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 II

Friday, January 14, 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.

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. 4

Conflict of Interest Statement:

LCDR Hilda Scharen, M.S. 4

Open Public Hearing

James McKenney, Pharm. D.,

National Lipid Association 8

Suzanne Hughes, R.N.

Preventative Cardiovascular Association 12

Stewart Levy, R.Ph.,

Impact Health 16

Robin Edison, M.D., MPH

National Institutes of Health/Human Genome 20

Boisey Barnes, M.D.,

Association of Black Cardiologists 24

Sidney Wolfe, M.D.,

Public Citizen's Health Research Group 28

Alice Rein, M.S.,

National Consumer League 32

Penny Kris-Etherton, Ph.D., R.D.

Penn State University, Department of

Nutritional Science 37

William Greene, R.Ph.,

American Society of Health-System Pharmacists 41

Steve Zatz, WebMD 45

Bob Dufour, R.Ph., WalMart 49

Jan Engle, Pharm.D.,

American Pharmacists Association 52

Christopher Maus,

Lifestream Technologies, Inc. 57

C O N T E N T S (Continued)

Laurie Tansman, M.S.

Mt. Sinai NYU Health 62

Questions from the Committee and Committee

Discussion 66

Questions to the Committee 129

P R O C E E D I N G S

Call to Order and Opening Remarks

DR. WOOD: Let's get started.

LCDR SCHAREN: Good morning. 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

interest 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 which he receives less than

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

for consulting with a competitor which he receives

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

consulting with a competitor 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 which she receives between $10,001

and $50,000 per year from the sponsor and less than

$10,001 from the competitor; Dr. Nelson Watts for

being and advisory board for two competitors for

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

firm; Dr. Neal Benowitz for consulting with a

competitor 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 to $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 12A30

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 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 product they may wish to comment

upon.

Thank you.

Open Public Hearing

DR. WOOD: Let me follow that with this

statement. Both the Food and Drug Administration

and the public believe in a transparent process for

information gathering and decision making. To

ensure such transparency at the Open Public Hearing

Session of the Advisory Committee Meeting, FDA

believes it is important to understand the context

of an individual's presentation.

For this reason, FDA encourages you, the

Open Public Hearing speaker, at the beginning of

your written or oral statement to advise the

committee of any financial relationship that you

may have with the sponsor, its product and, if

known, its direct competitors.

For example, this financial information

may include the sponsor's payment of your travel,

lodging or other expenses in connection with your

attendance at the meeting. Likewise, FDA

encourages you, at the beginning of your statement

to advise the committee if you do not have any such

financial relationships.

If you choose not to address this issue of

financial relationships at the beginning of your

statement, it will not preclude you from speaking.

Now, we will go to the first speaker. But

let me sort of lay out the ground rules first.

Each speaker will have five minutes to speak. We

will time you for five minutes and, after five

minutes, I will cut off the microphone. So your

lips will continue to move but that is all we will

hear. So I encourage you to get it done in five

minutes and let's get started.

What we would like to do is sort of line

up the next speaker to be sitting in the chair

behind Dr. McClung. The first speaker will be

Laurie Tansman from Mt. Sinai Hospital. The next

one will be James McKenney.

James McKenney? All right. The speaker

after that will be Suzanne Hughes.

DR. McKENNEY: Good morning, members of

the FDA, members of the advisory committee, it is

my pleasure to be here this morning. I am Dr. Jim

McKenney representing the National Lipid

Association.

My disclosures are as you see; speaker

honoraria from a number of pharmaceutical

companies, research grants from many, consulting

fees from some, no honoraria or other moneys from

J&J/Merck, Bristol-Myers-Squibb. The National

Lipid Association has received educational grants

unrestricted from all of these organizations

including J&J/Merck and Bristol-Myers-Squibb.

The National Lipid Association is made up

of the leading experts and thought leaders in our

profession in the area of lipids. People who are

in the trenches seeing patients every day,

physicians, cardiologists, preventive

cardiologists, endocrinologists, internists, family

physicians, pharmacists, nurses and dieticians.

Our principal mission is education. We

hold regional meetings throughout the year and

concentrate on exchange of information and

supporting each other. We also are interested in

issues that affect us and our patients.

As you know, we deal almost every day with

nonprescription medications as we try to manage our

patients of which we know little about the efficacy

or safety of the manufacturing quality but we know

that they are widely promoted with significant

claims of efficacy.

As we looked at this issue about a year

ago and talked to our members, the line of

reasoning went something like this. What do you

think about an over-the-counter statin? The

question would be how could they possibly do for

the consumer what I do every day. It is much too

complex.

But, as we thought further, it is clear,

millions of Americans, more than half at moderate

to high risk, are not yet receiving treatment after

many years now at this. We are not getting the job

done. So what do we do? We do more and better

educational programs, more and better drugs, more

and better screenings, more and better public

programs. How do we overcome this issue?

Well, we maybe should consider it. Maybe

it is a good idea to give consumers the opportunity

to be more involved in their own healthcare and

some tools to do that. So we concluded that the

key questions around the issue, as you said

yesterday, are the inherent safety and efficacy of

the product and the efficacy and safety of the

consumer who is trying to carry out that.

So the National Lipid Association went

about trying to find evidence. We felt like we

should be debating this issue on the evidence and

we did that. We conducted surveys of consumers,

physicians and pharmacists. We scoured the

literature. We found as many consumer-use studies

involving statins and we could, more than you have,

actually looked at, and would suggest that there

are some additional studies you should look at.

NLA, per se, did not take a position on

this but yet tried to foster an informed

discussion. We have summarized our findings in a

monograph which we have supplied to you and there

are copies available to the public outside.

We brought this information to four

advisory boards and three town halls the most

recent of which was at the American Heart

Association this past November. Many hundreds of

people participated in that.

I want to present to you very briefly

some, just a snippet, of some of the information

that we discussed and talked about. This came from

our survey of consumers where we found many people

are interested in this topic but, interestingly,

among those patients who said that they were likely

to purchase this product compared to those who were

less likely to purchase this product, there was no

difference demographically but a remarkable

difference in terms of their personal activity

about their own healthcare, their pursuit of diet

and exercise and the like. So it looks like there

is an activated consumer who is interested in this

sort of thing.

We were also comforted by their statements

that they would stay in touch with their

physicians, both before and during and after making

this purchase.

In terms of consumer use, per se, these

are the studies that we looked at. PREDICT and

OPTIONS were actually presented to this committee

in 2000 at a part of the petition from

Bristol-Myers-Squibb and, of course, CUSTOM, you

heard about yesterday.

Here are some of the findings from those

three studies. The consistency is remarkable here.

Consulting physicians, exercise, and so forth.

I want to share with you, as my green

light has come on here, the negative side of things

that raise concerns and then, finally, here is the

polling data we--[microphone off.]

DR. WOOD: Thank you very much.

The next speaker is Suzanne Hughes and the

speaker following that is Stewart Levy.

MS. HUGHES. Good morning and thank you so

much for the opportunity to address the committee.

My personal disclosures are as follows: I have

received speaking and consulting honoraria from

AstraZeneca, Bristol-Myers-Squibb, J&J/Merck,

Guidant Corporation and Pfizer. My expenses

related to my travel for this meeting are paid for

by the Preventive Cardiovascular Nurses

Association.

Our group is supported by membership dues

and funding from multiple members of the

pharmaceutical, medical-device and food industries.

We have not received any funding from the sponsor.

PC&A is a national organization of 2000

nurses dedicated to the primary and secondary

prevention of cardiovascular disease. We achieve

our mission through professional and public

education and through increasing consumer awareness

of the importance of reducing CVD risk and through

advocacy regarding nurses' role in the care of

persons at risk for heart disease and stroke.

The nurses on our board and who authored

this statement with me average 30 years experience

in cardiovascular nursing. We all remember when

care of the acute patient was reactive rather than

proactive and when available strategies for the

treatment of dislipidemia included only agents that

were given three times a day, were poorly tolerated

and only modestly reduced cholesterol levels and

cardiovascular event rates.

All of us in this room know that the

approval of Mevacor, the first HMG COA reductase

inhibitor in 1987, effectively revolutionized

pharmacologic treatment of dislipidemia. In

numerous well-designed trials over ten years,

cholesterol-lowering through the use of statins has

been found to be remarkably save and effective.

The results of these trials have demonstrated

substantial reductions in morbidity and mortality

but, of the millions of Americans eligible for

treatment with these medicines, only a fraction

receive these evidence-based therapies. Many who

begin taking these medicines fail to continue

therapy over time. Barriers to the initiation of

and persistence with treatment are complex and

multifactorial. Making a statin available without

a prescription is one strategy being explored to

close the under-treatment gap. This is an option

that may be appropriate for those at moderate risk.

The Board of Directors of PCNA

acknowledges the potential public-health benefits

of OTC availability of low-dose statins. We

support the concept of the switch to OTC status

based on the satisfaction of the following. The

research should indicate that the population who

chooses to use this product is comprised of

appropriate candidates for OTC lipid-lowering

therapy. The research should indicate that those

who elect to use the product follow the

instructions on the label with regard to dosage of

frequency.

The research should demonstrate that those

who elect to use the product consult with

healthcare providers for clinical follow up as

needed. The promotion of the product must be

accompanied by a responsible marketing campaign

targeted to the appropriate population.

In closing, we believe that the OTC

availability of a statin is likely to be associated

with important public-health benefits. This is

more than simply a box on a shelf. This new option

would allow Americans to take a more active role in

their own health and well being. The associated

marketing effort will raise awareness of the

importance of the treating dislipidemia as a

strategy to reduce overall cardiovascular risk.

We believe that this increased awareness

will stimulate important dialogue between the

public and the healthcare community. In response,

we should all embrace the opportunity to educate

our patients and the public not only with regard to

the use of pharmacologic lipid-lowering agents but

about the central role of nutrition and physical

activity on cardiovascular health.

The Preventive Cardiovascular Nurses

Association is committed to participating in this

important campaign that has clear potential to save

lives.

Thank you so much.

DR. WOOD: Thank you very much and thank

you for sticking to time.

The next speaker is Dr. Stewart Levy and

Robin Edison will follow that.

MR. LEVY: Good morning. I am Stewart

Levy from Impact Health. Our goals today are just

to talk a little bit about the industry, the

biometric testing industry, and also to give you

our position as Impact Health in the industry on

the opportunity for over-the-counter cholesterol

agents.

Also, we are going to give a little

background about the education, about how we reach

consumers, the process of how we perform health

assessments, clinical testing and examples of

different types of programs at retail.

Our overall mission is to create an

experience with the consumer that will drive

healthy decisions and what we call the teachable

moment which will drive decisions to promote

healthy decisions related to products, services and

lifestyles.

Impact Health has been around for over 17

years in this industry and we have a number of

organizations that utilize our services to support

their organizations and to reach consumers

including advocacy groups like the American Heart

Association, various ad agencies, consumer

organizations, employers including the U.S.

Government which hires our services such as the

U.S. Supreme Court and other organizations within

the government, health-promotion companies, food

organizations that are becoming very active in

performing cholesterol screening and blood-pressure

awareness programs at retail, managed-care

organizations such as Blue Cross, Blue Shield

plans, over-the-counter companies, pharmaceutical

industry and pharmacy chains.

I should also disclose that Impact Health

has not contractual relationships with either of

the OTC statin companies. We do project work on a

case-by-case basis.

As I mentioned, we have been around for

over 17 years and we hold very high standards in

quality. We have CLIA certification and we

actually are licensed as a moderately complex

laboratory. So we can actually do field-based

lipid screening in many of the states that allow

this. We do everything according to HIPPA

guidelines. We are not a HIPPA-covered entity but

we act as one because we have very valuable

laboratory information and biometric values with

our consumers.

We have the highest standards of

professional liability insurance. We also maintain

a very active quality-assurance program which makes

sure that all our policies, productions, practices

are necessary to assure that the laboratory results

are reliable.

We participate in both mandatory and

optional proficiency testing and we train our staff

extensively on the clinical relevance of the

problems, testing protocols, counseling, OSHA,

blood-borne pathogens and HIPPA guidelines.

There are different types of organizations

that perform clinical testing, as you may be aware.

The industry, itself, is what you would call a

cottage industry. There are very few national

firms that do what we do but, many times, local

hospitals, as some may be talking today, are in the

community performing health screening services as a

way to promote their hospital and their care in the

organizations.

There are also advocacy groups that do

this and also temporary nursing staffing firms that

do screening programs. Many of the programs are

not just one and done. There is an interest in the

industry to continue an ongoing relationship with

the consumer to make sure that their health is

followed up with physicians, et cetera.

It starts with the consulting and

marketing opportunity with the venue, with the

sponsor, and then what we will do is perform a

validated health risk assessment and a

questionnaire which will allow us to gain very

important information about medical history,

whether they are on other prescription products,

whether they have a family history of heart

disease, and we will use Framingham risk factors in

questionnaires into that assessment.

Then we will perform the clinical testing

with technology that you will hear more about

today. We will have health education performed and

our goal is to drive consumers to a healthcare

professional. We are not diagnostic. Let me

repeat; our goal is to screen that consumer to

promote healthy decisions so that they go to their

physician and get onto appropriate therapy or, in

this case, speak with their pharmacist.

We follow up with the program with reports

to the consumers, individual reports, reports to

the sponsors, to the venue. We communicate to both

the participant and the physician and we can

perform market research and outcomes measurements.

The process is to do a health assessment,

to do testing and to do the education.

I am going to skip over this slide and you

will have a handout because it is repetitive.

There are some examples of different types of

screening programs that are done at retail and with

different various groups. Here is an example of

one.

I am going to wrap up with our position

that there is professional staff to support

retailers in the field and also those that will

perform consultative--[microphone off.]

DR. WOOD: Thank you very much.

The next speaker is Robin Edison and the

speaker following that is Boisey Barnes.

DR. EDISON: Good morning. I will

describe our work exploring the question of

lovastatin teratogenicity in humans. You have

these materials in the handout.

We examined all case reports from MedWatch

and other sources which report exposure to any

statin drug in the first trimester of pregnancy.

This strategy does not permit causal inferences. I

will conclude there are potential safety issues

requiring careful study independent of whether

lovastatin becomes available OTC.

This overview of the mevalonate pathway

which the statins inhibit is familiar to you and

indicates the diversity of potential drug targets.

Cholesterol is synthesized by the embryo not only

for the rapid production of new cell membranes but

is probably also used in a concentration-dependent

manner to control the activity of patterning

molecules that direct morphogenesis, initially in

the midline central nervous system.

Here is an overview of our case series.

Of the 22 total malformation reports, I will

highlight patterns in these seven

lovastatin-associated cases. Three of these seven

included midline CNS defects. These numbers are

tiny. However, it is interesting that

holopresencephaly with a background prevalence of 1

in 16,000 births was reported not only following

lovastatin exposure but was also the only

malformation reported following cerivastatin

exposure.

Holopresencephaly is the classic disorder

seen in animals given other inhibitors of

cholesterol biosynthesis and is seen in some

patients with an inborn error of this pathway. We

also saw aqueductal stenosis and a large

neural-tube defect following prolonged lovastatin

exposure. Not shown, there were also two cases

reporting neurologic disorders both including

seizures and neurodevelopmental impairment.

The multiple malformation VACTERL

association was reported following the 10 milligram

per day exposure to lovastatin. This particular

case had severe defects throughout the axial

skeleton and has a background prevalence of 1 in

500,000 births. Again, of interest, there was a

second case of VACTERL association among the

malformation reports following simvastatin

exposure.

Considering biological plausibility, only

the lipophilic statins generated case reports of

malformations although the hydrophilic drug

pravastatin generated numerous reports as well, all

with "normal" outcome.

Lovastatin concentration in embryonic

tissues reportedly averages 25 percent of the

maternal plasma concentration and we know that its

pharmacokinetic parameters vary at least 10-fold

among individuals. With respect to

embryonic-tissue susceptibility, the earliest area

to undergo rapid expansion is the neuroepithelium

which shows the highest expression of HMG COA

reductase post gastrulation.

Animal studies using statins have shown

malformations primarily in the axial skeleton but

also include neural-tube defects,

neural-developmental deficits and visceral

malformations. Other chemicals that suppress

cholesterol levels have induced all three CNS

malformations reported clinically following

lovastatin exposure.

In vivo, lovastatin decreases cholesterol

levels in the CNS both globally and in specific

domains of cell membranes notably depleting

membrane sites where folate receptors are

localized. VACTERL association is induced in a

mouse model by decreasing the pathway activity of

the cholesterol-mediated morphogen, sonic hedgehog.

So we have an overlap of human and animal

findings in the CNS and two reports each of rare

malformations associated with cholesterol or

hedgehog downregulation. The apparently small

population of statin-exposed births reported by the

CDC Registry appears insufficient to presume these

reports reflect random events or biased

ascertainment. Regarding the question of why there

are so few malformation reports, many of the

malformations have quite high rates of intrauterine

lethality, 99 percent, for holopresencephaly and

mostly by Week 8.

It is unfortunate that none of the fetal

demise or miscarriage cases were autopsied to rule

out associated pathological conditions.

Clinically, most case reports stated the drug was

discontinued upon recognition of pregnancy

including the two cases of holopresencephaly. Both

VACTERL cases had more prolonged exposures during

organogenesis.

So these materials may support a

teratogenic hypothesis linking first trimester

lovastatin exposure with human malformations,

particularly of the CNS. Prospective studies are

required to adequately assess risk.

Thank you.

DR. WOOD: Thank you.

The next speaker is Boisey Barnes and the

speaker after that will be Sidney Wolfe.

DR. BARNES: Thank you for allowing me to

make this presentation. I am Dr. Boisey Barnes, a

practicing cardiologist in Washington, D.C. and a

founding member of the Association of Black

Cardiologists. I am speaking on their behalf

today.

Four years ago, the FDA rejected a request

for over-the-counter availability of low-dose

statins. Today, safe and effective use without

physician guidance remains a concern. The ABC has

given thorough consideration to this issue and does

not support OTC availability of statins at this

time.

Number one; while low-dose may reduce

cholesterol levels, they have not been proven to

reduce cardiovascular morbidity and mortality.

There are no trials of OTC statins for

effectiveness in primary prevention of heart

disease. There are no data on compliance with

over-the-counter statins.

Number two; there is concern about the

people who need high-dose statins might not get

them because they would be taking the OTC low-dose

statin that was an alternative to seeing the

doctor.

Number three; there is less justification

of using weaker statins because they do not provide

optimal risk reduction. It appears from recent

studies such as PROVEIT that lower LDL is better.

Number four; individuals may lose sight of

the need for lifestyle changes if they believe

taking a pill will suffice.

Number five; patients who purchase their

statins at the local pharmacy or supermarket will

miss one of the main messages of prevention

cardiology, the importance of global risk

assessment. A healthy lifestyle, low-fat diet and

exercise may achieve the same results as OTC

statins.

Number six; also will pharmacists have the

time to determine the individual's risk of coronary

heart disease before selling the drug and also

giving lifestyle advice.

Number seven; OTC medications are

generally for symptomatic conditions. This

medication is for an asymptomatic condition. When

will we start it? When will we stop it? Examples

of this are Prilosec for abdominal pain. You know

when you have discomfort. You know when to stop

it. Or Tylenol for knee pain. You know when to

start and stop it. This is an asymptomatic

condition. Stopping and starting medications can

increase your risk for an adverse event.

Number eight; there will be a problem of

underdiagnosing and overdiagnosing elevated

cholesterol. Elevated cholesterol does not have

obvious symptoms and signs.

Number nine; recognition of toxicity which

are mainly liver and muscle. I have never a report

of a patient dying of liver disease from a statin.

However, they may die from serious muscle

complications. The risk for muscle complications

is increased by coadministration of many

medications. The main one is gemfibrozil. From

the 3,399 case of rhabdomyolosis that were reviewed

extensively from the FDA that were reported, 58

percent of those were given concomitant medication

and the number one is that of gemfibrozil. There

are other immunosuppressive agents, warfarin,

anticoagulants and other medications. The risks

increase as you increase age and as you increase

the dose of the medication along with comorbid

conditions and renal insufficiency.

Number ten; females. Statins are

contraindicated for women who are pregnant or

breast-feeding.

DR. WOOD: Thank you very much.

The next speaker will be Sidney Wolfe and

then the speaker following that will be Alice Rein.

DR. WOLFE: About four-and-a-half years

ago, FDA had a general meeting on the principles

that should be adhered to when any drug is being

considered for over-the-counter switch. I think

that the two most important principles which are

relevant here today are: one, ease and possibility

of accurate self-diagnosis; two, the benefit:risk

ratio and the continued evaluation of it such as

continued cholesterol-lowering levels. Related to

that is the number of adverse drug reactions or

interactions and the ease of detecting them.

If there are numerous adverse reactions or

iterations which may not be fully known to the

patient or, conversely, to the physician who is not

aware that the patient is also using OTC drugs,

there is even more cause for concern.

If any one of these criteria is not met,

the decision to switch a drug to OTC is wrong from

an overall public-health perspective. If none of

the conditions are met, the switch is likely to be

an even greater public-health disaster having an

overall negative effect on health. For the switch

of any statin--in this case, lovastatin--none of

the conditions are met and it is virtually certain

that more harm than benefit would accrue to such an

ill-advised regulatory decision.

Despite the company's efforts to paint the

switch as something positive, the analysis by FDA

with which I concur seriously undermines any such

conclusion.

