Well, I was trying to.

DR. WOOD: Right. Well, let's see if they

can respond to that.

DR. HEMWALL: We don't have a quantitative

measure of the risk in humans. We have examined in

an abstract the number of prospective and

retrospective pregnancies, both in the lovastatin

and simvastatin database, and there is no clear

signal that rises above the level of background.

However, you can't rule out a certain multiple of

background just because of the pure statistics.

DR. GANLEY: Alastair, could I just

interject something?

DR. WOOD: Yes?

DR. GANLEY: We have obviously been

thinking about a lot of this internally, and I will

give you my perspective and others can chime in.

But I don't think I am as concerned about pregnant

women using this product. Remember, this has to be

a highly motivated population who would want to use

this and understand that they are going to get some

372

benefit from this. If a woman knows she is

pregnant, I think most women are very careful--I

may be wrong in that assumption--and I think the

evidence from the CUSTOM study where 12 women

actually showed up and chose not to use it, which

was the correct thing to do--well, that makes a lot

of sense.

Now, if these neurodevelopmental issues

are second and third trimester issues and a woman

may know she is pregnant by her second or third

trimester, well, I don't think she is going to

necessarily choose to take this drug. So, I don't

have this much concern about that.

I think the issue that I have is this

childbearing potential and what really is the risk

in that first trimester. I think, going back to

the CUSTOM study, what is difficult for us, or for

me at least personally, to understand is that

clearly someone knows their age, and if it is said

that this is for a woman greater than 55, well, why

did women less than 55 take it, other than being

overridden by a doctor?

Merck had some survey data at the end of

the study and I don't know if there is something

within that that could help us understand, well,

373

what was it that women did not understand there

that caused them to take it. Did they have their

tubes tied or was there something else in there

that gave them a comfort level? Because, clearly,

if 100 percent of the women in this CUSTOM study

were greater than 55, we probably would not be

having this discussion right now.

So, I think that is how we sort of have to

think about this, what went wrong there? Or, if a

lot of it was physician override, the prescription

labeling for Mevacor says if women of childbearing

age are going to be put on this, they should be

instructed about not getting pregnant, or they

should have some other type of birth control, or

something to that effect. But women still got

pregnant while on Mevacor.

So, that system failed in itself. The

system is not perfect whether it is prescription or

OTC so we are not going to get perfection. But I

374

think we need to understand a little bit why, you

know, there was such a high percentage less than 55

that chose to take it. Until we can understand

that I am not sure--you know, that may help us get

closer to the perfection part of it here. So, I

don't know. I know they had a survey, a certain

percentage of people were surveyed at the end of

the study to better understand their behavior. But

I think it would help us sort of consolidate this

issue and we could, you know, possibly address that

by some other mechanism and understand the risk in

the first trimester.

DR. WOOD: Well, it seems to me there are

two issues on the table. One is the one you just

articulated, how do we avoid them getting it and

how do we understand why they took it. If they all

had a hysterectomy, for instance, you know, that

would be different.

The second one that I am surprised nobody

from the agency or the company responded to

directly is, you know, if there are seven cases in

the database of adverse outcomes in pregnancy, just

375

by the seat of the pants, to me that seems

extraordinarily low. I am surprised, therefore,

that no one has offered us that kind of assurance

because it would seem to me that, given the number

of abnormalities in pregnancy that occur by chance,

that seems a pretty small number. So, it would be

interesting to know what the data are for--you

know, pick a drug. I am surprised that Merck and

no one else has told us because that is clearly the

issue that Neal was getting at. You know, he says

is this Accutane? It is clearly not Accutane and

we need to be clear on that. David?

DR. ORLOFF: Actually, I do think Merck

did answer the question in their own presentation

in this regard by concluding that, while they

believe there is a theoretical risk to exposure

with regard to fetal exposure in the first

trimester specifically related to potential

teratogenicity, they think, based on everything

that they know, that the risk appears quite low.

