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
Friday, January 14, 2005
8120 Wisconsin Avenue
Alastair Wood, M.D., Chair
LCDR Hilda Scharen, M.S.,Executive Secretary
MEMBERS OF THE NONPRESCRIPTION DRUGS ADVISORY
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
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
Susan Makris, Ph.D.
Special Government Employee Consultants:
Richard A. Neill, M.D.
James Schultz (Patient Representative)
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
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
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
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
In accordance with 18 USC 208[b], 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
DR. WOOD: Thank you very much. Perfect
timing. The next speaker is Penny
Kris-Etheron and the speaker following her is
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
DR. WOOD: Thank you very much to all the
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.
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: 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
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
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
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
DR. WOOD: Okay; that is a good point.
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
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
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
DR. WOOD: Dr. Hemwall, do you want to
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
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
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
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,
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
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
DR. HEMWALL: Yes; that is a good point.
The very first thing on the label--
DR. CLAPP: Excuse me. Let me just finish
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
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
I will take the slide now, Slide 174 from
the core deck.
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
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.
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
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
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
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
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
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
product. I am not sure if we have a breakout by
race or gender on diet and exercise. Do we have
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
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
DR. TAYLOR: One other question. In your
pharmacy promotional information, your pharmacy
intervention, how would you ensure that there would
be language compatibilities at the point of sale of
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
DR. HEMWALL: In neighborhoods where the
language is predominantly Spanish, we would have
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
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
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
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
So I am wondering what the health
consequences are for starting and stopping,
starting and stopping, this medication at this
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
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
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
The diet, the exercise and the medication
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
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
DR. GOTTO: It depends on how much the LDL
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
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
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
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
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
DR. CARPENTER: Correct.
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.
Is that a fair summary of what you are trying to
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
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
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
DR. WOOD: So your question is, is it
aimed at people with the anal group or the people
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
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
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
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
likely to see a doctor in using this, whether they
use vitamins and supplements. Everything is very
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
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
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
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.
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.
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
DR. TINETTI: That was only for six
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
DR. COHEN: Yes.
DR. WOOD: Dr. Clyburn: That was actually
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
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
But, in terms of the total population, the
total population gap, proportionately, in terms of
the population, it is very similar to the United
DR. WOOD: Dr. Parker and then Dr.
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
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
DR. GANLEY: Please write to your
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
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
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
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
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.
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
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
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
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
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
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
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
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: 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
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
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
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
DR. WOOLF: Absolutely.
DR. WOOD: Dr. Benowitz.
DR. BENOWITZ: I wanted to ask and follow
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
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
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
DR. LEVINE: I don't know. I just have
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: 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,
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
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
self-select appropriately and that, if they do make
a mistake, as I said, that they will still get from
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
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
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
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
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
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
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
good thing but the best way to handle this is
through some kind of coordinated public-health
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
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
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
concerned about their health. I am asking about a
person who might fall into the category of the
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
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
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
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
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
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,
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
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
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
DR. GOTTO: Yes. That certainly is the
case and some of the patients in the Heart
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,
DR. GOTTO: That's correct.
DR. WOOD: Then let's move on to the
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
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
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
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
Then, of course, the last question is the
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
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
seen speaks to the inadequacy of the Rx efforts as
Okay. So, Neal, you are giving a
DR. BENOWITZ: Yes.
DR. WOOD: Yes; a qualified yes. Keep
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
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
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
DR. WOOD: So, pull the lever. Is it yes
DR. McCLUNG: It is yes if you have to be
categorical. But there is always--it is not quite
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.
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
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
DR. TINETTI: I think he question is
really different if you include or not include the
part in parentheses.
DR. WOOD: I understand that.
DR. TINETTI: And you told us to ignore
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
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
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
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
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: 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
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
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
DR. ORLOFF: I want you to delete the
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
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
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
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
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.
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
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.
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
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: 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
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
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
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
DR. WOOD: I see. Okay.
DR. BENOWITZ: I was talking about
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
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
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
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
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.
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
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
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.
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
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
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
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
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
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
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: 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
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: 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
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
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
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
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
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
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?