First, the eased possibility of accurate

self-diagnosis. Since the proposed use is primary

prevention and people without symptoms, the correct

assessment relies entirely on lab tests and the

assessment of other risk factors. The data from

these studies of label comprehension and from the

actual use of lovastatin yield unacceptable results

as far as the ability of very many patients to

accurate assess all the factors necessary to

qualify as a candidate for this drug.

In terms of the label comprehension, as

you have seen in your materials, only 1 percent of

the respondents who stated they could use Mevacor

OTC right away actually self-selected correctly.

In terms of the actual-use study, the current

paradigm for the treatment of hypercholesterolemia

is individualized based on serum cholesterol and

the presence of risk factors.

One of the more disturbing comments I read

was that by an FDA reviewer who said the most

disturbing results are in self-selection. Over 80

percent of subjects in the study did not

self-select appropriately. Only 484 users

initially self-selected correctly and I think this

is important and, of those, only 68 were able to do

this without a physician's input. Sounds like a

prescription drug to me.

Nearly one-third of all users had ten-year

risk for CHD of less than 5 percent which is, as

you know, a level that does not call for statin

therapy.

Benefit:risk ratio and its continued

evaluation and adverse drug reactions. The

continued evaluation of benefit:risk depends on

cholesterol follow up, amongst other things, and

many did not have this in this little study.

Amongst the average reactions that may be difficult

to detect in the absence of physician involvement

in a prescription for this drug and, thereby,

intervene are asymptomatic elevations of liver

enzymes after taking lovastatin or asymptomatic

liver disease before using the drug unknown to the

patient.

The onset of myositis, muscle

inflammation, a possible predecessor for

life-threatening rhabdomyolosis, may not alert the

patient who is not necessarily under the

supervision of a physician and problems can occur.

A recent large case-control study

published a month or so ago in Italy also raises

the question of peripheral neuropathy. It is the

third such study and they said this is

hypothesis-generating, but this is another problem

that patient may not link to the drug.

In summary, since, as is the case for a

substantial proportion of those choosing to use the

OTC version of this drug, their risk for CHD is so

low that there is no evidence they will benefit.

They are being subjected to the various risks of

adverse reactions without any possibility of

benefit. Thus, the risks clearly outweigh the

benefits for this group.

In addition, it is clear that the

availability of easy-to-get OTC statins will deter

many from safer, less expensive, preventive

measures. Prevention of cardiovascular disease

must be a multi-pronged strategy to reduce risk.

The use of heavily advertised statins out of the

context of medical consultation may impair the

development of an integrated long-term strategy for

preventing strokes or heart attacks.

Diet and exercise, critically important

components, may be thought to be less important if

the primary strategy seems to be a statin drug.

The safety problems, although somewhat

rare for statins other than Crestor are especially

hard to detect and monitor without physician

involvement and, as mentioned above, must be viewed

as unacceptable for the large proportion of people

who cannot possibly benefit from the drug.

Even for those who might theoretically

benefit, for the small fraction that self-select

properly, there are serious questions of whether

the 20 milligram dose confers any clinical benefit

as quoted from, actually, the company.

In summary, we urge the panel, as we did a

few years ago, to reject to over-the-counter switch

of this drug.

Thank you.

DR. WOOD: Thank you.

The next speaker is Alice Rein and the

speaker following that will be Penny Kris-Etherton.

MS. REIN: My name is Alison Rein and I am

the Assistant Director of Food and Health Policy at

the National Consumers League. I am here today to

present some of the key findings from a research

project that we recently conducted to explore

consumer awareness of and attitudes about

cholesterol and possible treatment options.

My presence at this meeting is independent

of the sponsor but approximately 1 percent of NCL's

operating budget comes from unrestricted research

pharmaceutical grants of which this study was one.

I will begin my comments with a brief

overview of NCL. I will then explain our interest

in this topic, describe the research methods used

and present a top line of our findings. Given the

brevity of this presentation, I would ask that you

refer to two supplemental documents for more

detailed information. One is a full survey

instrument with annotated results and the second

part is a PowerPoint presentation depicting key

findings and graphic representation. Both of these

have been submitted for your review.

The National Consumers League, founded in

1899, is a private, nonprofit advocacy group that

uses education, research, investigation,

publications and public/private collaboration to

accomplish its mission of representing consumer

interest on marketplace and workplace issues.

NCL commissioned this research to explore

consumers' knowledge about the significance of high

cholesterol, their attitudes toward the possibility

of an OTC statin, their perceptions about the

relative benefits of OTC versus prescription

treatments and their perspectives on relevant

safety and use issues.

In exploring this topic, NCL is not

lending support to the approval of an OTC statin.

We look to the FDA to consider all of the clinical

and consumer use data and hope only that these

consumer survey data will help inform that

discussion.

NCL engaged Harris Interactive to conduct

this survey with members of the Harris Poll On-Line

Panel which consists of several million people who

have agreed to participate in survey research

projects. Interviews were conducted between August

26th and September 3rd, 2004. A total of 2,777

people participated in the survey, 730 of whom were

qualified to complete it.

The sample was composed of U.S. residents,

aged 35 or older, who were either at known moderate

risk for coronary heart disease or who were at

potential moderate risk for coronary heart disease

based on specified risk criteria. None of the

survey participants were using medical management

to treat their cholesterol.

We oversampled black and Hispanic

respondents and used demographic and

propensity-weighting techniques to ensure that the

data represented the national population of adults

aged 35 and older. Near the beginning of the

survey, respondents were asked to consider a full

description of the proposed OTC statin product.

In OTC/prescription comparison sections of

the survey, respondents were instructed to consider

a similar low-dose cholesterol-lowering medication

that is available only by prescription from a

doctor.

Here are six of our key findings. First,

American adults still require substantial education

about elevated cholesterol and its associated

risks. Almost 40 percent of all respondents did

not know their cholesterol level and almost 30

percent indicated that they were not concerned

about their cholesterol.

Second, there is an interest among

consumers in an OTC option for lowering

cholesterol. The majority of respondents indicated

that they would be at least somewhat likely to seek

out more information on the product, 67 percent,

discuss the product with a healthcare professional,

69 percent, or use the product, 58 percent.

The majority of respondents, 85 percent,

also agreed either strongly or somewhat that the

OTC statin option would be preferable to taking a

prescription drug to lower cholesterol.

Third, while most people believe at least

somewhat in the effectiveness of the OTC statin,

there are concerns about safety. The large

majority, over 90 percent, believe that OTC product

would be at least somewhat effective but almost

half did not think that the OTC statin would be

more effective at lowering cholesterol than diet or

exercise alone.

Over two-thirds are at least somewhat

concerned about the potential side effects of

cholesterol-lowering OTC and almost one-third do

not think that the benefit of a

cholesterol-lowering OTC outweighs the risk.

Fourth, the OTC statin option is most

strongly associated with concepts of prevention and

control of health. It is less associated with

concepts of dependence on caretakers and poor

health.

Fifth, compared to a prescription option,

the OTC statin is seen as more convenient, more

natural, less likely to cause side effects and more

appropriate for "someone with my healthcare needs."

A prescription option is generally seen as more

effective, more reliable, more trustworthy and more

suitable for someone in poor health.

Finally, respondents expressed a greater

likelihood to consider taking, recommend to a

friend or family member or seek more information

about an OTC statin relative to a prescription

statin option. There is far more information but I

will let you review that separately.

Thank you for considering this

information.

DR. WOOD: Thank you very much. Perfect

timing. The next speaker is Penny

Kris-Etheron and the speaker following her is

William Greene.

DR. KRIS-ETHERTON: Thank you and good

morning. My name is Penny Kris-Etherton. I am a

faculty member in the Department of Nutritional

Sciences at Penn State University. With respect to

personal financial disclosures related to this

meeting, I serve on the Medical Advisory Committee

for J&J/Merck. I have paid for all expenses

incurred to attend this meeting myself.

As a cardiovascular nutritionist with a

very deep commitment to educating dieticians to be

effective in dietetic practice, I support approval

of OTC statin drugs. Beyond the potential

public-health impact of OTC statin drugs on

coronary heart disease morbidity and mortality in

the United States, there are other benefits that

can be realized.

I am going to address two important

benefits today. First, OTC statins can be a useful

tool for dietician, nutritionists in practice to

help their patients achieve LDL cholesterol

treatment goals.

As you can see in this slide, diet has a

modest effect on LDL cholesterol compared with

statin drugs. This figure shows the relative

contribution of diet versus statin drugs in

lowering total and LDL cholesterol levels. Even

maximum dietary intervention doesn't always lower

LDL cholesterol sufficiently in individuals who are

at moderate risk for coronary heart disease. For

these individuals, OTC statins can facilitate

meeting LDL goals. Moreover, achieving a positive

treatment outcome greatly enhances the

dietician-patient relationship thereby achieving

greater LDL cholesterol with diet.

You can see with this next overhead what

is achievable with diet. Moreover, achieving a

positive treatment outcome enhances the

dietician-patient relationship and good

interactions between a patient and dietician than

can facilitate behavior changes to achieve

significant cholesterol-lowering reductions and

many other diet-related health benefits.

So the potential outcomes of OTC statin

drugs extend beyond cardiovascular disease with

improved lifestyle behaviors including diet and

physical activity, risk of other chronic diseases

can be decreased. Consequently, OTC statins could

have marked public-health impacts.

Secondly, the OTC program could

beneficially affect the nutritional inadequacy of

the diet. In addition, it may help facilitate

meeting dietary and physician activity guidelines.

The OTC implementation studies indicate that

subjects using OTC statins report improved diet and

physical-activity behaviors. Given the many

problems with diet and physical-activity practices

in the U.S., a program that facilitates positive

lifestyle changes could favorably affect public

health and deserves strong consideration for

support.

The United States diet is low in Vitamin

E, calcium, magnesium, potassium. It is high in

saturated fat, cholesterol, low in dietary fiber.

Very small changes in dietary practices can

facilitate achieving recommended micro- and

micronutrient intakes.

For example, inclusion of just one orange

a day can meet the RDA for Vitamin C. Inclusion of

one serving the dairy products could help achieve

calcium and magnesium RDAs and help meet

recommendations for potassium. Switching from a

higher to a lower-fat protein food could help

achieve saturated fat and cholesterol

recommendations for heart health. These are just a

few of many examples.

In summary, I believe, because of the many

substantive benefits of OTC statins, that the FDA

should approve them for use. The likely multiple

and beneficial health outcomes could have a marked

public-health impact.

Thank you very much for your attention.

DR. WOOD: Thank you very much.

The next speaker is William Greene

followed by Steve Zatz.

MR. GREENE: Good morning. I am Bill

Greene. I am the Director for Clinical Pharmacy

Services for Methodist University Hospital in

Memphis Tennessee. I also carry a faculty

appointment with the College of Pharmacy with the

University of Tennessee. I have served as a

speaker for Pfizer, for Merck and for

Ortho-McNeill, a subsidiary of J&J.

I presently come as a representative of

the Executive Committee of the Section of Clinical

Specialists and Scientists for the American Society

of Health System Pharmacists.

ASHP is the 30,000-member national

professional and scientific association that

represents pharmacists and pharmacy technicians who

practice in hospital inpatient ambulatory clinics

home-care and long-term-care settings. I am

pleased to provide the perspective of ASHP on the

proposed switch of lovastatin from prescription to

over-the-counter status.

ASHP believes that existing models for OTC

dispensing do not provide the safeguards required

to ensure the safe and effective use of statins as

part of a multi-modal approach to preventing

coronary heart disease. ASHP does support the goal

of extended consumer access to important

medications including statins. We encourage

consideration, therefore, of alternative

nonprescription dispensing models for statin that

would advance coronary-heart-disease prevention,

provide ready access to assessment and advice from

a pharmacist and make the drug readily available

through pharmacies.

ASHP has recommended that evaluation and

treatment of lipid disorders be guided by the

recommendations of the National Cholesterol

Education Panel, the latest of which are contained

in the Adult Treatment Panel III Guidelines.

Statins are certainly considered the drug of choice

for most patients with dislipidemia who require

lipid-lowering therapy. They are effective at

lowering LDL-C. They reduce events in patients at

risk and they reduce mortality in patients with

proven coronary heart disease. Clearly, there are

benefits of these drugs.

The effectiveness of these drugs in

reducing LDL-cholesterol has prompted calls for the

reclassification of statins as an OTC medication.

Although ASHP does not support reclassification to

OTC status as that status is currently constructed,

alternative nonprescription models for dispensing

these valuable medications should be explored.

To achieve the goal of safe and effective

use, any nonprescription-dispensing model for

statins should include or should identify

candidates based on an assessment of multiple risk

factors and other events related to the patient.

This process should develop an optimal treatment

plan consistent with ATP 3 Guidelines. This

process should allow patients and healthcare

providers to monitor the response to treatment

including adverse reactions. Finally, this process

should maximize the effectiveness of treatment by

encouraging adherence and appropriate interactions

with other healthcare professionals.

High-risk patients should be able to be

triaged for further evaluation. If statins are

appropriate therapeutic options, they should be

part of a multimodal approach to reducing overall

coronary-heart-disease risk. One study has

examined the use of statins in a simulated OTC

statin. The CUSTOM study provides interesting

information regarding the potential of patients to

adhere with an OTC process. However, a number of

adverse events were noted even in that study.

Caution should be exercised when

extrapolating such information to larger

population, especially information regarding

safety. A system that relies on voluntary

reporting of adverse events may be inadequate to

protect the public or detect subtle signals.

The existing model for OTC medications

would place the entire burden for performing this

evaluation and assessment on the patient. Wider

use of drug encouraged by OTC status will result in

a broader exposure and in increased risk to

patients.

ASHP believes that, for these reasons,

reclassification of statins to OTC status as

currently constructed is not advisable but that

alternative nonprescription models for dispensing

these should be explored. Since 1985, the Society

has advocated a policy that urges changes in

federal statutes and regulations that would create

and intermediate category of drug products that do

not require a prescription but are available only

from pharmacists and other licensed healthcare

professionals.

ASHP believes that the regulatory system

for this intermediate category should contain the

following features; first--[microphone off.]

DR. WOOD: Thank you very much.

The next speaker is Steve Zatz and the

speaker following that will be Bob Dufour.

DR. ZATZ: My name is Steve Zatz. I am

the Chief Medical Officer of WebMD. It is a

privilege to appear before you today to introduce

WebMD and describe our commitment to providing

accurate, clear and unbiased health-related

information to consumers and healthcare

professionals and to improving communications

between all parties in healthcare, particularly

patients and physicians.

Over the past year, WebMD has been working

with J&J/Merck Pharmaceutical Partnership to design

educational programs that can raise awareness and

educate consumers and providers on the management

of mild to moderately elevated cholesterol. WebMD

has also worked with J&J and Merck on a variety of

programs to educate consumers health professionals

on topics unrelated to cholesterol management.

We are here today not to speak for or

against allowing Mevacor to be available OTC but to

inform the committee members of our capabilities to

provide information to and facilitate

communications with patients and healthcare

professionals.

According to third-party research, the

internet has become the preferred medium for

consumers and physicians seeking healthcare

information today. WebMD has become the leading

and trusted on-line health destination. More than

80 million unique visitors a year view more than 2

billion pages across the WebMD Health Network to

research health and wellness information and access

our on-line communities and health management

tools.

With more than 500,000 physician visits

per month, MedScape, our health professional

website, has become the leading professional

destination on the web designed to meet the

substantial and growing information needs of

physicians and other healthcare professionals. In

2004, MedScape members completed more than 800,000

CME credit hours making MedScape the leading

on-line source on the web for continuing medical

education.

WebMD works with many of the country's

leading healthcare organizations and government

agencies including Health and Human Services, the

Centers for Disease Control, the National Cancer

Institute and several state public-health

departments to distribute their health information

on our websites.

In addition, we publish the official

references of the American College of Physicians

and the American College of Surgeons. We work with

numerous other professional societies including the

American Public Health Association, the American

Academy of Family Physicians, the American College

of Preventive Medicine as well as with foundations

such as the Commonwealth Fund and the Markoff

Foundation.

With more than 250,000 medical writers,

editors and physicians who develop our highly

regarded content, WebMD is the website most

recommended by physicians to their patients and

MedScape is the site most recommended by physicians

to their peers. Our mission is to provide timely,

accurate and balanced information that enables

patients to make informed decisions about their

care and enables physicians to provide care

consistent with the latest medical evidence.

In addition, with various health-condition

assessment programs and decision support tools,

WebMD is in a unique position to provide education

and targeted outreach to specific populations.

WebMD also provides health-decision support tools

and information for large corporate employers and

health plans to better enable employees and plan

members to take a more active role in their health

decisions and to better manage overall healthcare

costs.

Today, we provide these employee health

tools for many of a largest corporations in the

United States. When consumers and physicians need

healthcare information, they turn to WebMD. For

example, when consumers and health professionals

needed up-to-date and unbiased information on the

Cox-2 inhibitor class of medications, they turned

to WebMD in record numbers. As of December 31,

2004, over 1 million pages of information on the

subject had been requested by consumers and health

professionals through our websites and e-mail

newsletters.

In summary, WebMD is a significant source

for health information and we take very seriously

or responsibility to be an objective and reliable

information resource for Americans. We believe

that we can be a vital resource for educating and

linking consumers and healthcare professionals

regarding appropriate treatment options and stand

ready to support your efforts as needed.

Thank you.

DR. WOOD: Thank you.

The next speaker is Bob Dufour. The

speaker following that will be Jan Engle.

MR. DUFOUR: Good morning. My name is Bob

Dufour. I am the Director of Pharmacy Professional

Services and Government Relations for WalMart.

WalMart operates pharmacies in Sam's Clubs,

Neighborhood Markets, WalMart SuperCenters and

WalMart Discount Stores. In the 49 states we

operate, we have 3,500 pharmacies and 10,500

pharmacists on staff. On average, over 100 million

customers shop our stores each week.

Prescription statins have improved the

health of millions of consumers by lowering their

cholesterol levels. If the FDA determines that

Mevacor is appropriate as an OTC product, the

opportunity to better millions of more lives will

be possible.

Historically, products that have moved

from Rx to OTC status have increased both the

accessibility of the product and the affordability.

Consumer awareness of proper cholesterol levels may

also heighten with the availability of statins as

OTC products.

Preliminary plans have been discussed

between WalMart and Johnson & Johnson/Merck in

anticipation of the OTC approval. These plans have

included, first, testing in a limited number stores

a Heart Health section which would make consumers

more aware of the testing kits and other health

products available. This section, if successful,

could be implemented in more stores as demand for

OTC statins increase. Secondly, broadcasting a

continuing-education program available to all of

our pharmacists via our satellite network.

The objectives of this program include; A,

recall of the important concepts regarding lipid

metabolism and pharmacology of statins; B, list

cholesterol goals for American adults and discuss

the treatment gap between those goals and current

reality; C, discuss the clinical evidence that

supports the move toward broader access and

treatment with statin medications; D, identify the

types of people who would benefit from access to

nonprescription statin medications; E, describe how

pharmacists might best interact with self-treating

patients to ensure optimal outcomes from

nonprescription statin therapy.

Our third initiative would be support from

Johnson & Johnson/Merck at WalMart Health Fairs to

increase the awareness of consumers and their

cholesterol levels. This support would include

funding for consumers to have their cholesterol

tested as well as information about proper

cholesterol levels.

Fourth, WalMart and Johnson &

Johnson/Merck will further discuss the use of other

WalMart vehicles to increase awareness after the

launch including WalMart t.v., radio, pharmacy bag

programs, displays and in-store demonstrations and

information programs.

WalMart has provided input to Johnson &

Johnson/Merck on consumer-friendly packaging. Our

emphasis has been on the patients knowing when and

when not to take an OTC statin. Johnson &

Johnson/Merck has included warnings for consumers

when Mevacor is not appropriate and a four-step

process for consumers to determine if Mevacor OTC

is appropriate.

The American Pharmacists Association has

advocated for a pharmacy-care OTC category.

WalMart would be able to limit distribution from

our warehouses to pharmacies if the FDA determines

this category is necessary. WalMart Pharmacy

recognizes the significance of the decision FDA is

considering. If the FDA decides that Mevacor would

be appropriate as an OTC product, millions of

consumers who are at moderate risk for coronary

heart disease would have Mevacor OTC available as

an affordable option.

I appreciate the opportunity to be heard

today. WalMart Pharmacy is committed to providing

affordable healthcare to our consumers and our

associates. Thank you.

DR. WOOD: Thank you very much.

The next speaker is Jan Engle and that

will be followed by Christopher Maus.

DR. ENGLE: Good morning. Thank you for

the opportunity to present the views of the

American Pharmacists Association. My name is Jan

Engle. I am Associate Dean for Academic Affairs

and Clinical Professor of Pharmacy Practice at the

University of Illinois at Chicago. I am a former

President of APHA.

In the interest of full disclosure, APHA

did not receive funding to participate in today's

meeting and the views I am presenting are solely

those of the Association and its membership. APHA

represents more than 52,000 pharmacists, scientists

and student pharmacists in all practice settings.

It is our understanding that the product

sponsor's application includes a recommendation

that lovastatin, if approved as a nonprescription

drug, be distributed only in outlets with a

pharmacy.

Over the years, APHA has examined this

issue several times and, in August of 2004, we

convened a task force to make recommendations for

the profession's adoption of a pharmacy-care OTC.

So what is a pharmacy-care OTC? Pharmacy-care OTCs

are a category of nonprescription medicines

available in pharmacies on the open shelf with

other over-the-counter medications.