Again to reiterate what Dr. Meyer said and

what Dr. Davis-Bruno said, there are some animal

376

findings that suggest a theoretical risk. Although

there is nothing in the spontaneous reports of

exposures during the first trimester, there is

nothing that obviously stands out as a pattern, as

a clear pathological presentation that seems to

describe a syndrome of lovastatin fetal exposure,

nor do those reports completely allay any concerns.

So, nobody here can give the answer. You

have given an answer that says, flying by the seat

of your pants, you think it is relatively low.

Merck has not been so--you know, they don't fly by

the seat of their pants and they think it is

relatively low. I think the FDA has to conclude

that, on balance, it seems like it must be a

relatively low risk. But nobody actually can tell

you exactly what that is.

DR. WOOD: So, the FDA calls "the seat of

their pants" "on balance."

[Laughter]

Mary?

DR. TINETTI: My question has to do with

the long-term use of this medication. As we heard

377

today, this is really a new direction for

over-the-counter towards long-term use for primary

prevention. I think it is a very exciting

opportunity, but still playing by the old rules,

particularly with the actual use studies which I

think are still predicated on short-term use for

symptomatic conditions, my question to the FDA is,

is there any interest in having actual use studies

that will now more actually match the long-term use

of long-term medications if we are going to start

putting them over-the-counter?

My question to Merck is, regardless of

whether you will be required, is there going to be

some long-term monitoring if this does go

over-the-counter to make sure that as people's

cholesterols do go up after six months, do they

continue to monitor their medication if they now

take on new conditions such as diabetes that they

get more aggressive care and are not in a situation

of under-treatment?

MR. HANSEN: Can you bring up slide 1824?

[Slide]

As you have seen, both us as well as other

sponsors of OTC statins have done a lot of use

studies, and we really feel like most of the

378

questions, at least in that environment, have been

answered. So, we are very committed, if this

product is approved, to do post-marketing

surveillance and we have given a lot of thought to

this. The key issues we would be looking at are,

first of all, do consumers use it safely once it is

more available in the broad market and, secondly,

is their use consistent with the label.

So, here are the methods we have used with

other OTC medicines, and they would be extended

further in the case of Mevacor. The methods would

be that, first of all, we do surveys, toll-free

number, hotline, websites and third-party data

collection, and we would do this both among

consumers and healthcare professionals because both

of those would be important on how this product is

being used in the marketplace. Then, obviously, we

would want projectable samples to the population.

We think it is important to do a

379

pre-launch study because we want to understand

baseline measurements of awareness and attitudes so

we can see if this product, in effect, is having

the greater population benefit that we are

proposing. So, before the product hit the market

we would want to look at the number of untreated

people at risk and Rx users and understand their

attitudes, awareness and insight prior to being put

on the market.

As far as a post-launch study, we would

look at OTC users in addition to these untreated at

risk and Rx users, again, to see what kind of

dynamics there are with the OTC. We would use

predefined measurement frequency. What we

frequently do with OTCs is at six-month intervals

is data pulls to look at large populations to see

where we can modify the program. So, it actually

leads to actions which, first of all, if something

happened that we didn't anticipate or something

that we didn't see in the use trial, and if we do

see that, whether it is safety or behavior, to take

corrective actions in the marketplace.

DR. WOOD: Dr. Orloff points out that

Charlie Ganley's question didn't get answered and I

am just going to reiterate it, if I can, and let

380

you think about that while we are going through the

other questions. The question was, what are the

characteristics of the women who took the drug

while they were under 55, and tell us about the

characteristics of these women.

MR. TIPPING: Bob Tipping, from Merck,

again. Dr. Ganley, I believe your question was

about the younger women and how many women under

certain ages were actually using drug in CUSTOM. I

guess to answer that, first of all, I would remind

the committee that the age cutoff on the label for

women was driven by the risk factor approach, not

so much a concern about pregnancy.

But some of the information about the

women in CUSTOM from the user population--there

were 430 among the users in CUSTOM and 81 percent

of this group met the age criteria or did have the

interaction with a doctor. I think most

importantly, only 24 of those women were under 45

381

and didn't speak with a doctor. So, if we are

talking about a concern within an age group where

pregnancies do occur and then are happening within

the context of an interaction with their physician,

there are low numbers within CUSTOM that that is

actually happening.