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
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.
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
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
So what we are saying here is that the
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,
DR. HEMWALL: We don't have that readily
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
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
DR. HEMWALL: In a very strict sense, it
would. But there is a lot more kinetics around it
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.
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
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
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
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,
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
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
I was wondering how a patient is supposed
to know about the cyclosporine issue which has also
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
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
On the question of cardiac-transplant
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
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.,
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
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
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
630 of our 3,316 evaluators who were on any
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
I am going to start with Dr.
DR. WIERMAN: Somebody has asked you to
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.
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: 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.
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,
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.
DR. MEYER: There is actually, just to
directly respond to that, some interesting data
about use of symbols, though. For instance, there
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
pregnancy and no demonstrated behavior during
pregnancy and, therefore, that would make it
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
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
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
forms of contraceptive.
DR. WOOLF: Absolutely. So that is the
upper bound. But it is per year, so it is a
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
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
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
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
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,
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
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
DR. WOOD: Okay guys, does that put you on
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.
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
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
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
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
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
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.
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
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
DR. WOOD: Dr. Clapp.
DR. CLAPP: I think that slide--I was
intrigued by the slide yesterday because I think
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
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
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
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
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
So I want everyone to just try to put this
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
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: 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
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
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
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
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
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
I would challenge that the sponsor needs
to not only consider the label but consider the
nature of that kind of advertising approach,
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
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.]
A F T E R N O O N P R O C E E D I N G S
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
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
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
DR. DAVIDOFF: I think it is just asking
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
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?
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
DR. WOOD: No; just one question to start
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: 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.
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
problems. We know nothing of that.
DR. McCLUNG: I agree with Neal, so I
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
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
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
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
DR. WOOLF: I think there is a potential
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
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
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
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.
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
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
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
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
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
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
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
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
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
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,
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.
Other questions? Suggestions? Charlie?
DR. GANLEY: I think the one thing that is
worth having some discussion about in response to
these answers, not just directed at the women of
child-bearing potential, but when you think about,
if you go to Dr. Shetty's review where it went down
and it threw out the people where they made errors
and you end up with about 10 percent, I guess what
is somewhat difficult for that is that you have to
go through these multiple levels, one after
another. I suspect that a lot of us wouldn't get
them right in the end.
And so it becomes important, well, what
are the important things that someone really needs
to know in that hierarchy--what is your hierarchy
here? Is it important that you know your
triglyceride? Is it important that you know what
your HDL level is. It is hard to understand why
people didn't get the age thing right and there
wasn't more information on that.
But I think, as you go through this and
you keep asking questions and these different
points are in different parts of the label, it is
not totally surprising you get down to 10 or 20
percent. It is not surprising to me, in the
actual-use study, that you don't have 100 percent.
But I think it would be important for us
to understand what are the important things there
that the committee thinks the consumer needs to
know in that. Their cholesterol is important. Do
they have to absolutely know their LDL cholesterol?
The British have a different model. They don't
care what your initial cholesterol is. They do
care afterwards, apparently.
But that is an important thing because
half the people in her analysis, about 50 percent
of the people, got thrown out because they did not
get the LDL cholesterol right. Is that a dead-end
then, if they can't get that? So those are the
things, I think, that would help us in the course
DR. WOOD: I agree with that. I actually
think that the entry criteria were far too rigorous
and that a much larger proportion of the population
would benefit from the drug and then were defined
by that. I am not sure it is the least important
for this population to know what their HDL was. I
am not ever sure how important it is for them to
know what their LDL was. I am certainly sure it is
not important for them to know what their
triglycerides are at that stage.
I think, to ask people to remember three
numbers and kind of manipulate these is almost like
these tests for Alzheimer's that most of us would
fail, probably, if we took it.
So what I am suggesting, I guess, is that
we have a much more organized test that tests the
things we think are critically important and avoid
confusing people with a bunch of other information
that they don't need.
DR. FOLLMAN: I would like to talk about
one methodologic issue in the CUSTOM study that I
thought was sort of unfair and may have contributed
to the low percentage of people being correctly
So, if you look at the label, it says, do
you know your numbers within the last year. So
let's suppose a year ago, I got my LDL--
DR. WOOD: Hang on. We are talking about
pregnancy right now just.