What is different? With pharmacy-care

OTCs is the availability of the pharmacist and the

marketing of the product, where that product is

placed and the pharmacist's preparation to support

consumer-pharmacist interaction. Pharmacist

intervention is not required but it is strongly

supported for pharmacy-care OTCs for those

medications being used for chronic, asymptomatic

conditions or other conditions where consumers

would benefit from additional interaction with the

pharmacist.

The task force developed guiding

principles for implementing this new category. Our

recommendations address areas such as selection of

the product as a pharmacy-care OTC, supporting

consumer-pharmacist interaction, the scope of

consumer-pharmacist interaction and other relevant

services available at the pharmacy.

To support consumer-pharmacist

interaction, pharmacy-care OTC products should be

carefully placed within the outlet to facilitate

direct access to the pharmacist. Promotion of

these products should direct consumers with

questions to their pharmacist and outlets that

remain open when a pharmacist is not on duty, such

as a grocery store, for example, should provide

alternative methods to counseling such as the

telephone, the internet or even appointments with

the pharmacist and this would help facilitate this

interaction in a busy practice environment.

In outlets where the pharmacy is only

component of the facility, appropriate non-pharmacy

staff should also be educated about pharmacy-care

OTC products. Staff can direct consumers to the

pharmacy area and advise them of the pharmacist's

availability for consultation.

In terms of interaction between the

consumer and pharmacist, pharmacists can help

identify consumers who should use the medication

through screening methods, identify consumers who

should be referred to other healthcare

professionals and also provide appropriate support

including lifestyle recommendations.

For pharmacy-care OTCs used for chronic

conditions, the pharmacist can provide ongoing

support such as monitoring for compliance and

therapeutic endpoints. To prepare pharmacists to

deliver these services, the task force recommends

that pharmacists be educated and trained about

these pharmacy-care OTCs, the appropriate patient

population that should use these products, the

product risks, what the appropriate monitoring and

follow up should be, and also procedures for

referring consumers.

Other relevant services should also be

available at pharmacies that distribute

pharmacy-care OTCs. The task force recommends that

outlets provide support services such as

point-of-care testing when necessary to identify

appropriate consumers and monitor their progress.

When such services are not available in the

pharmacy facility, referral information should be

provided.

Consumers should also be encouraged to

report the use of these pharmacy-care OTCs to their

pharmacist and their physician. The task force

recommends that pharmacists add these products to

the consumer's medication profile. Documentation

of pharmacy-care OTCs will help pharmacists

identify drug interactions, protect against

drug-disease contraindications and monitor for

outcomes.

To conclude, an OTC designated as a

pharmacy-care OTC can provide significant benefit

to our consumers. The pharmacy-care OTC approach

would not only provide consumers with greater

access to important medications that can benefit

their health but would also ensure that consumers

have access to the medication expertise of

pharmacists to help them use those medications

appropriately.

Thank you for the opportunity to present

the views of the nation's pharmacists.

DR. WOOD: Thank you very much.

The next speaker is Christopher Maus and

he will be followed by Laurie Tansman.

MR. MAUS: Thank you so much for having me

today and giving me this opportunity to speak. I

am Christopher Maus, CEO of Lifestream

Technologies. We are not here to sway the board

one way or the other as to the efficacy and safety

of Mevacor going over the counter. However, the

support of technologies that are now available to

facilitate the NCEP Guidelines, many may not be

aware of.

Right now, consumer testing is becoming

more and more prevalent throughout those people

that are what we call focused on health management.

With over 100,000 cholesterol monitors now being

used in the consumer market and millions of tests

being performed, we see the health guidance to

consumers out there taking more control of their

own personal healthcare.

Our surveys, we showed that people that

purchased these home-testing devices, that 90

percent of them had seen physicians within 12

months. Of that, only 25 percent of the people

were actually on therapeutic interventions, drug

therapies. 79 percent selected dietary, exercise

and other therapies to facilitate their goals and

objectives.

One way or the other, the probability is

that 80 percent of the people are going to

self-treat. If self-treatment is inevitable, then

technology is crucial to support this and

self-management is an important component.

Physicians, pharmacists, consumers will see

point-of-care testing as a critical role.

There are basically three types of

testing; screening, the purpose of screening which

is identifying people at risk; clinical diagnostics

which is used by physicians for the purpose of

carrying out the treatment of medicine; and

monitoring, long-term support which actually

supports long-term compliance to the outcomes.

The NCEP now recommends home monitoring

and the NCEP 3 Guidelines recommends home

monitoring as good way of increasing compliance

which is the biggest issue that confronts all

therapeutic intervention for cholesterol lowering

since compliance is so low.

Total cholesterol is also identified as

good surrogate for LDL which we think is also a

very critical component for ease of use by the

consumer. Home testing for cardiovascular

asymptomatic conditions is not new. It is very

familiar to the consumer through blood-pressure

testing.

In the market since 1972, there are about

5 million blood-pressure cuffs sold in the United

States each year for people taking control of their

own health. Those monitoring blood pressure are

very similar to consumers. 80 percent of them are

not on drug therapy.

Our product was designed and used by both

pharmacists and consumers for both the pre and post

of an intervention. One of the product has just

been recently approved, cleared, by the FDA that

actually does the NCEP Guidelines in the device.

So the idea of a questionnaire that you have to

fill out to assess the risk factors are no longer

limited to just paper in someone's head. We

actually give you quantitative outcomes inside that

device along with the cholesterol tests.

Along with that, these products are

becoming less and less expensive with new

technologies that are being introduced that allow

you actually to hook directly into the computer

utilizing the same strip and seeing the data right

on line with the same risk assessments. Not only

do we utilize the risk assessments, we have

opportunities to direct the consumer to the

physician which we actually do on the risk

assessments as submitted to the FDA.

We do body-mass index also telling obesity

and amount of overweight. We prompt people to see

physicians when required and this is a

cost-effective assessment without the assistant of

a healthcare professional but has the ability to

interact.

Right now, the technology that we

introduced was the first ever presented to the FDA

that actually allows individuals to store data on

memory cards inside devices with the NCEP

Guidelines and recommendations in the device which

is transferrable. At the physician and pharmacy

site, they have the same ability to look at this

material and assess it. It can be e-mailed,

transferred to healthcare practitioners in the

areas that it indicates.

Pharmacy care also can print out actual

recommendation problems according to the NCEP.

This is no longer an effort of expressing medical

opinion in a non-medical environment but using

statistically correct data so you have continuity

of message to each and every individual. This can

be done at home, with the pharmacist or at the

physician's site.

The record-keeping capability and

management, the portability, also, is available.

We are not saying this is the answer. All we are

saying is the technology can support the

initiatives by this committee and by people seeking

to lower their cholesterol regardless of the method

in which they are doing it.

In conclusion, technologies are fulfilling

many of the goals and considerations of this

hearing and is affordable and convenient at this

time with over 25,000 pharmacies--[microphone off.]

DR. WOOD: Thank you very much.

The last speaker that we know of is Laurie

Tansman.

MS. TANSMAN: Thank you. Let me just

preface my comment by saying my views I am

presenting are solely mine not on behalf of my

institution. Let me also say that I am a fan of

the statins. They are a remarkable class of drugs

and it seems that the positive impact they may have

on our health has yet to fully be realized.

But that doesn't qualify it to have OTC

status. There are multiple reasons for this but,

as a registered dietician, I am going to limit my

remarks as they relate to lifestyle changes and I

apologize for talking so quickly.

In the same news article that I just

cited, Slide No. 2--I am going quickly--Dr. Robert

Bonow, past President of the AHA, was quoted

regarding is ambivalent feelings about the statins

being approved for OTC. There is another problem;

human nature. People who ought to be dieting and

exercising are going to feel that, since they are

taking a pill, they can now continue habits that

are unhealthy.

In an article by Gordon, et al., it was

written, "However, because of the widespread

availability of powerful medications, the value of

therapeutic lifestyle changes, per se, in

contemporary medical practice is often discounted

by clinicians, health insurers and patients."

This is my first concern. I feel

confident that people are going to pay even less

attention to lifestyle changes and more readily

resort to medication. If they do this, then what

about the impact of not making lifestyle changes

that are a necessary treatment for other medical

problems such as obesity, diabetes and

hypertension.

But let's first address the concern about

statins going OTC for those having a mild or

moderately elevated LDL cholesterol value. Diet

therapy is a cornerstone for treatment and is the

first treatment in treating such an LDL value.

Since it is Merck that is seeking OTC approval for

Mevacor, this slide is a direct quote from the 17th

Edition of the Merck Manual as it appeared on their

website regarding dietary changes in the treatment

of mild or moderately elevated LDL cholesterol.

As outlined in this next slide, these are

the guidelines for the therapeutic lifestyle

changes diet. What can clinicians do? Well,

basically, they can instruct patients to reduce

intake of red meat and fried foods, use skimmed

milk instead of whole milk, substitute low-fat

cheeses for full-fat cheese. But how many general

practitioners as well as cardiologists have the

time in their schedule to sit with a patient for

maybe an hour and review diet records for hidden

sources of saturated fats such as the use of

coconut milk. This is a staple in food preparation

for many ethnic groups.

How many physicians are going to review

diet records to develop a useful plan with a

patient to help them realize weight loss. If we

don't provide the opportunity for a patient to

realize appropriate dietary changes, then, of

course, the TLC diet may be unsuccessful and

medication becomes the only therapeutic option.

This is the real heart of the matter. In

a quote from an article by Gordon et al.,

"Moreover, therapeutic lifestyle changes can

generally be implemented less expensively than most

medications and, unlike single drug therapy,

favorably affect multiple risk factors."

If we don't provide the opportunity for a

person to realize appropriate dietary changes,

then, of course, the TLC diet may be unsuccessful

and medication becomes the only therapeutic option.

This is the real heart of the matter and, in a

quote from the article by Gordon that I previously

referred to, "The value of therapeutic lifestyle

changes, per se, is, indeed, often discounted by

health insurers as is evidenced by the lack of

insurance reimbursement for nutrition counseling

provided by registered dieticians."

This was an issue that I addressed in an

abstract I presented at a national conference in

1998. But so much for my first concern. My second

concern alluded to earlier is that if people are

going to pay even less attention to lifestyle

changes and more readily resort to medication, then

what about the impact of not making lifestyle

changes for obesity, diabetes and hypertension.

This was also identified by Gordon et al. in that

same article previously referred to; that is,

making lifestyle changes are not only less

expensive but favorably affect multiple risk

factors.

I am getting ahead of myself. I

apologize. I have to back up so I am just going to

read this to you. Approval of statins for OTC

would mark a major turning point for this drug

class and for OTC therapy in general as identified

in an article by McKenney. If statins are approved

for OTC, then OTC approval for oral antidiabetic

agents and antihypertensives cannot be far behind.

This is what I think is really, also, the

second heart of the matter and I implore you to

really, really, think about the impact an what is

going to happen if you approve for OTC statins.

This, I really, think is more important than

anything else.

Then, just in summary, I just want to say

that if we are going to get more aggressive about

helping those with mild or moderately elevated LDL

cholesterol--

DR. WOOD: Thank you very much to all the

speakers.

Are there any other public comments that

we have missed or anyone else that wants to add to

the public record? In the absence of hearing any,

then I think what we will do is we will take a

short break and reconvene at 9:30 to start on the

committee discussion again.

Thanks a lot.

[Break.]

Questions from the Committee

and Committee Discussion

DR. WOOD: Let's begin by seeing if there

are other issues that the committee want to address

from the discussion that we had yesterday and

continue that. After that, we will begin looking

in detail at the questions so yo might all want to

make sure you have them in front of you.

But let's begin with the questions, other

issues, other points of discussion, other things

that the committee members would like to discuss.

Dr. Benowitz.

DR. BENOWITZ: I just have one question

from this morning and that is to get a

clarification from FDA I guess about whether having

a pharmacy-only program where the drug can be

provided only in pharmacies, is that something

which can be done? It sounds like--some people say

that that is not provided for in the law. It is

proposed be Merck. I just want to know can it be

done.

DR. WOOD: Does somebody from the FDA want

to take that? Charlie?

DR. GANLEY: I am not a lawyer so I am

reluctant to give a definitive, but we have never

approved anything in the behind-the-counter.

DR. WOOD: I don't think that is the

question. What he is asking is can it be sold in a

store that has a pharmacy rather than a convenience

store.

DR. GANLEY: That is still an issue of

restriction. I misunderstood the question.

DR. WOOD: Maybe, Neal, one way to proceed

would be for the committee to discuss it under that

rubric and leave the decision as to how that can be

done to the FDA and their negotiators. If we feel

strongly, on the other hand, that the drug could be

sold in places other than pharmacies, then we ought

to give the FDA guidance on that as well.

So it seems to me there are two

extremes--three extremes. One is that the drug

shouldn't be sold over-the-counter. One is it

should be sold in stores that have a pharmacist and

one is that it could be sold in any kind of store

that can sell over-the-counter drugs.

I guess one of the issues for the

committee to debate is which of these options is

reasonable and which do they recommend. Is that

fair? FDA, is that fair? Bob?

DR. MEYER: I think that is fair. I guess

I would just emphasize that one should, in your

deliberations, regard the proposal for this

pharmacy-care type setting where this is only sold

in outlets where there is a pharmacist present as

being voluntary.

The reason that I think that is important

to realize--you know, we are not saying that we

have a definitive answer on that but you should

regard it as voluntary for the purposes of your

discussion. Again, the reason that is important is

if this drug were to be switched when it were to

become a generic drug, that voluntary agreement

from the sponsor would no longer necessarily hold

for that.

DR. WOOD: Okay; that is a good point.

Dr. Fincham?

DR. FINCHAM: I appreciate that

clarification. This gets very complex quickly.

Even if it is, at first, in a pharmacy that has,

quote-unquote, a pharmacist on duty, not all

pharmacies that have licenses in any of the states

have a restriction on when other types of products

may be sold.

For example, you may have outlet that is

open 24 hours a day but the pharmacist is present 8

to 10, 12 hours. So what happens when the

pharmacist, perhaps, is not on duty. I don't have

the answer to that, but I have not seen anything

that would indicate how that would be handled or

would be done. I think it is something to at least

think about.

DR. WOOD: Dr. Woolf?

DR. WOOLF: Lovastatin is available just

generic, is it not? So what would prevent one of

the generic companies to say, I want to make this

available over-the-counter and what would that do

to whatever the paradigm is in terms of educational

programs and all those kinds of issues.

DR. WOOD: Somebody from the

over-the-counter committee want to answer that?

DR. MEYER: Again, some of this is

treading on areas that are difficult for us. The

folks here are physicians, not lawyers, so the

exclusivity situation, I don't think we would like

to speak to. But, to the extent that anything that

Merck is proposing is put into their product

labeling, that labeling will hold for a generic

product as well.

To the extent anything in their program is

not in the labeling, there is a piece of that that

you must regard as being voluntary and may not

apply to any follow-on products then.

DR. WOOLF: So then the display that was

here is not part of their label and that is

voluntary.

DR. MEYER: Well, I will let Merck talk to

some of that because I see that they are ready to

do so. But I think much of that actually would be

considered labeling.

DR. WOOD: Dr. Hemwall, do you want to

respond?

DR. HEMWALL: Yes. In fact, it is all

labeling and it has been submitted as such and

would be under total review and approval authority

from the FDA. Any changes we would want to make to

that would require prior approval before we could

make those changes. That includes everything that

you have seen in your package and those things that

are connected to the package through the proximity

in the store may also be considered as labeling.

We obviously commit in that regard. It is

under the NDA. We can't go back on it and neither

can a generic. They have to be approved under the

same terms. As you heard from the American

Pharmacists Association, the pharmacy-care is

something that they strongly believe in and, I

think, as part of their overall program, they would

not authorize a generic to then be outside of the

pharmacy-care in the same category which has been

deemed pharmacy-care as we have launched it and

created it.

DR. WOOD: Do you want to comment on the

exclusivity in OTC?

DR. HEMWALL: Pardon me?

DR. WOOD: Do you want to comment on

exclusivity in OTC?

DR. HEMWALL: Yes. The exclusivity lasts

for three years under Hatch-Waxman.

DR. WOOD: Okay. So a generic could not

come--in answer to Dr. Woolf's question, a generic

could not appear for three years.

DR. HEMWALL: Correct.

DR. WOOD: Okay. I just wanted to

get--Dr. Bull?

DR. BULL: I just wanted to bring an

example to your attention with regard to where you

have complex--what are risk management or

conditions of approval. Accutane is a drug that

has a very, very complex set of documents attached

to it for both prescribers and patients. Those are

all considered part of the approved label and were

part of the conditions of approval. So what Merck

alluded to, that their materials are being

submitted as part of the labeling, that would then

entail those being considered conditions of

approval if so approved.

DR. WOOD: Dr. Clapp?

DR. CLAPP: I have some questions that

maybe Merck and the FDA can address in terms of

labeling of the Mevacor. It is kind of a conundrum

and that is if you--you are presuming that you have

tried a healthy diet and exercise to reduce your

cholesterol, according to the package insert,

before you then proceed to take the Mevacor.

Then, once taking the Mevacor, it says,

"If you stop taking it, your cholesterol will go

back up." Then am I to presume that if you, then,

try harder with a healthy diet and exercise, could

that not make Mevacor unnecessary if that change in

lifestyle then reduces your cholesterol, and then

stopping Mevacor might not make your cholesterol go

back up.

But, the other point of concern that I

have is then should Mevacor OTC say that if you

want to continue to keep your cholesterol within a

range of normal you must take every day for the

rest of your life. Should it be very clear that

there is an expectation that this is a lifelong

commitment to medication rather than an

intermittent commitment that is based on, I guess,

your whim.

I think there was data yesterday that said

after two years only 25 percent were continuing

statins. I am not sure if that was the

over-the-counter--no; it wasn't the

over-the-counter. It was prescription statins.

So, in the public-health interest, is it

appropriate that we then make it clear to people

that, if they take Mevacor, they should consider

themselves having a commitment to this medication

that is lifelong.

DR. WOOD: I guess a number of people have

raised the issue of diet and exercise and the

efficacy of it. Somebody maybe ought to comment on

that. Tony, do you want to comment on what the

actual outcome is with diet and exercise long term.

DR. HEMWALL: Could I have Slide 174 from

the core deck, please.

While they are bringing that up, I will

answer your other questions with regard to

instructions on the label. As you have heard, we

have studied consumers very carefully and

extensively for a long time before we created the

actual final label.

They are very different in the way they

approach the information, but one of the things

that we have learned is that people sometimes think

that, once they get their cholesterol down to goal

that they are cured and that they can stop taking

the product. So that is why that message is there,

that you will go back up if you stop taking the

product.

But, certainly, the program encourages

ongoing diet and lifestyle. That is what is found

in the materials that come in the accompanying

education program and then, of course, in the

newsletters that follow, and staying on the product

for the duration of the time that you are still

getting to goal. That is why the encouragement is

to get your cholesterol tested again in a year to

make sure you are still at your goal, in which

case, you may continue to take it on a yearly basis

as you continue to monitor your cholesterol which

could extend to a much longer period, as you call

it, as a lifetime.

That would be the important thing. Now, I

am not answering your question.

DR. CLAPP: The interesting point that you

are raising is that your counseling people to

change their diet and exercise habits at the same

time that you are encouraging them to take the

medication. So if, perhaps, you have a real

compliant consumer who is reading your educational

materials and decides to change their diet and

exercise dramatically--

DR. HEMWALL: Yes; that is a good point.

The very first thing on the label--

DR. CLAPP: Excuse me. Let me just finish

my question.

DR. HEMWALL: I'm sorry.

DR. CLAPP: Is it accurate to say that

their cholesterol will go back up because which

factor is it, indeed, that made their cholesterol

go down. So who reassesses this and then can we

accurately say thatm, if they stop the medication,

their cholesterol will go back up if, in fact, they

instituted some of the aggressive diet and exercise

exercise changes that you are promoting with the

medication.

DR. HEMWALL: Those are good points. Here

is the way we tried to address that is within the

label under the heading, How to Decide if Mevacor

is Right for You. Before using, you must have

tried a healthy diet and exercise to reduce your

cholesterol. So we are asking people to already

take it to that step to make sure that that is

already--they have taken it as far as they can.

Then, they are to get a fasting cholesterol test

within the appropriate period of time and then

determine, with that, having tried diet and

exercise--and that is exactly what we saw in the

type of consumers that are interested in using this

product.

I will take the slide now, Slide 174 from

the core deck.

[Slide.]

This is a slide you saw yesterday. It is

important to point out that these people that came

to the site, 80 percent had already previously

tried to lower their cholesterol with diet and

exercise and, with regard to their change while

taking the drug, the change in dietary patterns, 58

percent of them maintained that and another 40

percent, while on the program, did improve. So

that could contribute to some of the cholesterol

lowering.

Likewise, in exercise, 70 percent and 0.4

percent improved. So there was no deterioration,

as some have speculated, while taking the product.

Could I have core slide 155, please.

[Slide.]

This is the same data. It is shown in

another way. You can see that what we did was we

administered a MedFix diet test to everybody to

really get down to a more technical measure of what

their diet was. At baseline, 36 and 47 percent

were either on a Step 1 or Step 2 diet,

respectively, with 17 percent not on a Step 1 or

Step 2 diet. That is the American Heart

Association Step 1 or Step 2 diet.

By the end of the study, many had moved

up, either from a Step 1 or Step 2 or out of the

neither diet so that, by the end of the study, 89

percent were on a Step 1 or Step 2 diet according

to the American Heart Association definition. We

view this as very, very positive in the sense that

we are keeping people to maintain their diet and

exercise and, yes, it may be a component of the

lipid-lowering that they get but it is clear that a

lot of them have already tried that when they

started using the drug.