Then, one final point, while there were 37

percent of women in CUSTOM less than 55, less than

that age cutoff, if you look at the non-purchaser

population, 57 percent of that group were. So, we

can argue whether 37 percent among the users is too

high, but the label messages do seem to be working

in that, you know, there is a 20 percentage point

drop in the actual women who were using the product

as opposed to evaluating it in that age category.

DR. GANLEY: Do you have any data that

tells you why a physician would tell someone less

than 45 it was okay and did they provide them

information about potential risk if they become

pregnant? Because that is what the prescription

label says a physician should do.

MR. TIPPING: In no part of our program

382

did we confirm what actually took place in a

physician's office. We are assuming that that

discussion did take place.

DR. GANLEY: In your first survey you

could have asked the woman what did the physician

talk to you about.

MR. TIPPING: Right. We did not do that.

DR. LEWIS: Let me address that because I

see these women every day in my practice. There

are very few premenopausal women for whom I would

recommend lipid-lowering therapy but there are a

few because of the very high risk group that would

take special attention and really don't fit in this

CUSTOM category. But if you look at the CUSTOM age

breakdown, there are a lot of women that are in

this 45-55 group who may be postmenopausal and

maybe they have two risk factors so that the

doctor's evaluation could look at them and say,

yes, you are right, you fit NCEP criteria; one risk

factor plus age 55, you don't fit that but you do

fit by other criteria and, yes, give it a try.

There are large numbers of women in that 45-55

383

year-old age group that are spreading their 10-year

risk very quickly.

One of the things we looked at was the

comparison of the age spread from the CUSTOM women

to the age spread from the women in the CARE study

and the curves are almost identical, with about a

5-10-year break, pretty much predicting that this

is a group of women that is at risk and the risk is

maybe 5-10 years later than the men, who have not

been getting aggressive risk factor management.

DR. WOOD: Dr. Schambelan?

DR. SCHAMBELAN: Well, I think that this

was alluded to, the reason for the age selection

here is that, as you say, it is efficacy driven,

not avoidance of pregnancy. Nowhere on the label

does it mention anything about being concerned

about becoming pregnant. It says if you are

pregnant or breast feeding you shouldn't be taking

the drug. But there is no reason someone would

think about the risk of becoming pregnant from just

reading this label. So, I am wondering if this

couldn't be alleviated to some extent by adding

384

that and by having these people take it into

consideration because there are lots of people who

are going to use this who aren't going to talk to

their doctor, and that seems like a pretty simple

fix to at least get that to the consciousness

level.

DR. WOOD: Dr. Carpenter?

DR. CARPENTER: Yes, if I can divert from

the pregnancy issue, otherwise I can come back to

it later.

DR. WOOD: Go ahead.

DR. CARPENTER: My question is to Dr.

Shetty. I was really struck with somewhat of the

discordance between the survey of comprehension

versus the behavior information that was somewhat

discordant on a number of different categories. My

concern in particular has to do with the

concomitant medication risk, particularly

antifungals, certain antibiotics, and in the

over-the-counter setting and potential lack of

communication with a physician there is greater

potential for such drugs to be concomitantly

385

administered. Although the comprehension survey

indicated that people understood that

contraindication of certain co-administered drugs,

what was the behavior or the actual outcome in

CUSTOM as to the use of other contraindicated

medications?

DR. SHETTY: There were a total of 32

subjects that were taking interacting medications,

and 12 of them did not consult with a physician. I

think 10 of those 12 continued taking medication.

Maybe sponsor can confirm that. There was not a

large proportion of people that were taking

interacting medications.

DR. WOOD: Dr. Parker?

DR. PARKER: I had a question about study

personnel, a term that I see on the label seven

times. I could say that the word pregnancy is only

on there twice but this isn't about pregnancy. I

wonder, it is always "doctor or study

personnel"--you know, consult, talk to. I also

took a look at the little brochure, you know, that

helps me get a coupon and, you know, I guess

386

getting into the study that allows the

post-marketing surveillance. I want to direct this

to the FDA, to ask you to help me understand for

other drugs that have gone to the over-the-counter

status, has the study personnel status been a part

of labels, and what does that really mean, and

could this also be viewed as direct access to

buyers of products, and what are the implications

of that?