DR. FOLLMAN: Never mind.
DR. WOOD: So let's get to that because
that is one of the questions down here. So let's
just focus on the pregnancy issue. Any further
discussion on labeling for pregnancy? Yes?
DR. CARPENTER: Just looking at the
current box, there is simply the statement, do not
use if you are pregnant or breast-feeding. I think
that message should be strengthened enormously. I
think there should be a rationale provided. I
think that people remember things better or pay
more attention to them if there is some indication
of the consequences.
I think some of the data presented this
morning, although we don't have strict incidence
data that we can use in a label, it certainly
provides an association between not a simple or a
limited defect but a very severe congenital defect.
I think I care for some of the children with
holopresencephaly and, believe me, it is not like
anal-genital distance problems. With that
association, some allusion to the severity of the
consequences needs to be on this box.
The second piece is that the label is
really the gestalt of the whole presentation and I
think the sense that this is a natural product and
wholesome needs to be, perhaps, played down
although it is considered one of the selling
DR. WOOD: Any other comments? Dr.
DR. SNODGRASS: With regard to women of
child-bearing age, it seems to me that you could
think about the possibility of a large black-box
warning equivalent. But then that still, perhaps,
may not be 100 percent what you want. Then you
could get into, well, can you, in an
over-the-counter situation require pregnancy
testing--I don't see how, logistically, that would
be feasible in an OTC setting--but require
pregnancy tests before you can purchase or use this
In the absence of that, then going back to
saying, do a large prospective study of the 400,000
or whatever number of women are using this per year
to look at outcome, actually, in depth,
prospectively look at outcome because, if that data
is pretty strong, then all these others become less
of a consideration, and it is strong that it is not
a significant human teratogen, then these others
become less of a consideration.
DR. WOOD: Dr. Parker?
DR. PARKER: Just as a comparison, I think
the Heart Health Questionnaire that we used in the
U.K. starts at the very beginning, I think, just as
a model to compare in terms of clarity and ability
to understand. At the very beginning, it starts
with, are you male, 45 to 54, 55 and over, or
female, 55 and over. If you are not, that is it.
It seems that the age alone relates very
specifically to child-bearing potential. In terms
of prioritizing the need to know in order to be
able to do what you need to do, I would consider
this as a model which was not tested in the
DR. WOOD: It also asks whether you have
reached the menopause which would broaden the group
a little bit and still prevent pregnancy.
DR. PARKER: Just an alternative model to
DR. WOOD: It asks both, actually. Any
other discussion? Dr. Makris?
DR. MAKRIS: It might be worthwhile just
beefing up some of the language about pregnancy
because just asking the question or saying, do not
use if you are pregnant or breast-feeding, that
presumes that somebody knows already that they are
pregnant. But there may be women who actually are
trying to become pregnant and who are not pregnant
yet and, perhaps, it should say, if you are trying
to become pregnant or if you think you might be
pregnant, to include those as well.
DR. WOOD: Or you think you might become
pregnant, I guess. Dr. Woolf?
DR. WOOLF: I have a bit of a dilemma.
One the one hand, we are telling people, women, not
to take it unless they are 55 and older and unless
you are in Italy and there are very unusual
circumstances, none of those women are going to
On the other hand, how are we going to put
on the label if, by any chance, you are less than
55, that you have to do something and you could get
pregnant, what are you going to do about it? So
how do you put that into a label?
If it is going to go into the label, I
would strongly urge that it says that if you think
you may be able to get pregnant, that you need to
speak to your physician prior to starting Mevacor
OTC. But I don't know how you deal with the two
parts of that.
DR. WOOD: I think part of the problem
right now, and the Chairman should shut me down, is
that the exclusions and contraindications are mixed
up with the indications. So, for instance, you are
told not to take it if you have got heart disease.
But that is not because heart disease is an
exclusion. It is because heart disease actually
means you must take it and you should be seeing
your doctor to take it.