DR. CLAPP: At that point, did you teas

out the difference by continuing the study by

stopping those who were taking them Mevacor and

seeing whether or not their diet and exercise

changes had been a major factor in keeping their

cholesterol lower?

DR. HEMWALL: No; we did not. But diet

and exercise is usually a few percentage points, 5

to 7 percent. According to some studies, we are

talking about a total lowering that was seen here

in the order of 20 to 25 percent with lovastatin.

DR. CLAPP: Do you think it is accurate to

say, then, that the labeling should--it is

appropriate to say that the consumer should

understand very clearly that, from your

perspective, that, even though they change diet and

exercise, that they will need to take Mevacor as a

lifelong commitment to keeping their cholesterol

lower? Is that appropriate?

DR. HEMWALL: I think, again, that we

could certainly consider that sort of message. But

we really want people to continue to check to make

sure that other changes in their health status

don't require them to see a doctor or that the dose

of 20 milligrams of lovastatin is no longer enough

for them to achieve their NCEP goal.

So, in other words, we don't want to give

the message that all you need to do is take 20

milligrams of lovastatin the rest or your life and

you are okay. We want to make sure that there is

ongoing reevaluation of their status and what they

might need in the future.

DR. WOOD: These are all good points.

Bob, do you want to--

DR. MEYER: I'm sorry. I want to ask a

point of clarification on Slide 155 which you just

showed. Are those the same patients contributing

to the percentages at the beginning as at the end?

DR. HEMWALL: Yes; they are.

DR. MEYER: So these are just people who

completed the study.

DR. HEMWALL: Exactly. So, in other

words, for some people, there is just a benefit of

diet and exercise even if they didn't continue on

with the drug.

DR. WOOD: Dr. Caprio?

DR. CAPRIO: We have been provided with a

number of things to read and we have listened to

many presentations but, perhaps, I have missed it.

I want to know what is the position of the American

Heart Association in this matter. If anyone knows

it, please share it with us.

DR. WOOD: In their absence, we would have

to impute that so I guess we should pass on. That

is an interesting question but I am sure they are

keen to get cholesterol lowered. Whether they want

to weigh in on this is an issue they have obviously

debated and decided not to, I think, is the

position.

Dr. Benowitz?

DR. BENOWITZ: I just had a very simple

follow-up question on the generic OTCs. If there

is an 800 number required for Merck to provide and

a generic comes out, and we think that 800 number

is important, will that be part of what is required

for a generic OTC manufacturer as well?

DR. GANLEY: That is not as easy a

question as it seems because we generally don't

require 800 numbers. But, as Dr. Bull had said, if

that is part of the conditions of approval that we

clearly specify is necessary, then it comes down to

our lawyers looking at that and agreeing that that

is something that would be part of the program.

I know it is not a complete answer. That

is the answers we deal with internally, too, when

we try to answer these ahead of time.

DR. ORLOFF: Just to follow that up, I

think the answer is, however, that it is a

possibility. So it is certainly not something that

can't happen.

DR. WOOD: I think, again, that comes back

to the options we have got and debating which one

of these we decide on and then deciding what these

are.

Dr. Fincham?

DR. FINCHAM: Thank you. Yesterday

afternoon, we heard some presentations regarding

the post-launch surveillance that might occur with

lovastatin if it goes OTC in the United States. I

am just curious what the company has done in the

United Kingdom since last may from a surveillance

standpoint.

DR. HEMWALL: We have actually done quite

a bit because that was something that is very

important and we are planning on learning as much

as we can from the U.K. and taking as much of those

learnings to the U.S. and implementing a similar

system. We have two people from the U.S. on our

planning committee there to monitor that, Dr. Randy

Juhn and Dr. Valentin Fuster.

I will let Steve Mann give a little more

of the details.

DR. MANN: We have undertaken some

general-survey work about what has happened so far

and I can show you a very small survey if that is

of help. But, broadly, we think that the pharmacy

protocol is operating much as we expected. Since

that pharmacy protocol was piloted, that is not

really a surprise.

What we are more interested in doing going

forward is to take a prospective look in a cohort

of subjects as to how the actual pharmacy model

operates, how the self-medication model operates,

in practice. As Ed has said, we have a

distinguished body of academics helping us design

that study to determine what best to look at.

But, certainly, amongst the items of

interest, we will certainly be looking at, firstly,

how well the model predicts actual risk by looking

at a subset of people and looking at their full

risk profile to check that the model is correctly

identifying people as we expect it to.

We will, then, also look at how people

comply, how they adhere to the treatment and also

to their lifestyle measures. We will, in a

subgroup of those subjects, also look at LDL-C

lowering a surrogate for what we might expect to

see in terms of endpoint reduction.

There are various other ideas under

discussion but that, certainly, will be the core

program of a prospective looking forward.

DR. WOOD: Dr. Davidoff?

DR. DAVIDOFF: I would like to get back to

this issue of whether people will maintain their

diet and exercise, which is a very interesting

question that clearly was on a lot of people's

minds. I was quite intrigued by the finding in the

CUSTOM study and, in some sense, encouraged or

heartened by that because it would be very nice to

believe that the decision to take over-the-counter

statins might actually encourage people to continue

to do things that they ought to be doing anyway

that are not pharmacologic.

But I have to also admit that I have

substantial concerns about that information in

making generalizations from the data that we have

seen. In the first place, dietary surveys, even

validated ones, they may be reliable but I think,

as everyone knows, may not be all that accurate. I

mean, in my youth, I ran a diabetes unit and I was

very familiar, spent of lot of time on diet in the

nutrition literature. It is quite clear that

self-reports of diets are not terribly reliable.

But, even accepting those data, I would

also get back to the issue of the sample here

because this was a fairly selected sample of people

who clearly had, in the first place, responded to

an ad to come participate in the study, then

self-selected to actually participate, knew they

were going to be getting some reimbursement, et

cetera, et cetera.

This is not the general U.S. public. If

the drug goes over-the-counter, it will be 260

million people who are going to have this available

to them. I would argue that the likelihood that

this finding in the CUSTOM study applies to that

broader sample is not very great and that there may

very, very well be people in the general public who

began to use over-the-counter statins who, in fact,

would feel that this was a magic pill and they

wouldn't have to continue to diet and exercise.

DR. WOOD: Dr. Taylor?

DR. TAYLOR: Actually, I would like to

take up where Dr. Davidoff left off. I agree with

you that the CUSTOM sample is a very narrow sample.

For example, were the advertisements in Spanish?

Maybe they were. That is a credit. But I am

concerned about the fact that 28 percent of your

sample was a non-Caucasian sample. I think--I

don't remember; what was a low literacy, how much

that was of the sample.

As you know, our U.S. population is

in--the non-Caucasian population is growing and, by

some date in the future, is projected to be the

majority. With that in mind, and given that this

CUSTOM study was a self-selected sample, I am

wondering if, on all the measures that you had

outcomes, like compliance, lower cholesterol,

lifestyle changes and that, that that 28 percent

perform at the same level.

Do you understand my question?

DR. HEMWALL: Yes; the 28 percent you

refer to are the evaluators and then there is a

subset of all of those that actually used the

100

product. I am not sure if we have a breakout by

race or gender on diet and exercise. Do we have

that?

DR. WOOD: You did show data earlier on

minority populations that had a high rate,

actually, as I recall.

DR. HEMWALL: This was a very common

finding in all of our surveys and those that were

done independently by the NLA and the National

Consumers League with regard to the type of

consumer that is interesting in using a product

like this, they are already very health conscious

and are doing all the things, like diet and

exercise, to manage their health and this is not

unusual that this is the type of cross-section that

would be interesting in using the product in the

CUSTOM study.

So we don't necessarily agree that it is a

narrow band of people that doesn't represent the

group that would use it in the real-world

marketplace.

DR. TAYLOR: One other question. In your

101

pharmacy promotional information, your pharmacy

intervention, how would you ensure that there would

be language compatibilities at the point of sale of

the product?

DR. HEMWALL: Language compatibilities?

Are you speaking Hispanic?

DR. TAYLOR: Hispanic.

DR. HEMWALL: Yes. Actually, Johnson &

Johnson and J&J Merck are very committed to

reaching out and marketing to the Spanish community

and have a number of programs already in place for

the programs, or the projects, that are already

available OTC. In fact, we are launching a Spanish

label for Pepsid AC this month and we have already

had Spanish-language advertising. We intend to

have that same level of Hispanic community

reach-out and other minority communities as well

for a product like this.

DR. TAYLOR: But what about at the point

of sale?

DR. HEMWALL: In neighborhoods where the

language is predominantly Spanish, we would have

102

Spanish materials.

DR. TAYLOR: But pharmacy intervention is

a critical part of what you are proposing.

DR. HEMWALL: Yes; and it would be only in

pharmacies so it would be in the pharmacists and in

Hispanic--

DR. TAYLOR: But would there be staff who

would be bilingual or be able to communicate? Many

of the patients that I see that are Hispanic don't

speak any English.

DR. HEMWALL: I don't have an answer for

whether or not individual pharmacies, in those

communities, would have bilingual pharmacists.

DR. TAYLOR: But, as a part of what you

proposing, I think that is a consideration.

DR. HEMWALL: I think it is a good idea

and that would be something we would want to make

sure that we have the proper training and the

materials in both languages.

DR. WOOD: Dr. Patten, do you want to

comment on this?

DR. PATTEN: We have heard survey results

103

indicating that the general public considers OTC

medications to be less risky than prescription

medications. That being the case, I am wondering

if there is any information available, or if it has

already been presented, I missed it and I would

like to revisit it, what are the consequences of

starting and stopping and starting and stopping a

statin.

I am guessing that, if it goes OTC, that

will happen fairly frequently as people run out, it

is a week or two before they get back to the

drugstore or the pharmacy, or they are pinched for

money this month so this is something that goes by

the board.

So I am wondering what the health

consequences are for starting and stopping,

starting and stopping, this medication at this

strength.

DR. WOOD: So the question is are there

adverse effects of starting and stopping or are

there beneficial effects in inadequate--

DR. PATTEN: Right. What happens to lipid

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levels? Do they go up and down and up down and

what are the health consequences.

DR. WOOD: Dr. Gotto?

DR. GOTTO: Tony Gotto. There is no

credible evidence that stopping a statin causes a

rebound or any increase in risk if the risk is

related to the LDL cholesterol level. As the

cholesterol and LDL go back to baseline, you would

lose the benefit of having the LDL reduced.

But you can be sure that when you stop it,

it will go back up into--related to the previous

concern, I would have a concern if you had a

statement that led somebody to think if they took

it and, for some reason, had to stop it, it would

cause some immediate reaction, have some health

consequence such as stopping, abruptly stopping a

drug like clonodine.

So that is not the case with the statin.

It is a lifetime recommendation in a sense that it

only is effective as long as you take it in

lowering cholesterol. Now, if the AFCAPS/TexCAPS

study, we did see a benefit for two years after the

105

study was over, an increased reduction in

cardiovascular events and also there was a benefit

within the first year.

But the lipid levels are going to go back

up either if you go off your diet or exercise

program or if you stop taking the medication.

There have been two studies comparing

statins with diet. One, Hunninghake and colleagues

published in the New England Journal of Medicine in

which they had a patient on lovastatin in one group

and on an American Heart Association diet, and

there was about a 25 percent or so change with the

lovastatin group and about a 5 to 6 percent change

in the American Heart Association.

There was a subsequent publication about

two years ago with a much more extreme diet, very

large amounts of fiber, nuts. It was an atypical

diet. But at least you can concoct and put

together a diet which, in that case, gave the same,

approximately the same, amount of reduction of LDL

as lovastatin.

The diet, the exercise and the medication

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all work together. I think the over-the-counter

Mevacor is aimed for healthy people who have an

interest and want to diet and exercise but need

something more than that to get down to their

target LDL levels, at least that is the intended

population. Those are the recommendations. So

this makes something available for an individual

who is not able to get there but with a combination

of diet, exercise and medication may be able to

achieve their target and reduce their

cardiovascular risk.

DR. WOOD: But, while you are up, isn't it

also true that only a very small proportion of

patients who have a validated risk are able to

adequately reduce their risk with diet and exercise

alone?

DR. GOTTO: It depends on how much the LDL

is elevated.

DR. WOOD: Right. But I meant, with

elevated risk due to LDL.

DR. GOTTO: Yes. Yes; if they have got a

markedly abnormal LDL, that is correct. It is

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difficult, also, to get patients to follow a diet,

exercise or take a medication over a period of time

and you are right. Most patients are not able to

maintain diet sufficiently adequate to keep their

LDLs in range.

There are some publications, Frank, that

there is a correlation, positive correlation,

between both diet-and-exercise adherence as well as

medication with the other two so that an

individual--people who were followed over a period

of time on a diet are more likely to maintain the

diet if they are also exercising.

They are also more likely to maintain

adherence to their medication if they diet and

exercise. So I think there is a correlation

probably related to the type of individuals who go

into a program of prevention to begin with.

DR. WOOD: They are people who know all

about everything; right?

Dr. Follman, did you want to comment

directly on that?

DR. FOLLMAN: I wanted to talk a little

108

bit about the on-and-off aspect. There is concern

maybe that use of Mevacor might be intermittent.

The discussion around this is focused on what would

the risk benefit be for an individual due to statin

interruption and then reintroduction.

I am thinking of a different kind of

potential risk would be, say, call it

desensitization where an individual, because they

have tried a statin and given up on it, will, in

future, be less inclined to seek a doctor the

period of time when their LDL is really quite high

and they really need it.

So the fact that they used a statin and

had forgotten about and thought, oh, I have tried

that statin thing. I don't need it anymore. When

they really need it, it is no longer available. It

changes their future health-seeking behavior, if

you will. So I am wondering if that has been

thought about, if it is a concern or not.

DR. WOOD: Dr. Snodgrass?

DR. SNODGRASS: My question is regarding

the CUSTOM study and maybe both FDA and Merck could

109

address this. In the low-literacy group, I thought

it was about 11 percent, was there a subanalysis of

the low-literacy group with regard to correct

choice?

MR. TIPPING: This is Bob Tipping, again.

We did look at the behavioral results from CUSTOM

in a number of subgroups, the low-lits, difference

in race, differences in age. But, specifically, to

your question about low literacy, there are 12

percent of the users who were classified as

low-literacy based on the REALM test and the

behavior was consistent that the behavior against

the self-selection messages and the behavior around

the decisions to stop use were consistent in that

12 percent subgroup.

DR. WOOD: Dr. Carpenter?

DR. CARPENTER: Another concern much like

Dr. Follman's regarding the episodic use of

statins, is there any evidence about refractoriness

to either subsequent courses of statins or

alternative behavioral methods of lipid control

following multiple on-and-off courses.

DR. WOOD: So the pharmacological

desensitization.

DR. CARPENTER: Correct.

110

DR. WOOD: I guess the answer is no, but

someone else may want to answer that.

DR. PASTERNAK: There is considerable

evidence that there is no resistance that is

developed by going on and off because, in the

course of studying all of these drugs, not just

Merck but all of the pharmaceutical companies

studying statins, many of the trials are, in fact,

done exactly that way with on-and-off periods.

DR. CARPENTER: Thanks. A second question

has to do with anecdotal comments I have heard

about abuse of statins in eating disorders. I

wondered if there is any other potential for abuse

of these medications.

DR. WOOD: Let's just make sure people

understand the question. There is a suggestion

that particularly young women abuse statins

sometimes because they believe that fat is bad and

something that reduces fat will make them slimmer.

111

Is that a fair summary of what you are trying to

ask?

DR. CARPENTER: Correct.

DR. WOOD: Okay. Does anyone have data on

that one way or the other?

DR. CARPENTER: Or other potential areas

of abuse of these medications.

DR. WOOD: But maybe a statement that it

doesn't do that would be helpful.

DR. HEMWALL: I don't even know the

reports that you are talking about so I--do any of

our experts? Have they heard of this before? No.

DR. CARPENTER: This is not published.

DR. HEMWALL: It may be something one

would try but it probably doesn't work, so the

positive reinforcement wouldn't be there.

DR. WOOD: Dr. Clapp?

DR. CLAPP: I wondered if Merck has done

any postmarketing research from when you

direct-market to consumers a medication like you

said Prevacid, have you studied to see whether or

not consumer behavior is appropriate in terms of

112

the usage in determination that their purchase is

appropriate for the complaint that they have and,

if so, could you extrapolate that to consumer

behavior that you predict, not just from the CUSTOM

study but--how does direct marketing to the

consumer affect purchase behavior that differs from

solicitation for a study like the CUSTOM study?

MR. HANSON: I don't have the exact data

but I can tell you Johnson & Johnson had to switch

a monostat. We have been doing postmarketing

studies on monostat since its approval around 1990.

So, as it went from 7-day to 5-day to 1-day to

cream to pill, each one of those has been done,

looked at, from a postmarketing standpoint in

conjunction with the FDA.

So, if there are any issues, we certainly

go back and address those. I just don't have the

data. But there is precedent for postmarketing

with an OTC.

DR. WOOD: Dr. Tinetti?

DR. TINETTI: My question relates to

yesterday when we heard about the treatment gap. I

113

interpreted the data that the benefit to the

population, because the benefit to the individual

is pretty small, given their absolute risk of

having an adverse event, was predicated on the

total population who are eligible for this

medication having access to it.

This morning, when we were concerned about

some safety issues, I heard a much narrower

definition that it would only be the people who are

"interested in their health" and have high health

literacy that would be most likely the people that

would access this medication.

So I guess I would appreciate some comment

from the people, who they really think the target

group is for this medication and how that actually

affects the public-health benefit. It would

certainly mean we need to know what percent of the

population meet the criteria that you just

mentioned would probably be the takers of this

medication.

DR. WOOD: So your question is, is it

aimed at people with the anal group or the people

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without health insurance?

DR. TINETTI: No. Yesterday, we heard

that it was aimed at the entire population of

people who meet criteria. In response to Dr.

Davidoff's comment, it was concern about people

taking this medication and whether or not they

would stop exercising and diet, et cetera.

We heard that probably the people that

would take this medication are those who are

overall adherers. That is my question, which--we

are hearing two sets of target population and what

effect, which one do they really think and what do

they really think is going to be total

public-health benefit.

DR. PASTERNAK: It is, I think, a semantic

point and I think we will have a two-part answer

today. The target remains the target. The target

is the target as defined by NCEP, ATP 3 is

moderately high in moderate-risk people. So that

is the target.

The question, though, and I think it is

important one, goes to who, among that target, are

115

likely to use it. That is not target. That is

use. And that is where we have information to

share with you.

MR. HANSON: I would like to look at slide

1978.

[Slide.]

As Dr. Pasternak said, we are targeting

everybody who is at moderate risk treatment-gap

section. However, we have found, and I mentioned

the 34,000 people we have talked to in the past

seven years, very strong consistency in the market

research we have done, quantitatively as well as

the CUSTOM study.

I think this is very relevant for a lot of

the discussions that have taken place today because

it shows along each of the columns some of the

issues discussed. So what this looks at are these

are the likely people who are likely to take action

and try and OTC. You will see whether it was done

with market research, done by Merck or done by

outside organizations with regards to diet and

exercise, their doctor visits, whether they are

116

likely to see a doctor in using this, whether they

use vitamins and supplements. Everything is very

consistent.

So, although we are targeting a population

that is 15 to 20 million, what our research says is

it is going to be much more selective than that.

It is going to be these people who are interested--

DR. TINETTI: What number is that?

MR. HANSON: That will in the range of 3

million to 5 million people. Again, that is very

rough.

DR. TINETTI: So, if it is 3 million to 5

million, then how does that translate into the

population benefit of this medication?

MR. HANSON: I will ask Dr. Cohen to

address this, show this, from his core slide.

DR. WOOD: Just before you leave,

presumably, of course, that is all predicated

before an advertising blitz starts.

MR. HANSON: Actually, these studies

simulate what will happen with advertising because

we actually do these to forecast sales from a

117

business standpoint. So what we do is we show

consumers an advertisement, simulated

advertisement, in a general population.

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

But if you start advertising OTC medicines, then

groups that have not thought about lowering their

cholesterol will be exposed to that in a way that

they have not been up to now.

MR. HANSON: That's true. But the way we

simulate this is we do go to a general population,

whether they are interested in cholesterol or not.

We show them an advertisement for OTC cholesterol.

We tell them the price and the numbers that I am

quoting are the ones that say, after I have seen

that, whether I am interested or not, these are the

ones that say they are going to buy.

It is not real-life but we try to

simulate--

DR. WOOD: If you went out and asked

people about TEVOs and, if they have never heard of

TEVO, they won't know about it. If you have an

advertising blitz for it, you will know about it.

118

So you extend your proportion of people enormously

at that point.

DR. COHEN: Jerry Cohen. Thank you. That

is a good question. Just to reiterate, yesterday,

I identified the treatment gap and the size of that

gap was between 6 million and 15 million people in

the moderate-risk group. What we estimated was, in

that gap that we have identified by the label,

approximately 3 million to 5 million additional

people will come on to therapy.

When we look at the public-health

benefits, it applies to that group. As I mentioned

yesterday, this is not a panacea. It is not going

to fix the entire treatment gap. But if we have a

million patient years, a million people using the

drug over the ten years estimated, we would see a

reduction between 20,000 and 35,000 coronary

events. That is the huge public-health impact.

DR. TINETTI: What adherence rate did you

use to calculate that?

DR. COHEN: We used an adherence rate of

people persistently taking the drug.

DR. TINETTI: For ten years.

DR. COHEN: Yes.

DR. TINETTI: 100 percent.