DR. HEMWALL: I think you need some

clarification. The materials that you have in your

background packages and all the materials,

including the box and the internal materials, were

actually the materials used in the CUSTOM study.

So, in every position where you would see normally

"talk to your doctor" it says "talk to study

personnel or pharmacist."

DR. PARKER: So, these wouldn't be the

ones that would go forward? This was just for the

CUSTOM study?

DR HEMWALL: Right, and that is to be

distinguished from actually going to their doctor

387

but in areas about study personnel and adverse

event reporting.

MR. TIPPING: Could I come back and just

add some additional information on the potentially

interacting medications.

DR. WOOD: Sure.

MR. TIPPING: Just very briefly, we agree

with Dr. Shetty's number. There were 12

individuals at the beginning of the trial who were

on a potentially interacting medication and used

Mevacor without a doctor's interaction. Two of

those, however, indicated that they had stopped

their interacting medication. Then I would add to

that that during the course of the study there were

only two individuals who were prescribed a

potentially interacting medication. In both of

these situations the drug was clarithromycin and we

didn't get into the actual behavior. We

conservatively listed them amongst our 21 but, in

fact, the reported behavior from these two

individuals was that one discontinued his Mevacor

at the time of the clarithromycin and the other one

388

interrupted his Mevacor dose during his course of

clarithromycin therapy. So, small numbers of

individuals but I think they were exhibiting

exactly the behavior that we would hope the label

would drive.

DR. WOOD: Dr. Taylor?

DR. TAYLOR: I guess I was concerned a bit

about Dr. Shetty's analyses and how they differed

in many respects, not only in terms of the number

of pregnant women, the number of individuals who

had--for example, 55 percent of users had greater

than one relative contraindication according to the

label and, yet, even with all those problems--I

will call them problems--there were no serious

signals that were seen, and perhaps this is related

to the relatively small sample that you studied.

Nonetheless, in actual practice we violate those

categories anyway. So, the argument that the

CUSTOM is not sufficiently sensitive may be true

but, on the other hand, as a practitioner I see a

lot of women who are in their 40s, with some

counseling of course, and I think some of that can

389

be taken as labeling.

So, I just sort of want to put a little

balance in there. That is neither a pro nor a con,

but in a real functional sense, a lot of

things--mistakes, if you want to call them

that--that occurred in CUSTOM occur every day and,

despite that, the safety record is fairly good.

DR. WOOD: Dr. Watts?

DR. WATTS: I don't want to revisit the

pregnancy issue but I do want to visit the next

step. I realize that drugs, whether prescription

or OTC, are potentially available to children in

the household. Prescription drugs typically would

come with a child-proof lid. I wonder what

precautions you are taking to prevent accidental

ingestion of Mevacor OTC by children, and if you

can give me some idea of how much drug might pose a

problem for, say, an average one year-old or 18

month-old child who might get hold of it?

DR. HEMWALL: Well, first and foremost,

the package will be in child-resistant packaging

and, obviously, that is something that is done with

390

prescription drugs as well. We can go to some

slides that we can show you but it is almost

impossible to overdose acutely on lovastatin.

Very, very large doses have been tolerated. It is

actually written up in some detail in your

background package. We have the data from poison

control centers. So, even though we are expecting

full child-resistant packaging and that is our

plan, if some child were to inadvertently be able

to break open a lot of blisters or bottles and get

into it, it would be very hard to overdose.

DR. WOOD: Dr. Schade?

DR. SCHADE: There is a portion of this

package that is very confusing to me. I understand

that the company is targeting the intermediate risk

group, but it seems to me they are actively

excluding a high risk group. This is what is

confusing to me, it says, "do not use unless

directed by your doctor if you have...," and then

they list six things. Included in those six things

are, one, ever had a heart disease (heart attack or

angina, and then diabetes.

Now, let me put this in the context of the

real world. I come from New Mexico where a very

high percentage of our population has no insurance

391

and the only doctor they ever see is in the

emergency room where they come in once a year with

their pneumonia or something else even if they are

at high risk. Of course, we also have a very high

incidence of diabetes. So, I see them reading this

and they are not going to see a doctor. Even if

they have a doctor, it often takes four months to

get in to see one.

I don't understand why we are actively

excluding the high risk group when the high risk

group, in fact, would probably benefit more from 20

mg of lovastatin than from nothing at all and that

is really the alternative here. In other words, in

the real world where we have many uninsured people

who can't afford to see a doctor, who don't see

doctors, this drug might be of great benefit. And,

I don't understand whey the packaging here seems to

directly try to ward off the high risk population.

Now, Dr. Gotto made a comment with which I

392

agree, that in the best of worlds all these

patients would be put on 40 mg of simvastatin and

be followed with their LDLs. Well, the fact is

that it doesn't happen in my state and I would like

to see this changed to encourage people at high

risk, who are unable to see a physician, that this

drug might help them, and a statement to the effect

that they ought to see a healthcare professional

because the dosage may be insufficient, or some

other reason, but not to actually ward them off

from taking a drug that may be really beneficial to

them.

DR. HEMWALL: Yes, we agree with you that

people at even high risk could benefit from taking

this if they were taking nothing else, but we still

want I think to stay within the realm where we are

treating the people that could most benefit by this

than trying to get the people that could benefit

from more comprehensive physician care, treating

their diabetes and their post-MI more aggressively

with full physician involvement. So, this would be

a gap I think in reaching the balance between

393

trying to attract the right people and then

directing the people that are at higher risk to see

their physician. But we take your point.

DR. WOOD: Yes, I agree with Dr. Schade.

It seems to me that there is a huge problem in

listing as a contraindication the patient who needs

it most, which doesn't make a lot of sense in any

sense, and it also trivializes the

contraindications. So, it does seem to me that it

is important that patients understand that

something is a contraindication, not really a very

strong indication which is co-mingled right now.

So the strongest indications are also

contraindications in your label, which is crazy.

MR. HANSEN: I just want to clarify, it is

not a true contraindication--

DR. WOOD: I understand.

MR. HANSEN: --what we say is "do not use

unless directed by your doctor." Then within the

materials a phrase that has been very helpful and

that is that "OTC medicine may not be enough for

you. You may need prescription therapy." So,

394

there is that balance we are trying to make by not

inducing high risk people.

DR. WOOD: Neal?

DR. BENOWITZ: A question for the FDA,

somewhere I saw mentioned that the marketing

material or promotion material is regulated by FTC,

not FDA, once it is approved. Is that right?

DR. GANLEY: The advertising is FTC.

DR. BENOWITZ: So, will you be checking

out their materials as well to make sure that it is

balanced?

DR. GANLEY: We can ask a company for

their advertising material and they don't have to

send it to us.

[Laughter]

Let me put it this way, and we ask all the

time. I have been in OTC quite a few years and I

can't remember the last time someone sent me some.

It is interesting, you know, usually who we get it

from is a competitor.

[Laughter]

But I think the other thing is that we do

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have a relationship with FTC, and FTC has a huge

market they have to oversee and they are making

judgments as to what they are going to put their

resources to if they have to take an action because

someone is marketing outside the labeled

indications.

DR. BENOWITZ: I am sure this will come up

tomorrow and I don't know if we will have a chance

to talk to the sponsor, but I have a concern about

appropriate communication of benefits to people to

decide where they are going to spend their money

and efforts, and I think it is workable but I think

with a lot of drugs there are concerns, as everyone

knows, about over-promotion and this could be

really over-promoted.

DR. GANLEY: That is what I was trying to

point out in my initial discussion because the

label is focusing on a certain population, as we

discussed at length. Depending on how a drug is

marketed or advertised, clearly could pull in a

population that was not originally intended. Now,

that is taken in the context of, you know, a

396

company is such a good marketer that they are able

to convince someone to buy a drug that treats no

symptoms for them for the rest of their life. So,

you know, you have to put it in that context too,

that someone will really have to want to take this

drug. But I think it is important for someone to

understand, you know, what is the benefit up front;

how long I have to take it; what is the downside to

this; and whatever population you are pulling

in--you know, if they don't understand the label

and they are just going to buy the product because

they are very health conscious and they want to

control their cholesterol, well, I am not sure that

is the best thing but that is the way, you know,

people make decisions sometimes.