119

DR. COHEN: Per 1 million. That is for

just a million. If it is 3 million who continue to

persistence over the ten years, you can multiply

the 25 times 3, et cetera. Or you can reduce it

proportionately as you wish.

DR. TINETTI: So, in the perfect--

DR. COHEN: But that means persistent

taking ten years, a million patients, this is what

we would see. And we saw earlier the persistence

data is very, very good. It is just as good as was

pointed out earlier in the Rx treatment.

DR. TINETTI: The only persistence data we

have are randomized controlled trials over five

years, not actual use.

DR. COHEN: The CUSTOM data that was

shown--

DR. TINETTI: That was only for six

months.

DR. COHEN: Six months; correct.

DR. TINETTI: That is only six months

which doesn't tell us very much about ten years.

DR. WOOD: Are you finished with your

response?

DR. COHEN: Yes.

DR. WOOD: Dr. Clyburn: That was actually

120

my question but I want to follow up a little bit.

When we talk about target populations, the vast

majority of the patients in the CUSTOM study didn't

meet your eligibility requirements. So does that

modeling hold true given that the vast majority may

not be in that moderate-risk population?

DR. HEMWALL: The model that Dr. Cohen

described applied the exact parameters of the

CUSTOM population, the CUSTOM population, itself,

not the target population.

DR. WOOD: Dr. Schambelan.

DR. SCHAMBELAN: This is probably an early

question, but, since you have had six months

experience in the U.K. and I realize that you are

planning to do an assessment of outcomes, do you

have any idea what the sales have been and, in

121

particular, what is the target population in the

U.K. compared to the 3 million to 5 million that we

have heard about here in the U.S.? Six months.

DR. MANN: I have to say, what we have

tried to do in the U.K. is a staged approach to

this. Our first concern has been to make sure that

the model in the pharmacies is working so that when

people are stimulated to go in and talk about this

that they get a good response.

So we have really concentrated on that for

the moment. Television advertising has only begun

on Boxing Day, the 26th of December of last year.

So I think it is early to say what the consumer

response will be.

I think it is fair to say, though, that in

the U.K., because we are starting from a level of

population knowledge about coronary heart disease

that is probably considerably less than it is in

the United States, we do expect it to be a fairly

slow build and we anticipate a lot of education

being needed on a population level to get people to

understand that this is a concept that may apply to

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them.

But, in terms of the total population, the

total population gap, proportionately, in terms of

the population, it is very similar to the United

States.

DR. WOOD: Dr. Parker and then Dr.

Follman.

DR. PARKER: I wanted to talk for a couple

minutes and hear where the FDA might be as well as

where the sponsor might be on the issue relating to

advertising. Obviously, we have the results of the

actual-use study which show us that there were many

people who self-selected incorrectly for whatever

reason. My guess would be they didn't understand

what they needed to do and it seemed like maybe it

would be a good idea.

So, perhaps, there was some sort of

persuasion that led them to decide to do this. I

am not really sure because we don't know a lot

about those people. I would like to know a whole

lot about those people because that really concerns

me. But we don't have a lot of information on

123

that.

But I know that, were this product to go

over-the-counter, it would be heavily advertised.

There is a slippery slope, however you define it,

between advertising and educating the public.

The requirements for the label are that

the ordinary person can understand what they need

to know based on what they read on the label. I

think the actual use calls to question the ability

of many people to be able to do that.

Advertising takes it to a new level.

There was some mention yesterday of perhaps--and

advertising is not under the control of the FDA.

It is under the control of the FTC. So I am

wondering--there was a slight mention yesterday

that perhaps looking at the FDA having a stronger

role in regulations regarding the advertising, and

I am wondering, perhaps, how the FDA feels about

that. But I would also wonder whether or not the

sponsor might be willing to partner with FDA in

trying to see that happen.

DR. WOOD: I doubt the FDA is going to

124

answer that.

DR. GANLEY: Please write to your

Congressman.

DR. WOOD: Right. I thought that. So the

message is advertising should be under FDA control

but there is not a public statement to that effect

from anyone.

Dr. Follman. If there is anyone else

wants to talk before we start on the questions, you

had better indicate it now. Go ahead.

DR. FOLLMAN: I wanted to talk a little

more about the treatment gap and the potential for

underdosing. Dr. Cohen just mentioned--we had a

brief discussion about the 1 or 2 or 3 million

people that they expect would be brought in who are

moderate risk under an over-the-counter program.

The presumption is, and I think it is a fair

presumption, is that they would get benefit from

receiving a statin. I think that is unquestioned.

So we can do some calculations. Actually,

the calculations I will be describing briefly are,

given an article by Dr. Brass and so I am changing

125

them slightly, but I think they will help inform

the discussion now.

If we have an individual who is in the

center of the target for Mevacor OTC, say, with an

LDL of 150, and they have a Framingham risk score

of 0.15, and they are brought in to use

over-the-counter Mevacor, their risk will go down

by about 20 percent, say. So the risk of death

will go from 0.15 to about 0.12.

If we translate that to 100 people that

are brought in, we would expect three fewer CHD

events for these people that are brought in. So

that is on the plus side. There is no question in

my mind about that.

On the downside, though, there is a

concern which is mentioned in Dr. Brass' article

about underdosing. So, in the CUSTOM study, we did

see that about a third of the patients had LDLs

larger than 170. So, if they had optimal therapy,

they would reduce their risk even more than they

would reduce it with Mevacor at 20 milligrams. So

the calculation you can do is you assume that a

126

person with a Framingham risk score who is

inappropriately taking over-the-counter medication

reduces his risk by a little bit so it will go down

to about 24 percent.

If that person is optimally treated, his

risk will be cut in about half and his risk of

death will be about 15 percent. So if we bring in

100 people into OTC over-the-counter therapy when,

in fact, they would have been getting optimal

prescription therapy, we have caused nine more

deaths.

So, to balance this in a simple way, you

could say, if we bring in three new people,

moderate risk, for which it is intended, but we

also bring in one person who should be on optimal

therapy but is now getting Mevacor

over-the-counter, we are indifferent in terms of

the population-based risk:benefit here.

So it is not just bringing in these

people. There is this concern about underdosing.

Now, I should say that these calculations

I have described here which were also given in Dr.

127

Brass's article, are, under certain assumptions, a

person with an LDL of 150 versus 200 and so on.

But the important point, I think, not to get too

specific, is that there will be some underdosing

and it is much worse to have a person go from

optimal therapy, or what would have been optimal

therapy, to under-therapy. That is worse than

bringing in someone who is at low to moderate risk

into something that gives him a moderate benefit.

DR. WOOD: That is true, of course, but

just to make the other side of that case, every one

of these people had the opportunity to get

prescription therapy right now and, for whatever

reason, didn't avail themselves of that

opportunity. I guess, secondly, perfection is the

enemy of the good. People are not being denied

therapy because of that. It is that they are not

currently, for reasons we don't fully understand, I

guess, are not availing them of that right now.

DR. FOLLMAN: It is a fair point. So,

like the person in Arizona Dr. Schade alluded to

yesterday who is at high risk and not going to do

128

anything, if he is not going to go get prescription

statin and he does get a statin maybe underdosed

with OTC, that is in that plus, too. So we don't

really know the full dimensions of this.

There is some concern about under-dosing.

It is complicated and I just want to frame the

argument here and point out that under-dosing is

more of a concern, I think, than bringing in people

who would not be getting statins otherwise in the

moderate-risk group.

DR. WOOD: I am not sure I understand

that. I am going to keep that line of conversation

going. I mean, by offering therapy to people, you

don't preclude others who should avail themselves

of a different therapy from getting it from their

doctor.

DR. FOLLMAN: No, you don't. But--

DR. WOOD: Hang on. There is a sort of

philosophical issue here, sort of almost

libertarian issue, that should you deny the right

to people who want to take something because other

people are behaving inappropriately. That is an

129

issue the committee is actually going to have to

grapple with, I think.

The people who have LDL's over 170, which

I thought was interesting in the sponsor's

document. There were people in there with LDLs

that were extraordinarily high and, interestingly,

these people seemed to consult their doctor and get

advice about which 3A4 inhibitors they shouldn't be

taking which seemed improbable to me, that if the

doctor hadn't treated their LDL. That these same

doctors were sort of experts on drug interactions

just seemed to me a little hard for me to swallow.

But I was surprised that they didn't sort

of raise that. I am grappling with that but I am

not sure that we have exhausted that topic. So go

ahead.

DR. FOLLMAN: I think that is an extremely

common concern initially. In fact, when I first

heard about this option and when colleagues,

clinical colleagues, of mine react to it, the

concern is exactly what was just stated. I think

the data, both the data from studies that were

130

submitted to this panel in 2000 and in CUSTOM

suggest, however, that that concern is invalid,

that, as Dr. Wood just said, this is not taking

people away from the medical system.

You can debate how much it is driving them

into it but there is no evidence that it is taking

people out of that. In terms of the medical

system, even former Presidents being cared for by

physicians stop taking their statins.

DR. WOOD: Apparently on their physicians'

advice, we were told in the paper. Sorry; I will

let you finish. Go ahead.

DR. FOLLMAN: Just to finish up. These

studies are all done in the prescriptions world and

so people who do come into the CUSTOM study, et

cetera, weren't getting statins. I am thinking

about the individual in this over-the-counter world

who would have seen a doctor and gotten optimally

dosed but, in this hypothetical over-the-counter

world, he doesn't bother to see a doctor. He

thinks, well, I will take care of it myself with

Mevacor over-the-counter, and, hence, he is

131

underdosed.

So there is this concern. The studies

that were done have been done in this prescription

world. I don't think we really know to what extent

this will be a problem, in which way the balance

will tilt at the end of the day.

DR. WOOD: Okay. Good point.

Two more questions and then we are going

to turn to the FDA's questions unless there are

people with compelling points. Now is your moment.

Dr. Woolf.

DR. WOOLF: I would like to come back to

the issue of teratogenicity that was raised

yesterday and we were provided with a lot more data

this morning. Back of the envelope, we are told

that roughly there are 5 million Americans who are

likely to use the product the way the company hopes

it will.

There are roughly 5 percent of the CUSTOM

women were 40 to 45 years of age. I have no idea

what their fertility rate is but that is roughly a

quarter of a million women. Some of them will get

132

pregnant on this drug and there are some concerns

that were raised this morning that, I don't think,

certainly, can be ignored. We don't know what the

magnitude is but I don't think it is trivial.

So I wonder, given this information, what

the company will do when this goes out into the

real world and people can walk past the display and

say, oh; I think I am going to improve my heart for

the future and take the drug without really looking

at it quite as closely as they need to.

DR. WOOD: So you are talking about the

pregnancy risk.

DR. WOOLF: Yes.

DR. WOOD: We are going to come to that

under Question 4. Just to keep us moving, I think

we are going to have plenty of discussion, I

suspect, at that time. So would you be agreeable

to deferring that until we get to that actually on

the questions.

DR. WOOLF: Absolutely.

DR. WOOD: Dr. Benowitz.

DR. BENOWITZ: I wanted to ask and follow

133

up on a comment I think Dr. Wolfe made about a

potential adverse effect of peripheral neuropathy

quoting three case-control studies. This was

something that we hadn't heard about before and I

was not aware of it. I am just curious to know

more about that, what the data look like.

DR. WOOD: Who was it that quoted it? Oh;

Sidney Wolfe. Okay.

DR. LEVINE: A lot of these studies are

hard to interpret because a lot of these patients

who are taking statins are also diabetic or have

other things, and they have peripheral neuropathy

from that.

We actually have looked at EXCEL and

AFCAPS for peripheral-neuropathy adverse events and

there is no difference between actives and placebo.

In our WAYS database, actually, the reporting

rate--we have about 363 reports on peripheral

neuropathy and, with the 27 million patient

treatment years, the reporting rate comes out to

1.34 reports per 100,000 patient treatment years

and the background rate is 7 to 15 cases per

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100,000 years.

So our reporting rate is less than what

the background treatment rate--if there is an

association, it seems to be very rare. I think the

benefit would outweigh the risk.

DR. BENOWITZ: I am just curious. What

were the odds ratios in those three case-control

studies? Were these large odds ratios or small of

what? I have no idea what any of the studies

showed.

DR. LEVINE: I don't know. I just have

our data.

DR. WOOD: Does the FDA know that? Is it

currently in the warnings or precautions?

DR. ORLOFF: No; but I think we would

agree with the sponsor's assessment.

DR. WOOD: All right.

Dr. Neill?

DR. NEILL: Because I think we are going

to be discussing these eight questions real quickly

and because I find myself rethinking same thoughts

at each question and because I believe each of us,

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as a committee and probably audience members, are

interested in having this be as focused a

discussion as possible, I feel compelled to just

share briefly some of the concerns that I have.

First, I want to summarize what I have

heard over the last day and a half. First, this is

a large public-health problem and that it can be

fixed by taking Mevacor OTC it is going to fill a

treatment gap and we are going to increase, even,

people who are high risk taking statins and that is

an added benefit and, because we have failed to

meet that public-health goal of increasing the

numbers of people on statin, we are being asked to

consider implicitly, if not explicitly, changing

what constitutes the OTC-ness of a condition, and,

instead of focusing on relief of symptoms,

self-diagnosis and monitoring and the ability to

carry this out in the absence of a learned

intermediary, we are going to be focusing, instead,

on a patient's ability to self-select, the ability

to adhere to recommendations from a box and the

ability to access a learned intermediary when

136

needed.

Implicit in each of these is a

risk:benefit ratio for an individual patient that

is favorable across the board.

I have also heard that this switch would

be safe, although there are questions about

interactions with the number of medications and

other herbal preparations and questions about its

use in pregnancy. I have heard that, even if it is

not safe, that the people who don't self-select or

who might not appropriately self-select using those

other meds or being pregnant are probably going to

benefit anyway. I will be honest. I think that

may be true.

I have heard that it is effective based on

AFCAPS/TexCAPS data that, I fear, is not

generalizable to the OTC setting and is based on a

proxy LDL measure of use over six months rather

than a real outcome of interest to me which is

whether my patients live longer or suffer fewer

heart attacks or strokes.

I also have heard that patients can

137

self-select appropriately and that, if they do make

a mistake, as I said, that they will still get from

benefit.

Lastly, I have heard that patients adhere,

if only for six months. One thing I have learned

as a family physician is that I no longer ever say

to a patient, you must be on this medicine for the

rest of your life. There are two reasons for that.

The first is something better always comes along.

The second is sometimes we know better and you have

got to change for that reason.

Unfortunately, both for the FDA and for

Merck, sometimes we know better and medicines leave

the market. Unfortunately, when something new

comes along, it typically is always more costly and

less available to the patients.

Now, we are about to talk about eight

questions and we have been given some very careful

guidance from the FDA almost like jury

instructions. I was talking with one of staff

earlier in terms of how we will think about these

things. The good thing about being a jury is, once

138

we get the instructions, unlike the FDA that cannot

and does not consider cost or public-health

benefit, we can pretty much consider what we wish

to.

The kinds of things that I consider are

that having more people on Mevacor would improve

the public health and I honestly believe that that

is the case. And I believe that Merck, as a

company, deserves a lot of praise, both for

bringing this class of medicines to the market, for

innovating, for taking the risks to even ask this

important question, should we consider a new class

of OTC.

If we have failed so miserably in the

public-health arena as to have this many people not

being adequately treated, then is this something

that we could try instead. And that is, I think, a

real and valid question. It is not going to be

answered by this group but it is a good question to

bring up and I am sorry if, in some respects, Merck

ends up as a whipping boy because your history, as

a company, does not deserve that. You are some

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good folk.

Okay. Having said that, I do have one

last--sorry--I recognize that there are some other

motivations that are at work here. I recognize

that there is an interest in expanding a market

share. This is a good thing if it gets more people

on medicine.

I realize that there is an interest in

increasing marketshare, however big it may be, and

that somebody is going to get three years of

exclusive rights to OTC marketing, and I do believe

marketing will happen.

Lastly, I recognize that the changing OTC

Mevacor is only one way that we can meet this

important public-health goal. We have heard about

a lot of others including health and diet and I

trust that most of you listening, like my patients

and like myself, understand that it is hard to do

the right thing when you are reaching for ice cream

in the refrigerator, when you sit in a meeting for

two straight days and don't really have the time to

do the physical activity that we are told by the

140

federal government we would be doing every day.

As a result, I don't think that this is an

appropriate way to address this important

public-health issue. It is not an appropriate

model for other chronic-illness management. I

would not be interested in sitting through meetings

about anti-hypertensives and oral anti-diabetic

medications. We do not know enough about the

ability of mass-market campaigns to effect change

at the public-health level.

What we do know is that, despite JNC7 and

NCEP and all of the other federal and public-health

programs that have been around to bring these kinds

of issues to the awareness of the American public

and that have cost a lot of taxpayer dollars, there

are other efforts--Atkins comes to mind--that have

not only made money but have been more effective at

bringing these messages in front of the people.

Perhaps competition is a good thing in

this regard. That is another reason why I applaud

Merck for asking this really tough question. I

think having competition across the market is a

141

good thing but the best way to handle this is

through some kind of coordinated public-health

marketing effort.

I am a little saddened that FTC and FDA

can't speak, that HHS or we, as the public, can't

get to the point where we can discuss, in some

controlled and considered way, things that, in the

U.K., have been able to be discussed. I appreciate

that, in the U.K., Zocor is OTC. I think it is

wonderful. Many things about what happens in the

U.K. I would love to have here. They spend a

fraction of their GNP on what we spend.

Without talking about the value that they

get for that dollar, if nothing else, if, by

switching to OTC, I could get some agreement that

we are going to reduce our overall health spending

to that sort of level, I would say, great. Let's

go for it.

Now that I have got that off my chest, I

am going to be as quiet as I can for the rest of

the day. Thank you.

DR. WOOD: Okay. Looking at the weather

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outside, you could feel right at home in the U.K.

The final word before we take the

questions is from Dr. Patten.

DR. PATTEN: Thank you and I am sure my

question will not be nearly as eloquent as my

predecessor here. I have a couple of questions

about the possibility of inappropriate dosing and I

would like to refer back to the hypothetical

patient that comes in with an LDL above 170 but

makes the decision to use Mevacor OTC.

What are the possibilities that a

pharmaceutical aid, let's say, would say to the

person, well, just take two a day, or that the

person, himself or herself, would conclude, well, I

will just take two a day.

So, if you have a person on what amounts

to OTC 40 milligrams a day, what are the possible

consequences to be taking that dose relatively

unsupervised.

My other question about inappropriate

dosing has to do with the person who is within the

desired range but we are talking about people very

143

concerned about their health. I am asking about a

person who might fall into the category of the

worried well.

There is a great deal of information

available to the public about, "lower it; lower it;

lower it; the lower the better." So someone

decides, well, I will just buy myself this little

added increment here of health or safety or risk

aversion. Has there been an arm of a clinical

trial looking at impact of 20 milligrams over a

sustained period of time on a person whose LDL is

already in the optimal range?

DR. HEMWALL: There are a lot of questions

contained in there. I will try and address them.

DR. WOOD: Let me try and summarize what I

think I heard the questions.

DR. HEMWALL: Okay.

DR. WOOD: Is there a risk from taking

more than one tablet a day, namely two, and you

might want to put in context the prescription dose

is up to 80 milligrams.

DR. HEMWALL: That's correct. The

144

prescription dose is up to 80 milligrams and I

think that if someone were to take--on the question

of whether or not they should be doubling up on

dose which, by the way, we found very, very little

evidence of in the CUSTOM study, the question might

be raised, No. 1, the doubling of dose only gets

you another 6 percent of lowering so it is not like

a doubling of effect. That is just in terms of the

pharmacology.

Second, if someone is being advised along

those lines, they would probably also consider the

economic impact in that buying two boxes a month of

an OTC 20-milligram dose is probably going to be

more expensive than getting generic paid

out-of-pocket for even a 40 or 80-milligram dose in

prescription. So there would be an economic

disincentive to actually behave in that way.

The second part of the question was

related to if someone was lower in the range, say,

even below 130, and they took 20 milligrams for an

extended period of time, I believe there is a large

body of evidence that says even those folks would

145

benefit although their absolute reduction may be

relatively less because they are starting at a

lower level of risk.

Certainly, Dr. Pasternak could address

that further, but there would still be benefit.

DR. PATTEN: What was the nature of the

question in the CUSTOM study that got at this

issue, whether or not a person would ever consider

taking more than one of these a day. Was that

specifically asked?

DR. HEMWALL: We monitored how many boxes

they purchased and how many pills they returned at

the end of the study and then tried to do the

calculation of how many days they were actually on

drug.

Now, one of the things that we had to keep

hands off on with the consumers was actually

keeping a diary card because, once you ask them to

keep a diary card, then you are taking away the

hands-off approach and you are trading an

artificialness which has them actually marking

every day that they took the pill which would,

146

then, possibly be criticized for not being

realistic and naturalistic.

DR. GANLEY: Can I just follow up on that

because I think she asked a very important question

and I am not sure it was directly answered. It is

a population of people who have what would be

considered a normal LDL or a low LDL and take the

medicine for a prolonged period of time. Are there

adverse events associated with that that we are not

aware of because that is generally not the

population who sees it on the prescription side.

So it is a very important question because

there are a lot of people out there that take

dietary supplements for their cholesterol health.

These people may get pulled into this. So I think

it is important to understand are there any data

that has looked at that.

That is, I think, what your question was

trying to get at.

DR. WOOD: I guess there are data that

have looked at driving the LDL down to 70 and 80.

So maybe we should hear that.