DR. BENOWITZ: I certainly agree with you.

I think the dietary supplement industry is an

example where you can market to a lot of people

taking medications to allegedly improve their

health for many years at a billion dollars of

expense. I just think that at some point in time

someone should make sure that the benefits to the

397

individual are really made clear to them so they

will know what they are getting, and how long they

have to take the medicine, and what it is going to

cost them. I just want to be reassured that FDA

will be doing that at some level.

DR. GANLEY: Again, if it is an

advertising issue we don't have much control. If

it is a labeling issue or something to that effect

that will adequately convey that message, then we

do have control. I think that is why it is

important to understand did someone adequately

understand the benefit. You raised it earlier in

terms of the absolute benefit to them--you know,

may be a better way of trying to convey it to

someone so they really understand that. I think

that is very important.

DR. WOOD: But although the FDA may be

unwilling to step into that, this advisory

committee could provide very strong recommendations

that the FDA should take control of advertising

over-the-counter drugs. I am serious--not that I

am ever reactionary, right? I mean, we could make

398

that as a recommendation tomorrow, Neal, if you

thought that was important and, you know, we would

see probably fewer young ladies skipping through

fields of daisies, and so on. Yes, Dr. Woolf?

DR. WOOLF: I have to get back to the

question of post-marketing surveillance. The EDMAC

committee has probably asked about this at every

committee meeting where we have been asked to

approve a drug, about how effective it is, and it

is certainly an issue that has been in the news the

last month or so.

How can we be assured that, in fact, there

is appropriate post-marketing surveillance that is

carried on despite the promises in this room this

afternoon? What teeth are there that six months

after the drug has been approved for

over-the-counter use, assuming that it is, that in

fact data is being collected, being distributed and

being looked at based upon that surveillance?

DR WOOD: The short answer is there

aren't; there is no assurance.

DR. GANLEY: I am not sure what the

399

question is. If something happens and someone

takes the time to fill out a MedWatch report,

whether it is prescription or OTC, we look at those

things, as would many companies--look at them

seriously.

DR. WOOLF: I understand that--

DR. WOOD: He is talking about Phase IV

studies.

DR. WOOLF: Merck has promised a

post-marketing surveillance survey to do something

far more elaborate and proactive than that, and the

EMDAC committee has heard this before, that a

company will do that but my understanding is the

FDA has a hard time trying to enforce that.

DR. WOOD: He is talking about a Phase IV

study.

DR. BRINKER: Excuse me, I didn't mean to

interrupt you. I am Alan Brinker from the Office

of Drug Safety. Let me just say that if you have a

specific concern that you want to raise for the

post-marketing environment, then that is engendered

to Merck to provide a protocol and we will look at

400

that. So, you know, we have almost ten years worth

of experience in looking at this drug alone, plus

all the statins. So, we have a pretty good handle

on that. But if you have a concern, then we will

follow it up in the post-marketing environment.

DR. ORLOFF: But to respond to your

question about how much leverage does FDA have with

regard to enforcement of these sorts of commitments

on the part of the sponsor, in the absence of a

contingent approval, for which there is a

regulatory instrument that would not apply here as

far as I understand, that is to say an

over-the-counter switch, we do not have a legal

regulatory handle.

That said, as you yourself have pointed

out just for the endocrine and metabolic drug area,

across the different drug areas or the

pharmaceutical classes that are regulated in the

United States, there are multiple such commitments

that are essentially described at the time of

approval as a matter of public record and there are

clear incentives in that alone for the companies to

401

adhere to or to maintain those commitments.

At some level, it is a gentlemen's

agreement, if you will, but from one instance to

the next there is no necessary reason for you or

for the public to believe that a commitment is not

going to hold. So, our job here, and your job, is

to think about what sorts of information you think

FDA should be concerned about garnering in the

post-marketing period, to propose that, and we can

take it forward from there.