DR. GOTTO: There are patients, people,

who have familial hypobiliuric proteinemia who go

through life with levels, very low levels, of

147

cholesterol and LDL and, except for some minor

transport abnormalities across the red blood-cell

membrane, there are no abnormalities that you can

detect with having very low levels of cholesterol

or LDL.

In a number of the trials that are either

ongoing or some I have been involved with such as

the MIRACLE trial and the PROVEIT trial where there

were very low levels of LDL, there was no toxicity

associated with it.

So I think, at 20 milligrams of Mevacor,

there is no clinical evidence that taking 20

milligrams of Mevacor in someone who is below the

range will do any harm.

DR. WOOD: Aren't there data that you

addressed that getting your LDL down 70 may have

some benefit.

DR. GOTTO: Yes. That certainly is the

case and some of the patients in the Heart

148

Protection study had lowere levels. Then the

PROVEIT study, with acute coronary syndrome

patients having a LDL of 70 was better than--or 64,

actually, was better than having one at 94.

DR. WOOD: Just to reassure people, and

this is a question, there does not appear to be any

generic--unfortunately choice of word--but any

generic adverse effect of driving your LDL down to,

say, 70.

DR. GOTTO: That's correct.

DR. WOOD: Then let's move on to the

questions.

Questions to the Committee

In order to try and get us to go through

these as efficiently as possible, what I would like

to suggest we do is we try to confine our

discussion to each question as we address it

directly. You will see other issues come down

below, but let's try and avoid bringing these up

until we get to that question, just to try and

focus what we are talking about.

The first question, which you should all

149

have in front of you, and I will read it to you;

taking into consideration the efficacy data from

the various trials plus any additional information,

and I would remove "provided by the sponsor"

because there is plenty of other information as

well, please respond to the following questions.

Firstly, does the proposed target population merit

treatment with a statin to lower cholesterol and

thereby reduce heart-disease risk? Secondly, has

the sponsor provided adequate rationale for the use

of the fixed dose of lovastatin 20 milligrams to

lower cholesterol and heart-disease risk in this

population? I would ignore the example right now

because I think there are other issues there, too.

So, let's start with Question a.; does the

proposed target population merit treatment with a

statin to lower cholesterol and thereby reduce

heart-disease risk. Discussion? Sorry, David; do

you want--

DR. ORLOFF: I just want to give two

minutes on the way these questions were structured,

just to be sure.

DR. WOOD: Start the clock. Just kidding.

DR. ORLOFF: So that I hope there can be

less confusion. The first four questions really

150

relate to the intrinsic safety and efficacy

qualities of the drug at the dose proposed and ask

for judgment based upon the review of the data

presented, recognizing, of course, that there are

data lacking, specifically, to answer these

questions where true judgment is necessary, but for

your best answer on these. So these are intrinsic

qualities of safety and efficacy of the drug.

Questions 5, 6 and 7 go to the CUSTOM

actual-use study results. We ask for your judgment

as to what those results imply with regard to the

safety and efficacy of Mevacor OTC according to the

proposed program.

Then, of course, the last question is the

ultimate one.

DR. WOOD: As they say. All right. Is

that helpful to people? Are there any other

questions you want to ask the FDA directly before

we begin the discussion that would clarify your

151

understanding of what we are supposed to be doing?

In the absence of that, let's move ahead. Any

discussion? Okay. Nobody wants to discuss this

before we answer the question?

Let's move through the question then; does

the proposed target population merit treatment with

a statin to lower cholesterol and thereby lower

risk. Am I right that Dr. Ryder can't vote? So we

will start with Dr. Woolf.

DR. WOOLF: My answer is yes.

DR. BENOWITZ: I would say yes but only in

the context of the sort of compliance that was seen

in clinical trials taking the drug for five years.

DR. ORLOFF: Again, the intrinsic quality

of the drugs. We thank you for that comment. It

is implied. This is really a question, is there a

rationale for treating these people.

DR. WOOD: I guess as we go through all of

these questions, it is important to sort of keep in

mind that perfection is the enemy of the good here.

I think that may be even truer in OTC settings than

in Rx settings, although much of the data we have

152

seen speaks to the inadequacy of the Rx efforts as

well.

Okay. So, Neal, you are giving a

qualified--

DR. BENOWITZ: Yes.

DR. WOOD: Yes; a qualified yes. Keep

going.

DR. CAPRIO: I would say yes.

DR. BLASHKE: Yes.

DR. CARPENTER: Yes.

DR. PARKER: Yes.

DR. FOLLMAN: Yes.

DR. PATTEN: Yes.

DR. McCLUNG: Most patients in that group

deserve therapy.

DR. WOOD: Sorry; say that again? I am

not sure we got that.

DR. McCLUNG: In the target group, there

is a range of risk. Overall, the average risk in

this population merits therapy but there are

patients in this target group whose risk is

relatively low compared to the others in the group

153

and it is not convincing that either, from a

risk:benefit ratio, or, certainly, from a

cost-effectiveness standpoint, that therapy for

everyone in this target group merits therapy

always.

DR. WOOD: So, pull the lever. Is it yes

or no?

DR. McCLUNG: It is yes if you have to be

categorical. But there is always--it is not quite

so clear.

DR. WOOD: Put him down as maybe. Let's

go back to Dr. Davidoff who missed his chance to

vote. We will come back to you at the end, Frank.

DR. CLYBURN: Yes.

DR. MAKRIS: Yes.

DR. CLAPP: Yes.

DR. SCHADE: Yes.

DR. TAYLOR: Yes.

DR. SCHAMBELAN: Yes.

DR. WOOD: Yes.

DR. TINETTI: Yes.

DR. WATTS: Yes.

DR. NEILL: Yes.

DR. WIERMAN: Yes.

MR. SCHULTZ: Yes.

154

DR. FINCHAM: Yes.

DR. SNODGRASS: Yes.

DR. WOOD: Dr. Davidoff?

DR. DAVIDOFF: Yes.

DR. WOOD: So you need to vote. She

hasn't got a vote for you.

DR. McCLUNG: Yes.

DR. WOOD: Thank you. So we have 25

yesses and no no's. Remember, you can abstain if

you really want to, if people are unsure of what to

say.

The second part of this question, then;

has the sponsor provided adequate rationale for use

of a fixed dose of lovastatin 10 milligrams to

lower cholesterol in heart disease in this

population. Let's have discussion on that point

first.

DR. TINETTI: I think he question is

really different if you include or not include the

155

part in parentheses.

DR. WOOD: I understand that.

DR. TINETTI: And you told us to ignore

that.

DR. WOOD: I would like us to do it with

and without that part because I think it does--

DR. TINETTI: It is a very different

question.

DR. WOOD: I think it significantly alters

the question. That is why I wanted to do it both

ways first, if that is agreeable to people.

DR. TINETTI: So we are going to vote

twice, then?

DR. WOOD: Maybe we should discuss it with

and without and see if that helps us. How about

that? Mary, do you want to head that off and

explain why you think it is--

DR. TINETTI: I think the big difference

is whether or not there is enough evidence to

suggest that a sizeable proportion of the

population will be able to reach this level. The

problem is we don't really have those data. The

156

CUSTOM study is not able to do it and the

randomized controlled trials are a very select

population. Even they were only for five years.

So the problem is we don't have any

information on the second part. It would be a pure

guess. But, overall, I think it is a reasonable

question and most of us will answer yes to it.

DR. WOOD: The reason I have concerns

about it was that it seemed to me to imply that you

didn't get benefit unless your LDL was reduced to

less than 130 milligrams per deciliter.

DR. ORLOFF: Alastair, I think your point

is a good one. Really, what the question--you

know, these are questions intended to make sure

that no one has a fundamental disagreement with at

least it initial part of this approach because, if

they do, then it is a non-starter. The first

question was should some of these people be treated

with a statin. The answer seemed fairly

straightforward. The question here is is a

20-milligram dose of lovastatin an effective dose

of lovastatin? Is there evidence that you can

157

reduce heart-disease risk in this population with a

20-milligram dose of lovastatin.

Forget the 130 thing.

DR. WOOD: All right. We have had further

clarification. The reason we are doing that is we

think people may benefit--just for the record,

people may benefit even if they don't get their LDL

down to 130.

Dr. Follman?

DR. FOLLMAN: I think the thing in

parentheses is clearer to me, will a sufficient

proportion be able to reach this LDL. I think the

first part speaks to the point I was trying to make

yesterday, will it have a benefit compared to what.

So if we compare the fixed dose of statin

to people getting nothing, the answer in my mind is

absolutely clear, they would get a benefit. The

question that is not at all clear in my mind is

compared to a prescription world, would there be,

in a population basis, a benefit to this.

We don't have evidence of that to my mind.

The study that comes closest to this, though it is

158

imperfect, is the lipid-lowering trial compliance

of ALLHAT which showed really no difference between

usual care, which is, you get statin when you think

you need it, as opposed to a fixed dose of

pravastatin.

So, depending on the reference group, I

have one or two different answers to this question.

DR. ORLOFF: I think it is reasonable for

me now to try to clarify a little more. In an

effort not to get bogged down in these, this

question is independent of the marketing status of

the drug. Is 20 milligrams of lovastatin an

effective dose of lovastatin?

DR. WOOD: That is why I deleted the

second part.

DR. ORLOFF: I want you to delete the

second part.

DR. WOOD: Okay.

DR. SCHAMBELAN: That assumes the patient

is adherent to the medication, David?

DR. WOOD: No.

DR. SCHAMBELAN: Or is that just putting

159

it into this population and seeing how it works in

terms of adherence, or are you asking will it

reduce heart disease risk if taken in the

prescribed amount on a continuous basis. What are

you asking us?

DR. WOOD: I would say--

DR. ORLOFF: Is there evidence that this

is an effective dose? It is assumed that

effectiveness, or at least optimal effectiveness,

depends upon adherence to labeling, whether it be a

prescription drug or an over-the-counter drug.

DR. WOOD: But, pragmatically, the answer

to the question has to be are there clinical-trial

data that support that conclusion.

DR. ORLOFF: That is exactly the question.

DR. WOOD: So that presupposes that people

took the drug inadequately or adequately. Okay.

Any further discussion on this point? All right.

Then let's start again and we will start at the

opposite end this time with Dr. Snodgrass.

DR. SNODGRASS: I guess I need to ask a

little discussion here. The question, I think, is

160

framed in a way that is not a straightforward

answer. It is the fundamental--I think this is

just very elementary. It is fundamental

therapeutics that you individualize your dose for a

patient in the patient-care setting.

But, in a public setting like this, you

have got a fixed dose because you can't individual

it. You have got a fixed dose. So there was some

response but it is not going to be optimal. So I

think that is just a distinction here. So, when

you see this kind of question, has it provided

adequate rationale, I would look at that in one

sense, with those words. But if you are saying

beyond that, is the question is there really formal

prospective randomized clinical-trial data that 20

milligrams is effective across some percent of a

population, I think that is maybe a slightly

different question.

DR. ORLOFF: That is the question. I

apologize for having to partake too much in this

conversation. But, irrespective of marketing

status, why not phrase it this way. Although you

161

have not had the length and the breadth of the

efficacy and safety data that were presented for

lovastatin for its initial approval presented here,

I guess it is reasonable to ask you were we asking

you whether to approve a 20-milligram dose of

lovastatin, say, in addition to a 40 and an 80 and

so on, has there evidence been presented in your

package and in the presentations that 20 milligrams

is an effective dose, or is it an ineffective dose

and is something more needed.

DR. WOOD: Okay. Does that help, Dr.

Snodgrass?

DR. SNODGRASS: I think it helps somewhat.

I think the way I view it is it will be helpful to

some percent of the population and that makes it

somewhat helpful. So my answer would be, in that

context, yes.

DR. WOOD: So perfection is the enemy of

the good, again. Okay.

DR. FINCHAM: Yes.

MR. SCHULTZ: Yes.

DR. WIERMAN: Yes.

DR. NEILL: Yes.

DR. WATTS: Yes.

DR. TINETTI: Yes.

162

DR. WOOD: Yes.

DR. SCHAMBELAN: Yes.

DR. TAYLOR: Yes.

DR. SCHADE: Yes

DR. CLAPP: Yes.

DR. MAKRIS: Yes.

DR. CLYBURN: Yes.

DR. McCLUNG: Yes.

DR. PATTEN: Yes.

DR. DAVIDOFF: Yes.

DR. FOLLMAN: Yes.

DR. PARKER: Yes.

DR. CARPENTER: Yes.

DR. BLASCHKE: Yes.

DR. CAPRIO: Yes.

DR. BENOWITZ: Yes.

DR. WOOLF: Yes.

DR. WOOD: Okay. It is 25 yeses, no no's.

The next question addresses, as the first

163

question, that starts to address the toxicity of

the drug. Question 2 addresses hepatic toxicity.

Before we get into going through the individual

questions, maybe we should see if there is any

discussion on this point first.

Dr. Parker?

DR. PARKER: The only comment I had just

related to the fact that the U.K. puts the warning

about alcohol use. I understand that they do that

because it came up in discussion that that was

recommended and so it is there. I just take note

of that again, alcohol use is extremely common in

our own country and I think we may want to consider

whether or not it is clear to someone that liver

and alcohol use relate to the same thing on the

label.

DR. WOOD: Let me suggest that--I think

that is a good point. Let me suggest that we sort

of put in a supplemental question in between 4 and

5 that addressed whether there are other issues

that we should address in terms of toxicology or

whatever that we have not addressed specifically

164

under these and we will try and capture all of that

at that time if there are issues.

Any other discussion? Yes, Dr. Benowitz?

DR. BENOWITZ: I just want a

clarification. I probably should have seen this

but I know, in the U.K. package insert, there was a

description of symptoms of liver disease and a

warning, if you develop these symptoms to call your

doctor and stop the medicine.

The safety issue here implies that there

is some effective warning for OTC. Is that warning

the same or is that present in the current proposed

label?

DR. WOOD: Well, it seemed to me the

question here related to preceding liver disease at

first. So, presumably, that would come from a

history of liver disease.

DR. BENOWITZ: You are talking about a. I

was talking about the whole--I was talking about

c., actually.

DR. WOOD: I see. Okay.

DR. BENOWITZ: I was talking about

165

Question c.

DR. WOOD: Why don't we hold that until we

get to that point.

DR. ORLOFF: Let me take a crack at

clarification, yet again. This always happens at

the question time. You realize that your best

intentions fell short with regard to simplicity.

Our intent here is really, Question No. 2 is about

the proposal for this to be marketed OTC in the

absence of either baseline or follow-up

liver-function monitoring.

What I would say is, taking into account

a., b., and c., not as questions but as issues

about undiagnosed liver disease and safety and the

extent to which it has been addressed, about

hepatic risk specifically in that population

and--well, we don't even need to go to c. The

question is, what is the level of comfort, or has

there been adequate information provided, to go to

market OTC without liver-function test baseline

assessments or ongoing monitoring.

DR. WOOD: So, would it make it easier if

166

we just asked, does the committee think that

liver-function tests are required before the drug

is taken and are required during the drug's

administration. I mean, that would get at the

question; right? Okay.

Neal, does that help?

DR. BENOWITZ: The only issue about c. is

is it safe.

DR. WOOD: Yes; I know.

DR. BENOWITZ: If you get rid of that, I'm

fine.

DR. WOOD: Right. So, with Dr. Orloff's

permission, we are going to rephrase the question a

little bit and say, do we need to have

pre-treatment liver-function tests for patients

taking 20 milligrams a day of lovastatin

over-the-counter.

The following question will be, and maybe

this can be answered together, do we need

liver-function tests during administration. Is

that fair? Okay.

We will start at the other side, again.

167

First of all, is there discussion on that that we

want to have?

DR. CARPENTER: Speaking from the

pediatric point of view, one can imagine the

situation where, although this is not in the age

group approved for over-the-counter use, that

pressures may be to have some patients obtain this

medication in such a fashion.

Now, that is a specialized class of people

in which the data regarding potential hepatic

complications with these drugs is, I think, more

limited. We have to consider, with the population

that we would use, the encounter with an

over-the-counter distribution system that it may

get neglected to do what we would probably wish to

do, given that this is a special population.

DR. WOOD: I guess--you may want to

address that. We are reviewing the drug for the

indication that is being sought. It is probably

unreasonable, unless we see a major safety issue in

some other population, to debate its potential

safety or not in populations that are wildly

168

outside the age group or other parameters that are

being sought for.

But, you know, I would defer to the FDA if

they think that is important discussion to have. I

mean, I guess--well, go ahead.

DR. ORLOFF: What I was going to say is,

first of all, this drug, I assume, and Merck is

going to confirm this in case my memory is failing

me, will be marketed not for use in children. That

is the first thing.

The second thing is what do we know about

the safety of statins in children where I think you

are right. The data are limited. There is a

limited number of studies in a relatively small

number of children with heterozygous familial

hypercholesterolemia and, obviously, there is a

smattering of children with homozygous FH who have

been treated.

In those studies which, all-told, on

statins probably count in the several hundreds at

most, for up to a year, my recollection of the data

is that there is absolutely no liver signal at all.

169

These are at doses of, I believe, 20 and 40 of

lovastatin, torvastatin, 20 milligrams--I don't

remember what--simvastatin as well, I believe, 20

milligrams of simvastatin.

But that is all we know. I think the

issue of pediatrics came up yesterday and I

apologize we didn't get to it in response to that

question yesterday.

DR. WOOD: Dr. Follman?

DR. FOLLMAN: I just wanted to--the

question talks about the evidence that the sponsor

has provided. I think it is important to know that

we are talking about baseline liver-function tests

and undiagnosed liver disease. Liver-function

testing is a requirement or in the label for

prescription statin and so all the evidence that we

have about the safety of statins in terms of liver

problems is in this population that presumably

doesn't have liver problems at baseline.

So, if we look for data or evidence for

this select group, there was one small study that

was done. It is a retrospective study that the

170

sponsor mentioned where there are about 340 people

with elevated liver enzymes who were looked at

prospectively with a statin compared to a group

with elevated enzymes who didn't get a statin and

they showed no real difference there.

So I wanted to just reinforce the point

that we have a huge body of evidence on the safety

of statins in terms of this for the screened

population and we don't have that much evidence,

this was one study and another very small study,

regarding the issue whether they should be checked

at baseline for liver abnormalities.

DR. WOOD: Does the sponsor want to

respond to that question in any way?

DR. WATKINS: Paul Watkins, University of

North Carolina. I really don't have any additional

comments other than was made yesterday. As you

saw, some preliminary data of a much larger study

that is ongoing at Kaiser, the final results and

analysis will be forthcoming.

But the only point I made then is that we

know in the 27 million patient years a significant

171

proportion of those will have had fatty liver and,

undoubtedly, viral hepatitis. In spite of that, we

all know the remarkable safety record from a liver

standpoint.

So the incremental risk in people with

preexisting liver disease, if it exists, has to be

very small. The overall risk has to be small in

that population.

DR. WOOD: Dr. Wood, may I just make a

comment here. I hope this will be useful to the

committee members. Yesterday, Dr. Hemwall had

actually mentioned that the sponsor has already

submitted to the agency a supplement to make

changes to the label with respect to LFT, and,

actually, it is LFT recommendations, not

requirements, in the label.

While we can't comment on an application

that is still under review, certainly the sponsor

is open to discussing what they are proposing. I

would want to share with the committee what has

occurred with other statin labels. Over the past

five to six years, we have received applications

172

requesting changes to the label to pretty much ease

up on the requirement of LFT monitoring.

The data submitted are based on large

controlled clinical-trial data. I think it is

reasonable to say that, if similar data are

submitted to the agency for Mevacor, we would be

hard-pressed not to grant them similar changes to

their label. Similarly, as the sponsor has alluded

to, there are preliminary data that we have not

reviewed and we have encouraged them to submit it

to us because we do feel that, given the weight of

evidence of the safety of this product with respect

to liver toxicity, this would be very useful

information for us to review and possibly change

the label based on those data.

DR. WOOD: Okay. That is very helpful.

Dr. Davidoff?

DR. DAVIDOFF: Not having gone into the

evidence with the kind of thoroughness that might

be involved in doing, say, a Cochran systematic

review, the data that I have seen are not

persuasive to me that there is any significant

173

risk.

That makes me also raise the question

about the wise use of healthcare resources. I

mean, everybody knows that, in this country, we are

spending vast amounts of resources on healthcare.

I am not just talking about cost here. I am

talking about people and time and equipment and

supplies and money.

If liver-function tests are really, in the

clinical sense, not necessary, it seems to me it is

worth considering whether requiring an ineffective

use of healthcare resources which are getting

increasingly precious is something that we should

take into consideration. It is not just a matter

of cost in the strict financial sense.

DR. WOOD: So, Dr. Parks, you have been

told to hurry up.

Dr. Taylor?

DR. TAYLOR: Actually, my questions were

mostly answered. It was a regulatory question

about the requirement of having LFTs since it was

not required but recommended for the prescription

174

label.

But I would, I think, like to see--I would

like to see a stronger label in regard to liver

disease and alcohol in particular, similar to the

Zocor label. I think the current label, as we have

reviewed, is not sufficiently strong.

DR. WOOD: Let's hold that thought because

I will give you the chance to offer that later.

Any other discussion, then? Then let's

move, I guess, to the rephrased questions which, if

I can remember them again, are, do we think that

liver-function tests are required prior to starting

lovastatin therapy and, as a supplement to that, do

we think that liver-function tests are required at

some regular basis during therapy to ensure the

continued safety of the drug, something like that.

Is that okay?

DR. ORLOFF: I just remind people, again.

Dr. Parks mentioned the Kaiser study that the

sponsor presented in brief yesterday had not been

reviewed. But the issues are two. One is, is

there sufficient evidence of the safety in patients

175

who have existing liver disease and is there

sufficient evidence, presumably because the

evidence we have now is--the vast majority of the

exposures in trials are in patients who don't have

baseline liver disease. That, on top of whatever

other information is brought to bear, is there

enough information there to support safety in

long-term use without follow-up monitoring.

DR. WOOD: And then the unspoken

assumption which I am not sure we know either, is

that measuring liver-function tests and finding

them to be abnormal would actually protect that

patient from some further damage which is not a--so

that is an important consideration before, as Frank

says, we advocate a test.

Let's start again, then, with Dr. Woolf.

Are people comfortable doing both of these at once?

Okay. Let's do that.

DR. WOOLF: I do not think that we need to

require LFTs before or during. The answer is no.

DR. WOOD: So the answer is no. The way

we are asking the question is if you don't think we

176

should do it, then the answer will be no.

DR. BENOWITZ: No, no.

DR. CAPRIO: No, no.

DR. BLASCHKE: No, no.

DR. CARPENTER: No, no.

DR. PARKER: No, no.

DR. FOLLMAN: No, no.

DR. DAVIDOFF: No and no.

DR. PATTEN: No and no.

DR. McCLUNG: I agree with no and no.

DR. CLYBURN: No and no.

DR. MAKRIS: No and no.

DR. CLAPP: No, no.

DR. SCHADE: No for both.

DR. TAYLOR: No for both.

DR. SCHAMBELAN: No for both.

DR. WOOD: No and no.

DR. TINETTI: No and no.

DR. WATTS: No and no.

DR. NEILL: No, no.

DR. WIERMAN: No and no.

MR. SCHULTZ: No and no.

DR. FINCHAM: No to both questions.

DR. SNODGRASS: No and no.

DR. WOOD: So, obviously, everybody voted

177

no. The next question relates to another toxic

problem from statins which has been in clinical

trials more common, I guess, serious muscle

toxicity The question says; statins have been

associated with the development of serious muscle

toxicity. Furthermore, drug-drug interactions with

lovastatin may increase the risk of muscle

toxicity. Is the risk of muscle toxicity with

lovastatin 25 milligrams acceptable for an OTC

drug?

Do we have any discussion on this point?

DR. WATTS: I think this question raises

the issue of whether or not patients can

appropriately self-select. I think, for patients

who stand to benefit--that is, those who are at

moderate to moderately high risk, then the muscle

effect, I think, is reasonably safe.

But for patients who don't stand to

benefit, I think the muscle concern is not

178

acceptable. That is discussion. That is not a yes

or no answer.

DR. WOOD: No; I realize that. So, for

patients who don't stand to benefit, who are the--

DR. WATTS: I can extend it into an

answer, if you like, and that is that, given the

problems that I see with self-select, that,

overall, for the population who self-selects, I

don't think it is safe.

DR. WOOD: Okay. Any other discussion?

Mary?

DR. TINETTI: I just had a question and

maybe it came up yesterday but I missed it is

probably the drug that most likely is going to be

used by this population is erythromycin. We use it

fairly frequently. Do we have any evidence for the

short-term use that people are using erythromycin

with the 20 milligrams. Is there any evidence of

an concern with that combination?

DR. HEMWALL: The best evidence comes from

a slide we showed in our core presentation

yesterday when the time was, before we knew about

179

the CYP 3A4 interaction, there were people in

AFCAPS that were actually coadministering

interacting drugs. If one of you knows that core

slide, you can bring it up right now. Otherwise, I

will give you the number.

[Slide.]

These are the most potent of the CYP 3A4

inhibitors. In this case, there were over 500

patients randomized to lovastatin 20 to 40

milligrams that were given these strong

CYP-3A4-interacting drugs. This included

erythromycin and clarithromycin but the other two

there, the ketoconozole, nitraconazole and only one

or two on nefazodone. The point of the two azoles,

they are even more potent than erythromycin and

clarithromycin.

So you have got a group of 500 people

receiving these drugs and their risk of having a

musculoskeletal side effect is very similar to that

seen with the placebo group receiving the same

drug.

So what we are saying here is that the

180

label is very strong about checking with your

pharmacist or doctor if you have a new prescription

or you are already taking medication. But if

someone slips through and is taking a medication,

then the absolute risk is still very, very small

even though the relative risk may be increased.

DR. WOOD: While you are answering that, I

guess the signal with Baycol was first evident with

the interactions with an elevation in CK. So, do

we know if the 48 or whatever it was that was up

there on the top line of that slide, what

proportion of these had an elevation in CK as the

reason for being there and how high did the CK,

CPKs, go?

DR. HEMWALL: We don't have that readily

available.

DR. WOOD: Okay. If you come up with

that, let's get back to that later. The other

question is do we know what the increased C and AUC

is with erythromycin, with lovastatin. Well, we

do, but why don't we quote it.

DR. HEMWALL: Using the enzymatic assay, I

181

believe it is around four- to five-fold.

DR. WOOD: So that would take you from a

dose of 20 milligrams up to a dose of 80

milligrams.

DR. HEMWALL: In a very strict sense, it

would. But there is a lot more kinetics around it

than just--

DR. WOOD: Understood. How strong is the

dose-response relationship of muscle toxicity?

DR. HEMWALL: There is a dose-response

relationship that increases but it is still rare at

the high dose of lovastatin.

DR. WOOD: Dr. Carpenter?

DR. CARPENTER: Should we consider this

question for our target population, for the target

population, as opposed to overall because we deal

with selection issues with later questions.

DR. WOOD: That is a helpful comment.

Yes.

DR. BLASCHKE: I just had a question about

this last slide before you sit down. I was unclear

what the placebo population was taking there in

182

that slide.

DR. HEMWALL: In order to match the

groups, the placebo group was also taking the same

interacting drugs, but not lovastatin.

DR. WOOD: Dr. Davidoff?

DR. DAVIDOFF: I seem to recall that there

has been concern with other statins with their

interaction with fibrates in producing muscle

damage. Am I mistaken and, if I am correct, is

there any information on the interaction of this

dose of lovastatin and fibrates?

DR. WOOD: The gemfibrozil story with

Baycol was particularly because of the multiple

pathways that were inhibited by gemfibrozil with

Baycol which made it particularly susceptible to

that. This is a drug metabolized by 3A, so it

wouldn't be as susceptible as the others. But the

sponsor should answer that question, I guess.

DR. HEMWALL: All lipid-lowering drugs are

associated with muscle side effects. If you

combine two lipid-lowering drugs, you get increased

rates of muscle side effects. In the case of

183

cerivatstatin, there was a particular interaction

with a metabolic pathway that was exacerbating that

effect that is not seen with lovastatin.

DR. ORLOFF: I am sure Merck has more

precise numbers but let me just add a little bit

and say that the pharmacokinetic interaction with

cerivastatin, between gemfibrozil and

cerivastatin--that is to say, impacting systemic

exposures to cerivastatin was marked compared to

lova. So, as Dr. Hemwall has said, something like

five-fold increase--

DR. WOOD: Eight-fold.

DR. ORLOFF: Eight-fold increase of

cerivatstatin with only a two- to three-fold

increase in lovastatin. It is believed, and I

think the sponsor would agree here that it is

not--the precise nature of the interaction between

gemfiboizil, specifically, and lovastatin,

specifically, to augment the risk of myopathy is

not fully understood. But, in all likelihood, it

is both a tissue site--that is to say, at the

muscle, pharmacodynamic interaction but also,

184

perhaps, to some extent, a pharmacokinetic

interaction whereby gemfibrozil increases the risk

of myopathy from lovastatin, per se.

DR. DAVIDOFF: That is helpful, but all

that said, what are the clinical data on the

occurrence of rhabdomyolysis with that drug

combination. That was my question.

DR. WOOD: Do you want to respond?

DR. HEMWALL: Do you have some information

on that? We can get that for you, if you want it.

But I guess one of the more relevant comments would

also be that someone taking a fibrate is most

likely to be under the care of a physician managing

their lipids and would not likely also take an OTC

statin on top of that.

DR. LEVINE: I have the data from our

postmarketing database. Of the 336 reports of

rhabdomyolysis, there were 97 reports which

included fibrates. 96 of them were gemfibrozil.

Of the ones that we know the doses, 16 were at the

20 milligrams, out of the 97.

DR. WOOD: Dr. Taylor?

DR. TAYLOR: I wanted to be reminded of

the muscle-toxicity data from the CUSTOM study and

the other question is I don't think we ever saw

185

data on the average number of medications that

individuals of the CUSTOM study, the users, were

on. I would like to know that.

DR. HEMWALL: It will take a couple of

seconds here. We will get a slide.

DR. WOOD: Why don't we work on that and

we will come back to you on both these questions.

Any other discussion? Dr. Benowitz?

DR. BENOWITZ: I am sure this is going to

be a small population, but I looked at the label

and I didn't see any way to warn the user--that is

people with transplants getting cyclosporine which

is obviously a question. I don't see an exclusion

for such a person there except if you had a heart

transplant. But a kidney transplant person, there

would be nothing on the box that says, "Don't take

it."

I was wondering how a patient is supposed

to know about the cyclosporine issue which has also

186

been associated with interactions.

DR. WOOD: Given the risks from a

transplant with atherosclerotic disease. I think

most of these patients will be on a statin.

DR. BENOWITZ: Probably. I don't know.

That might be the case.

DR. LEVINE: From our CUSTOM study, as you

recall, there was no myopathy reports and no rhabdo

reports. We did not measure CPK in that study.

There were 118 participants which is 11 percent

which reported myalgia as an AE. 79 were

considered drug-related and 39 were not considered

drug-related.

DR. HEMWALL: I think Bob has a

concomitant medications number. A couple of things

on the labeling, or course. Number one, there is a

lot of labeling reminding people to watch out for

myalgia. If you look at some of the packaging, you

will see the icon of the muscle pain, et cetera.

So this is something people are very much alerted

to.

On the question of cardiac-transplant

187

patients and cyclosporine, the internal package

materials also actually specify the drug

cyclosporine. But, more importantly, on the very

back panel, again, as we talked about yesterday,

people who have heart disease and I would think

cardiac transplant would fall into that category

and the consumer would know that or not to take

that drug. So that would, hopefully, eliminate

those folks.

DR. WOOD: Of course, I don't think Neal

is just asking about heart transplants. But I have

made a note that there is a list of exclusions we

are hearing about that maybe should be in the

label. We have heard about one from Dr. Parker and

from others. Maybe we should sort of collect them.

In this subsequent question, we are going to ask

between four and five--not 4:00 and 5:00 p.m.,

unless people--

MR. TIPPING: So the question about the

average number of medications, I think it was, that

people were on in CUSTOM. Again, because of CUSTOM

being a naturalistic behavioral study, we didn't

188

collect concomitant or prior therapy information to

the degree that you might expect in a traditional

clinical trial. Instead, we asked specific

questions, were you on lipid-lowering therapy, were

you on an interactive medication, things like that.

So we do have information on

lipid-lowering therapy. I think the most important

thing you are asking about is the interactive meds.

DR. TAYLOR: Right. Specifically. But I

wanted to also get back to this issue of whether

the CUSTOM population represented the general

population because, in that age group, I would

think that--the number of medications might be a

marker for the population. If you have the same

rate of additional medications, that would give

credence that you were dealing with the same

population.

MR. TIPPING: I think we have information

on the number of individuals--the number of

evaluators in CUSTOM that were on any prescription

medication. Can you find that number for me? I

need a pair of glasses for this one. There were

189

630 of our 3,316 evaluators who were on any

prescription medication.

DR. TAYLOR: 630 out of how many?

MR. TIPPING: 630 of our evaluators--so it

is out of 3,316.

DR. WOOD: How many of these went on to

elect to take it? I guess that is the question.

What is the proportion in that group?

DR. TAYLOR: I guess my point is that if

you ended up with a group that none of them were on

other medications, that wouldn't look like the real

world. I guess that is my point.

MR. TIPPING: Let me go back and take a

closer look at this table.

DR. WOOD: Okay. Any other discussion on

this point? Then let's move to the question.

Statins have been associated with the development

of serious muscle toxicity. Further more,

drug-drug interactions with lovastatin may increase

the risk of muscle toxicity. Is the risk of muscle

toxicity with lovastatin acceptable for an OTC

medicine?

I am going to start with Dr.

Snodgrass--I'm sorry?

DR. WIERMAN: Somebody has asked you to

190

limit that to the targeted population because we

are going to come back to the ability to

self-select. Are you talking about--

DR. WOOD: Well, I guess--help me.

Explain.

DR. McCLUNG: Let's confine it to the

target population. I think, for the purpose of

discussion about the muscle symptoms, that would be

a cleaner thing, and then deal with the capacity of

patients to self-select as a separate question.

DR. WOOD: Okay. That's a good thought.

Dr. Snodgrass?

DR. SNODGRASS: Yes.

DR. FINCHAM: I hate to do this but what

is the targeted population? Is it anybody that can

purchase the product? Now, just let me--is it

anybody that can purchase the product or is it

those that select to use the product based upon

reading the label.

DR. WOOD: Or a third question is is it

those who select it correctly. I think, and I

don't want to put words in your mouth, but you were

talking about the population that was on the label.

Am I correct?

DR. FINCHAM: Yes.

191

DR. WOOD: Okay.

MR. SCHULTZ: Yes.

DR. WIERMAN: Yes.

DR. NEILL: Yes.

DR. WATTS: Yes.

DR. TINETTI: Yes.

DR. WOOD: Yes.

DR. SCHAMBELAN: Yes.

DR. TAYLOR: Yes.

DR. SCHADE: Yes

DR. CLAPP: Yes.

DR. MAKRIS: Yes.

DR. CLYBURN: Yes.

DR. McCLUNG: Yes.

DR. PATTEN: Yes.

DR. DAVIDOFF: Yes.

DR. FOLLMAN: Yes.

DR. PARKER: Yes.

DR. CARPENTER: Yes.

DR. BLASCHKE: Yes.

DR. CAPRIO: Yes.

DR. BENOWITZ: Yes.

DR. WOOLF: Yes.

DR. WOOD: So everybody voted yes.

The next question relates to pregnancy,

192

Category X. Before we sort of get into that

question, it seemed to me that the FDA ought to

consider--have symbol that they put on packages

that says, "Not to be taken by potentially pregnant

women," sort of INTEL inside that was popularized,

and that that would provide us with a lot more

reassurance if there was some kind of--and I am not

smart enough to work out how to do that, but we

should think about that.

Bob?

DR. MEYER: There is actually, just to

directly respond to that, some interesting data

about use of symbols, though. For instance, there

193

was once a silhouette of an obviously gravid woman

with the universal "no" sign above it. Lots of

people who looked at that then thought that that

medicine was actually a contraceptive. So you have

to be careful with those kind of considerations.

DR. WOOD: That reflects on the quality of

the symbol, I guess. But at least they thought

something; right? This is obviously an issue we

are going to have to think about.

So, let me read the question to you;

lovastatin and other statins are currently labeled

as Pregnancy Category X, the drug should not be

used during pregnancy. We have had a lot of

discussion that I would like not to repeat, if we

can avoid it, that talked about how one gets to be

a Category X product. You can get there either

from proven pregnancy toxicity or lack of efficacy

during pregnancy. Either of these will put you

into that category.

The company's position here, I guess, and

others is that this is no efficacy--there is no

requirement for this drug to be given during

194

pregnancy and no demonstrated behavior during

pregnancy and, therefore, that would make it

Category X.

The second part of the sentence is; Has

the spectrum and magnitude of fetal toxicity with

lovastatin 20 milligrams been adequately studied,

obviously an important question. Is the risk for

women of childbearing potential appropriate for an

OTC product?

It seems to me that we are going to have

to discuss, either here or later, is the adequacy

of the self-selection or self-exclusion appropriate

and are there ways to strengthen that.

So let's set off. Any discussion on this

topic? Dr. Woolf?

DR. WOOLF: I would like to come back to

the issue that was tabled before. We were told

that there are roughly 5 million people who are a

target for the drug. From the CUSTOM study, there

were roughly 5 percent of women who were age 40 to

45 and another 5 percent who were 45 to 50.

Since I have raised the issue and a member

195

of the audience was kind enough to give me the

pregnancy rates for these individuals, and it is 4

per 1000 per year in the 40- to 45-year age group

and a fifth of that, or 1 per 1000 per year, in the

45 to 49.

Assuming my algebra is correct and I am

not sure that it is, that leads to roughly 15,000

women per year who potentially could be taking this

drug not according to label but were in the CUSTOM

study. I would submit that the people in the

CUSTOM study probably do not represent the usual

consumer but somebody who are self-selected to

participate in the study. So there are roughly

15,000 people per year who will get pregnant while

taking the drug.

We were given some data this morning about

teratogenicity that we did not have yesterday that

suggests that there might be a class effect. That

has me concerned. With 15,000 women exposed and

even a few percent of them have an affected baby,

that is, to me, a big deal.

DR. WOOD: Any other--yes.

DR. WIERMAN: The only comment I would

make is your statistics assume, in that group

between 40 and 55, that they are not using any

196

forms of contraceptive.

DR. WOOLF: Absolutely. So that is the

upper bound. But it is per year, so it is a

cumulative exposure.

DR. WiERMAN: Absolutely. My only comment

on that, although I think it is an important to

discuss related to the pregnancy issue, that

cholesterol treatment in this highly motivated

group of patients that are seeking healthy

lifestyles, the data has repeatedly shown us that

women, especially premenopausal women, are not

focused on treating their cholesterol and, in fact,

it is hard to motivate post-menopausal women to

treat their cholesterol.

So the absolute risk versus the potential

theoretical risk for this adverse outcome, I think

we continually need to use data and not just

emotional responses to.

DR. HEMWALL: I would like to add, to put

197

that in perspective. The information I showed the

committee yesterday was to try to add what you

might consider the incremental risk calculation.

There are about 400,000 women per year, or at

least, shall we say, 400,000 prescriptions written

per year today for statins for women of

childbearing potential.

So we are talking about what may be the

incremental risk that you are concerned about, but

there is already this level of exposure going on,

admittedly under a physician's care but I think

that level of incremental risk is not greater than

the overall risk that we are already seeing.

DR. WOOD: Any other discussion?

DR. CLAPP: Just as he mentioned that

there are prescriptions written, 400,000 a year,

for women who are not in the age category that are

the targeted population, I think we have to have

concerns for the effects of direct marketing.

Although it is speculative for sure, we know that

the direct marketing will affect women who,

perhaps, have heard or it is registered that their

198

cholesterol is elevated and then, perhaps, rather

than seek medical treatment or change their diet or

exercise, purely speculative, as human nature would

lend some to do, would see the Mevacor and think

that this is an opportunity to make a change that

is in their health's best interest.

I can see an opportunity for many women,

black women, in particular, who, perhaps, do not

have the opportunity or the resources to have

ongoing medical care, accessing Mevacor because

they have been told at some point, because

screening for cholesterol officially starts at 20,

that their cholesterol is elevated and, perhaps,

not focusing in on the guidelines thinking that

they are doing something that is heart-healthy for

themselves, maybe putting themselves at increased

risk for this adverse outcome.

Although the data is unclear, there is

some concern. As the Merck scientist said

yesterday, reasonable scientists can come to

different conclusions. That is my concern with the

information about the potential congenital

199

malformations of the fetus or newborn child.

Additionally, the marketing of the

medication is concerning. I am looking at, and I

should have raised this yesterday, admittedly, I am

looking at some of the pamphlets included in the

package insert. They have a picture of a black

woman hugging a gentleman. I am not sure who the

target is here. I have been asking my colleagues

how old she is and some say over 55. Some say

under 55. But she looks like a lot of black women

who are not 55.

So I am not sure if she is hugging the

recipient of the Mevacor or if there is a

subliminal suggestion that she, herself, could be a

candidate for Mevacor because there is a sidebar

here and I am not sure what it is.

So we have her in closeup in other one,

but I am still unsure of her age.

DR. NEILL: She looks younger than 55

because she is tasking Mevacor.

DR. CLAPP: There you have it. We all

should take it for that reason. But, nonetheless,

200

I think I am concerned because we haven't seen the

phenomenon of direct marketing. The outcome that

people who, perhaps, are indigent but want to

improve their health and don't have the resources

but might want to take a pill. They don't diet.

They don't exercise.

I am skeptical--I know that it not the

targeted group, but I am concerned. As we know, at

least 50 percent of pregnancies are unplanned so

the cautions about pregnancy and lactation are

interesting but, if you didn't plan on becoming

pregnant, you are taking the medication and the

warning is too late for you.

DR. WOOD: Any other comments? This is

obviously an important issue. Dr. Patten?

DR. PATTEN: I share Dr. Clapp's concerns

and I have some questions in that regard. We have

animal-model data that indicates that statins can

be a factor in birth defects. We had a

presentation earlier regarding human consequences

and we have prevalence figures here, 1 in 10,000

for very serious defects.

I have a question for the FDA. The way

the question to us is going to be stated is, is the

risk for women of childbearing potential

201

appropriate for an OTC drug product. I would like

to know what you consider appropriate and I would

like to have this question answered with regard to

some other OTC drugs so I have a basis for

comparison here.

DR. WOOD: Okay guys, does that put you on

the spot?

DR. BULL: I think one thing, if we lived

in an ideal world, that should be kept in mind is

that the ideal targeted population, if the product

were to be used the way that it is supposedly being

indicated, which would be women who are

postmenopausal who would not be in their

childbearing years, you probably don't have the

problem we have.