DR. WOOD: Well, David, a third of the

Phase IV studies that are mandated are not started,

or weren't started in the last survey. So, I mean,

that is not entirely true. Anyway, let's move on.

DR. ORLOFF: But, Alastair, I want to make

it clear. I mean, I don't know any other way to

state it but on a case by case basis. I don't

think we can go into this process with an

assumption that no one's word is worth anything or

that putting this out in the public domain has no

weight. There is experience in the Food and Drug

Administration with the pharmaceutical industry of

402

success in adherence to Phase IV commitments.

There is apparently a record that may be overall

less than satisfactory, but that doesn't mean that

we can't talk about what is necessary now. DR.

WOOD: All right. We have one more question.

DR. HEMWALL: I just want to add that

Merck Research Lab has a perfect performance record

in adhering to Phase IV commitments that we make at

the time of approval, and we would expect to uphold

that record.

DR. WOOD: Frank?

DR. DAVIDOFF: Just to get back briefly to

the issue of pregnancy, it seems to me there are at

least two reasons for some reservations about the

existing data. One is that, as I understand, the

reported number of adverse pregnancy outcomes is

really very small. It is 7, or 30 or 40, depending

on which universe you are looking at. But given

the millions of doses and years that is quite

small.

But at the same time, as I understand

this, this is all voluntary reporting and voluntary

403

reporting is well-known to be grossly

under-reporting and it is not good sampling. So,

it is quite possible that the numbers are larger

than that and we really can't make a judgment about

that. But to assume that these are all the cases

that have happened is not probably appropriate.

The other comment is on the issue of the

apparent lack of a pattern of fetal abnormalities

and the outcomes of the adverse pregnancy outcomes

as somehow being reassuring and that there were no

common biological mechanism at work. On the other

hand, we are learning rapidly that the statins are

not simple agents when it comes to biological

actions. In last week's New England Journal there

was a very striking article about the apparently

cholesterol-independent actions of statins,

probably relating somehow to the inflammatory

response. So, I think that it is hard to interpret

this lack of pattern as meaning that this is

somehow not related to the presumed single action

of the statins because I think the actions are not

single; I think they are quite complex.

I think that that also gets to the issue

of assuming that the teratology or the damage to

fetuses is going to be related to myelination

404

because it assumed--somehow the simplistic

assumption is made that all they do is to interfere

with cholesterol metabolism. I don't think that is

fair. It seems to me that there might very well be

other developmental abnormalities that have nothing

to do with cholesterol metabolism. So, at least in

my own mind, I have maintained a little bit of

reservation from these data that I have been

hearing are being interpreted otherwise.

DR. ORLOFF: Alastair, I would like to

clarify. Understand, I am not a toxicologist and,

as I said, in terms of absolute risk,

unfortunately, all we are left with is hazarding a

guess. When I said there was no pattern apparent

that would suggest a lovastatin fetal syndrome,

yes, there are clearly multiple final mechanistic

effects of statins. But I think it is safe, for

purposes of at least beginning to conceptualize

this, to understand that there is absolutely no

405

evidence that statins work in any other way except

as HMG CoA reductase inhibitors. I mean, that is a

hard one to deny. Yes, HMG CoA reductase

inhibition itself engenders multiple cellular,

biochemical and systemic effects but these are HMG

CoA reductase inhibitors first and last.

Now, it may turn out that some of them do

have pleiotropic effects beyond HMG CoA reductase

inhibition per se but that has never been

established. They are designed as such, and I

think we have to start at least by considering that

that is their mechanism of action.

DR. WOOD: I completely agree with you but

I would just caution that what Frank I think is

saying is that beta blockers act exclusively by

beta blockade but practolol had an effect that was

independent of beta blockade. I think that is the

point he is trying to make.

But on that note, and the FDA having

conceded "seat of the pants" analysis, we are going

to stop for tonight and reconvene at eight o'clock

in the morning.

406

[Whereupon, at 5:15 p.m., the proceedings

were adjourned, to reconvene on Friday, January 14,

2005 at 8:00 a.m.]

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