Yesterday, the example of Accutane came

up. One of the reasons Accutane's risk management

is so critical is that indicated population is also

the population at risk for its indication for use.

202

So I would encourage you to keep in mind the way

that the drug--the target population, I think, is

certainly a critical one, but you also have data

that you are going to have to weigh as to what

happens in actual use.

DR. WOOD: But you are not--just to make

sure we all understand this. You don't mean to

imply that you think this is like Accutane, do you?

DR. BULL: Oh, no; not at all. But I

wanted to make that clarification because one of

the issues we struggle with with Accutane is that

the population, which is women of childbearing

potential, is also the population that has acne.

DR. WOOD: But I think the question that

we are being asked is--not to let you off the

hook--is you are asking us to decide whether it is

appropriate. I think you were being asked what you

think based on your previous experience, your

historical experience, your whatever is

appropriate, number one. Number two, I suppose, in

order to be able to answer that, what is your

assessment of the risk of pregnant women of this

203

product right now. Is that fair, Dr. Patten? Is

that what we are trying to--

DR. PATTEN: Yes.

DR. BULL: I feel as if you all are

flipping the question back to us which is why we

have convened you all here.

DR. WOOD: We are.

DR. BULL: I think one element to keep in

mind is that we have data from the actual-use study

that I think needs your input and evaluation

because the packaging, the label that was

submitted, certainly provided guidance to the

consumer as to--that had age guidelines. And you

have data that appears to be at variance with that.

I think that that is the open question.

I don't know if others from FDA want to

comment at this point.

DR. WOOD: I don't see a rush.

DR. TAYLOR: To follow up on some of this

discussion, I think it is presumptive to think that

the target population is going to be the population

that you think it is. Even in your own data, you

204

say that 37 percent of women users were less than

55 in the CUSTOM study. So I think it was mass

marketing. You are likely to get a great number of

individuals who are below 55 and maybe in some

reproductive range.

In terms of populations, in terms of

populations with elevated cholesterols and LDLs,

the population that I see--we start treating that

much earlier, perhaps, than another population. It

is not accomplished, generally, by lifestyle

changes or other changes, strong genetic penetrance

of elevated cholesterol.

So I could see a number of individuals in

the reproductive range going out and buying this

medication which would put them at risk.

DR. HEMWALL: I just thought it would be

helpful to put the question in perspective as Dr.

Clapp had asked. There are OTC drugs that have

significant teratogenicity potential. The most

important ones, of course, are the

nicotine-replacement products where the benefit to

have the population have easy access to

205

smoking-cessation products is seen to outweigh the

potential that women may inadvertently be exposed.

I think we can adopt some of the labeling

that has been used for those products to really

make it very clear that, if you are of childbearing

potential and/or considering having a child, trying

to have a child, that you should stay away from

these products.

Similarly, there are animal data for many

OTC products that show similar profiles, if not

worse, at least in the way animal data are

interpreted in terms of the exposures.

Do I have the slide on that? I could give

you some information.

[Slide.]

I apologize. It is a little hard to see.

But there are actually three OTCs here, cimetidine,

epinephrine and ibuprofen. You look at the effect

level, milligrams per kilogram and the dose ratio

to humans--excuse me; I am getting multiple

pointers handed to me. For cimetidine,

milligram-per-kilogram effect level, that is a 9.2

206

human ratio. Epinephrine, which is used in asthma

preparations, 0.78. Ibuprofen, which is commonly

used obviously has animal ratios that are even

below those of the human exposure. This is, by no

means, meant to imply that these drugs are unsafe

but this is the type of information that you see in

animal studies and it is the kind of factoring that

goes in in terms of benefit:risk.

The interpretation of the animal studies

and relevance to human exposures, these drugs are

still viewed as safe and, of course, do not have

adverse pregnancy outcomes above the norm in their

background. The exposure levels in lovastatin are,

indeed, higher than any of the these. Of course,

as we said, there may be some argument about what

the exposure levels are, but these, we believe, are

the appropriate ones and we think that we are very

much in range with what is acceptable for an

over-the-counter drug.

DR. WOOD: Dr. Clapp.

DR. CLAPP: I think that slide--I was

intrigued by the slide yesterday because I think

207

there is such a vast difference in comparing those

medications to Mevacor. For one thing, the

cimetidine, even if you find the anal-genital

distances a little wider or smaller, I don't think

it is comparable to holopresencephaly for some of

the skeletal defects that are suggested, perhaps

not proven but associated--or there is an alleged

or concern of an association between this

medication and that specific birth defect.

DR. HEMWALL: Yes.

DR. CLAPP: I am sure there is a lot of

distance for argument and for more information but

I don't think it is comparable. Secondly,

epinephrine--do you mean epinephrine that is used

for resuscitation for those who are in status

asthmaticus?

DR. HEMWALL: It is ephedrine.

DR. CLAPP: Is medication that is used by

a physician. It is not over-the-counter. So it is

something that is used at the discretion of a

physician administering it to a patient which is

not comparable to a patient buying an

208

over-the-counter medication.

The ibuprofen and fetal-duct constriction,

as I recall, happens during the third trimester of

pregnancy if there is an exposure to ibuprofen, the

duct anomalies. Ibuprofen; it is over-the-counter

but, perhaps--there is no warning on it but, as I

recall, that is a third-trimester exposure that

might be associated.

DR. HEMWALL: You are absolutely correct.

DR. CLAPP: So that is the difference

between something that, perhaps, there is an

association made but not proven in the first month

or two of pregnancy when a women would not be aware

of the pregnancy.

But, for a women who is taking

over-the-counter ibuprofen, she knows that she is

six-months pregnant by that time. Finofibrate, I

have no knowledge about that.

DR. HEMWALL: That is just a comparison of

a another lipid-lowering drug.

DR. CLAPP: Is that an over-the-counter

medication? I don't think so. So there is a

209

difference. Even though those are Category C--

DR. HEMWALL: Correct.

DR. CLAPP: The outcomes are different and

the method of obtaining them is vastly different

than that--

DR. HEMWALL: I agree with you on all

those points. The point I was trying to make is

that animal data can be found in a whole wide range

of drugs and most of the drugs are normally

classified Category C because there is actually a

benefit to use those drugs. You could see the same

thing in drugs for asthma or diabetes.

If we then just look at the clinical data,

which you saw another presentation of the same

clinical data that was presented yesterday in the

Open Public Session today, the FDA has reviewed

those data and the quote that the Office of Drug

Safety put in their review was that a causal

association between in-utero statin exposure and

identified birth defects cannot be made based on

this information.

So I want everyone to just try to put this

210

all into perspective of what the actual risk may

be, given the fact that half a million women in the

prescription setting are being prescribed statins

every year of childbearing potential, that there

may be an incremental increase in that number with

the OTC availability and we are very committed to

minimizing and making sure that those women that

could be come pregnant get a much, much stronger

label message than is currently in the label as we

have proposed today.

We are willing to work with FDA along

those lines.

DR. WOOD: Let's make sure the sponsor has

a chance to respond to these questions. Are there

questions from the committee that they want to put

directly to the sponsor about this specific issue?

Dr. Makris?

DR. MAKRIS: I just think that it is very

difficult to try and estimate what the risk

actually is because there really are some

uncertainties. Some were brought out this morning

that the human incidence data may actually be an

211

indicator or some birth defects.

In addition, in the animal data, there are

indications of behavioral alterations in offspring

that I don't think have been explored adequately to

determine whether or not these effects, in fact,

are attributable to early gestation exposures in

the animals or if they are relevant to humans.

Certainly, that is a type of birth defect,

a type of developmental anomaly as a functional

effect. So I think that these things have not been

adequately explored and probably need some

additional study. But it also prohibits us from

really getting a good handle on what the risk is.

I think that discussion about fortifying the label

is really appropriate in this situation.

DR. WOOD: Are there other questions that

we can put directly to--Frank, do you want to put

yours directly to the sponsor?

DR. DAVIDOFF: This is really more by way

of a comment on the very interesting data that

close to a half a million prescriptions are being

written for women in reproductive years for

212

statins, or perhaps it was particularly for

lovastatin, because I think the point here, or

there, is that those prescriptions are almost

certainly being written for women who are at really

quite high risk, high enough, of cardiovascular

events to warrant prescriptions for statin drugs.

Here we are dealing with a matter of

benefits being weighed relative to risks. Since,

as I hope to be able to talk more about this later,

I think the presumed benefits from the targeted

group for OTC lovastatin are at least an order of

magnitude, perhaps more, less per unit of

population than they are in the prescription

setting.

I think that shifts the benefit:risk ratio

here. So, even if the risk is really quite small,

as I am sure it is, for bad fetal outcomes or

pregnancy outcomes from lovastatin, I think that

you can't really extrapolate from those 400,000 or

500,000 prescriptions and the benefits that might

be expected from those relative to the risks for an

adverse pregnancy to the over-the-counter situation

213

where I think the balance of benefits and risks is

going to be very different.

DR. WOOD: Any other--Dr. Fincham?

DR. FINCHAM: Just a comment. In my own

mind, I cannot make the analogy between

nicotine-replacement-product labeling and what the

issue is with lovastatin in that pregnant women who

smoke are at risk, period, and they use

nicotine-replacement products. Is it less safe?

More safe? I don't know.

The only analogy I can see with lovastatin

is perhaps is somebody is using an herbal product

imported from the east that may have some of the

drug in it. So, in my mind, I would encourage us

not to talk about nicotine-replacement products in

this context. That is just an opinion..

DR. WOOD: Dr. Taylor?

DR. TAYLOR: Again, just a comment.

Lovastatin remains a Class X; is that correct?

DR. WOOD: Right.

DR. TAYLOR: I don't think we need to

forget that. Secondly, the medications that were

214

on the slide were mostly intermittently used

medications for symptoms whereas this medication is

proposed for chronic use over years. So I think we

have to factor that into whatever decision we make

relative to risk.

DR. WOOD: Dr. Carpenter?

DR. CARPENTER: Just a comment amplifying

Dr. Clapp's appreciated comments. There seems to

be a little concern of a mixed message that may

come through when looking at the label and

listening to the nature of the way, perhaps, we

heard this morning from the consumer groups, the

way this medication is already being perceived and

may be advertised in the future, and that is as a

more natural, more wholesome product.

I am concerned that, particularly in this

pregnancy setting, when the big picture and the

advertising and television and the color photos in

the store are going to convey this message and the

label is going to mention, don't take it if you are

pregnant, that the latter may get a much lesser

play.

I would challenge that the sponsor needs

to not only consider the label but consider the

nature of that kind of advertising approach,

215

although FDA, I know, has little to do with that.

But has there been any consideration in terms of

how to work out a theme regarding this issue given

the nature of the mixed message that you can sort

of see at present in this regard?

DR. WOOD: Okay. Here is what I propose

we do. I think this is obviously a very important

issue and I don't want to, in any way, short-change

it. So I think what we could do is to take our

lunch break now, return at 12:45, make sure we

complete our discussion at that time and then take

a vote. That will also allow the sponsor to give

any thought that they want to make any responses

after that.

I had hoped we would finish before lunch,

but that is out of the question. So we will be

back at 12:45 and start promptly.

[Whereupon, at 12:00 p.m., the proceedings

were recessed to be resumed at 12:45 p.m.]

216

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

[12:45 p.m.]

DR. WOOD: All the committee seem to be

back but we seem to be missing the FDA staff. Is

that right? We have all the committee?

As you remember, we left this issue, the

pregnancy issue. When we were broken, I tried to

reformulate the questions a little bit and see if

this works for people. I made the first question,

have you heard data that suggest to you that this

drug is so potentially toxic to the fetus to

prevent it ever being marketed OTC under any

circumstances. So, disregarding all the other

stuff about labeling and all these sorts of

questions first, within the context of what we

think about with any drug, and the relatively very

limited number of reports of any toxicity here,

whether anyone really thinks that is the case.

The second question was going to be is the

proposed labeling adequate to exclude women of

childbearing potential from taking this drug based

on the CUSTOM study or whatever other data we have

217

seen. If the answer to that is either yes,

obviously, or no, and, if it is not, what would you

want to see that would be adequate to get you to

the stage that that would be appropriate?

Does that sound helpful to the committee?

So let's proceed on that basis and let's discuss

the first question which I will repeat for

everybody's benefit. Have you heard data that

suggest to you that this drug is so potentially

toxic to the fetus to prevent it ever being

marketed OTC under any circumstances.

So, ignoring the quality of the labeling

studies, ignoring all that stuff for the moment,

just looking at the biology, if you will, what do

you think?

Now, do we want to have some discussion on

that first? Yes, Frank?

DR. DAVIDOFF: I appreciate your

reformulating that first question, but you have put

it in extraordinarily absolutist terms. I mean, it

is hard to vote on something ever being available,

et cetera, et cetera.

DR. WOOD: You are an editor, too. Give

me some--

DR. DAVIDOFF: I think it is just asking

218

for a kind of judgment that is very--

DR. WOOD: All right. We will soften it a

bit. But you get the sense, anyway. I meant it to

take an extreme position and then we can move back

from there. Can we have some discussion on that

first? No? Are we ready to vote on that? Then

let's take a vote on that.

DR. FINCHAM: Alastair, I am not sure

everybody was in the room when they heard your

reformulated questions. I was, but--

DR. WOOD: Then let me reread them again

with Frank Davidoff's proviso. My question is;

have you heard data that suggest to you that this

drug is so potentially toxic to the fetus to

prevent it ever being marketed OTC. I said, "under

any circumstances," to remove from this discussion

labeling issues and all the other kind of issues

that we are going to get to under the second

question.

The second question was; is the proposed

labeling adequate to exclude women of childbearing

potential from taking this drug based on the CUSTOM

study or whatever else you have seen. A sub of

that is, if your answer to that was no, what would

you want to see that would be adequate?

219

So let's start with Neal Benowitz. The

question is--let me make sure we understand which

way we are answering this. Have you heard data

that suggest to you that this drug is so

potentially toxic to the fetus that it would

prevent it being marketed. If you think you have

not heard such data, your answer would be no.

DR. BENOWITZ: Are we doing both questions

together?

DR. WOOD: No; just one question to start

with.

DR. BENOWITZ: My answer I think that it

could be marketed OTC with the proper warnings.

DR. WOOD: Maybe everybody should state it

like that so there is no confusion.

Dr. Caprio?

DR. CAPRIO: Yes.

DR. WOOD: Why don't you state it like

Neal did so there is no--if you are endorsing the

Dr. Benowitz provision--

DR. CAPRIO: Yes; with Neal.

DR. WOOD: All right.

DR. BLASCHKE: A third for Neal.

DR. CARPENTER: A fourth.

DR. PARKER: Fifth.

220

DR. DAVIDOFF: I would not endorse on the

basis of what I have heard so far.

DR. WOOD: So you are against Neal.

DR. DAVIDOFF: Maybe that, too.

DR. WOOD: I just want to make sure that

you would not endorse this marketing under--

DR. DAVIDOFF: Right.

DR. WOOD: Okay. Good.

DR. PATTEN: I also would not endorse.

Part of the problem, I think, is that, in this

large number of women that have been exposed Rx, I

have heard nothing about studies of the child

post-birth developmental problems, behavioral

221

problems. We know nothing of that.

DR. McCLUNG: I agree with Neal, so I

would endorse.

DR. CLYBURN: I endorse it as all.

DR. MAKRIS: I would endorse it

recognizing that there are uncertainties and that

the labeling may be able to handle that.

DR. SCHADE: I endorse it.

DR. TAYLOR: I would not endorse it.

DR. SCHAMBELAN: I would endorse it.

DR. WOOD: I am with Neal.

DR. TINETTI: I would endorse.

DR. WATTS: I would endorse.

DR. NEILL: I would endorse.

DR. WIERMAN: I would endorse.

MR. SCHULTZ: I would endorse.

DR. FINCHAM: I, too, would endorse.

DR. SNODGRASS: I would not.

DR. WOOD: Let's get a tally here. Oh;

let me read to you the question--did you hear the

questions? No?

DR. WOOLF: No; sorry.

DR. WOOD: We divided the issues into two

questions. The first question was; have you heard

data that suggest to you that this drug is so

222

potentially toxic to the fetus to prevent it every

being marketed OTC under any circumstances. The

purpose of that was to try and dissect out labeling

issues, all of the uncertainty of that. So we are

talking here about the biology, not the other

issues.

The second question was; is the proposed

labeling adequate to exclude women of childbearing

potential from taking this drug based on the CUSTOM

study or whatever else you have seen and, depending

what you think about that, if you thought no, then

we would want to know what you would want to see

that would be adequate.

So we are not dealing with that question

right now. We are just dealing with the first

question.

DR. WOOLF: I think there is a potential

problem.

DR. WOOD: Dr. Follman, did we get a--

DR. FOLLMAN: I would endorse it.

DR. WOOD: So we have 19 yes and 5 no.

Dr. Clapp is not back yet.

Let's move on to the second part of that

question, then, which is the more operational

issue. The operational issue is, is the proposed

223

labeling adequate to exclude women of childbearing

potential from taking this drug based on the CUSTOM

study or whatever other data that we have seen out

there.

Dr. Parker is not here but I am cognizant

of the fact that there are other exclusions that we

talked about coming back to later and we should

come back to them later as well.

So, can we have some discussion on that?

Go ahead, Dr. Makris.

DR. MAKRIS: I was just going to ask if,

as part of this, we are going to be recommending

some changes or just that some changes happen and

that these be put forward by the sponsor.

DR. WOOD: I think we have the option to

do both. I think the first question is to decide

224

if we think what was presented was adequate and, if

not, then I guess I would imagine it would be

helpful to the agency and to the sponsor to hear

what kind of changes we would be looking for that

would provide an adequate labeling package or

whatever issues, a package that was used measure to

the patient's understanding or whatever.

Frank?

DR. DAVIDOFF: I am not sure that I can

think of package labeling per se that would

reassure me enough because the CUSTOM study are

really not reassuring. I would, however, be quite

supportive of a behind-the-counter mechanism and I

wonder if this discussion and this potential action

might not be useful in that it might trigger a

serious discussion and proposal for moving in that

direction.

I realize the FDA or this committee

doesn't have the jurisdiction on that, but, in

terms of really getting a serious debate going, I

learned, during the lunch hour, that, as I

understand it, a number of states have actually now

225

legislated behind-the-counter mechanisms as legally

empowered. So I wonder if that might not--the time

might not be ripe to move in that direction.

DR. WOOD: Dr. Fincham?

DR. FINCHAM: If I might add, that is on a

very case-by-case specific basis. It deals with,

perhaps, cough syrups that contain codeine and

other types of products so it is not across to

board. It is certainly a case-by-case basis.

DR. WOOD: That is one issue to think

about. There are others as well. Dr. Parker?

DR. PARKER: I would just say that, from a

methodologic standpoint, I have concerns about both

the label comprehension and the CUSTOM because I

think, at the end of the day, what we are looking

is to see can people understand what they need to

know in order to be able to adequately self-select

and use.

I don't think we have as much information

about that as we need. One of the concerns that I

have methodologically is that I think the real

experts about product understanding come from

226

users, users and non-users. In the studies that

were done, we really do not have insight from the

population, for example, that self-selected to use

incorrectly.

I think there is very valuable information

that could be gained methodologically by

approaching those studies differently. So I think

that, really, what is required is more rigor

methodologically to look at both label

comprehension--I cannot understand doing a

label-comprehension study and not making its

results a part of an actual-use study saying that I

understand that there were thousands that were

tested prior to that.

But, unless the results of the

label-comprehension study are perfect, then it

seems like the results of that study could be fed

into the actual-use study in order to make the

label that then goes forward even better.

I think, certainly, the work that has been

done in health literacy which points out that we

have 90 million Americans--and I must say, given

227

the size of that number, many would say that that

does represent the skills of "an ordinary American"

whose struggle with very common, everyday tasks

like using a bus schedule, that the task is

daunting to take something as complicated as this

and make it something that the ordinary citizen can

understand.

The solution is not dumbing down the

information because the information is too complex

to be dumbed down. The solution is to figure out

now to effectively communicate very complicated

information that is absolutely essential for

self-management. I absolutely do applaud the

efforts to try to encourage self-management.

I think that the science, the methodology,

has got to be so rigorous to advance our ability to

communicate very difficult information and that is

really where we are stuck. I think that the people

who didn't self-select correctly and became users

did so because they didn't understand what they

needed to do. I can't imagine that they wanted to

just go buy it and do it.

So I think it is going to take stepping

back from that. The real experts are the users,

the users and the selectors and non-selectors. We

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are going to have to take that population and

really partner with them to see what we can learn

in order to get the kind of information that is

really required for adequately being able to

self-manage.

DR. WOOD: I have two--first of all, a

Chairman's comment. I would like us to confine our

comments at this point just to the labeling as it

relates to child-bearing potential because we are

going to come back to other labeling issues later.

Then I have my own comments on this question, if I

can make some.

I can't see how we can possibly say that

the labeling is adequate given that only 1 percent

of people got it right and not even the most

liberal schools with great inflation and so on

would allow to think that was a particularly great

great. So I think the answer is that the label

comprehension studies and others need to be redone.

But it seems to me that is something that

could be negotiated between the FDA and the

company. So I think they are not adequate right

now. I can't imagine how we could say they were

adequate given the data.

But I would like to, having said that,

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suggest that we introduce very rigorous criteria

for determining that women of child-bearing

potential exclude themselves based on a

label-comprehension study. That seems to me fairly

easy to do, fairly easy to test, and it might have

to be tested multiple times to find the right

approach to do that.