You are told not to take it if you might
be pregnant. Well, you know, these are orders of
magnitude different in terms of contraindications.
One is a contraindication and one is not. So all
of that needs a lot of polishing and work it seems
to me. But I agree with you. I think that could
be separated out.
Any other comments? Do we need to vote on
the question of whether we think the labeling is
adequate? Does anyone think the labeling is
currently adequate? If so, speak up.
We have had a discussion on the changes of
the label that speak directly to the pregnancy
issue, so I think we can pass--sorry; Dr. Makris?
DR. MAKRIS: I think it might be
worthwhile to talk about the idea of recommending
further testing although that was part of the
question that was laid out here and a number of
folks have actually brought that issue up. I think
it is worthwhile maybe discussing it more.
DR. WOOD: Testing for--pregnancy testing?
DR. MAKRIS: No--well, additional testing,
or additional studies, a prospective--
DR. WOOD: Oh; teratology testing.
DR. MAKRIS: Yes.
DR. WOOD: Oh; I see. Okay. Any
discussion on that?
DR. McCLUNG: I would propose that we wait
and do that after we discuss the rest of the
labeling issues. It is not specifically confined
to the pregnancy issue and we have got more to
discuss about that. At the end, I think that is an
important thing for us to come back to.
DR. WOOD: Okay. That sounds like a good
In that case, we will move on to Question
5. Question 5 is; does the frequency of
appropriate self-diagnosis and self-selection
support the conclusion that lovastatin 20
milligrams can be used safely and effectively in
the OTC setting. Please describe which analysis
influenced your decision.
Any discussion on this? Does that mean
everybody thinks it worked? Dr. Woolf?
DR. WOOLF: This may be a radical approach
but I think the CUSTOM study was a failed study.
The way it was set up, only 10 percent of the
population actually met the criteria. Half the
patients didn't have a cholesterol to begin with.
For some reason, people couldn't understand their
age and then we can debate whether it is important
to know your HDL or not.
So, if you simply look at the study from
that standpoint, the answer was that it didn't
work. If you then add a whole bunch of ad hoc
analyses after that and add some common sense, you
say, well, people selected themselves properly.
But that is equivalent to saying, well, why did we
do the CUSTOM study at all because we can just use
some common sense. If you are middle-aged and you
are overweight and you have a family history, you
probably have an elevated cholesterol, and your
cholesterol is too high and you ought to do
something about it.
So I don't the CUSTOM study was terribly
convincing at all. So, therefore, I can't use it
to support the over-the-counter indication.
DR. WOOD: Okay. Any other discussion?
DR. TINETTI: I have some concerns as
well. I think the problem is that we are talking
about this new model of long-term treatment for an
asymptomatic condition and, unfortunately, the
actual-use studies are still in sort of the old
paradigm. So, almost by definition, they are not
set up to answer the kind of questions we are
But, in addition to that, is, even in the
best scenario, people who volunteered to be part of
this study and had incentives to participate had a
difficult time self-selecting and most of them said
they had to talk with their physicians which,
again, begs the question, is that an
In addition to that, there is a small
number of older people--the low literacy was set at
eighth grade which is probably higher than what
most people would consider low literature. So I
think, in many levels, this study does not address
the questions that I think will be important in
DR. WOOD: Any other discussion? Dr.
DR. FOLLMAN: This is a point I tried to
make earlier. It has to do with defining who met
criteria or not. According to the label, if you
have your cholesterol test done within the last
year and your numbers are acceptable, and you meet
the other risk criteria, you should take the
That is not the way things were counted
here. Let's suppose that three months ago, I took
my LDL and it turned out to be 150. Let's suppose
I meet all the other criteria for the test.
I go to the CUSTOM study, get a
finger-stick test and it is 182. Now I am not any
longer eligible. I would be counted as a did not
meet the criteria. I think that doesn't make sense
to me because, according to the label, I should be
meeting the criteria. Within the last year, my
numbers were in the right.
We know that the cholesterol numbers will
bounce around both because of reproducibility
errors and because of changes in time over the
course of the year. So I think, in some sense, the
methodology was overly harsh in defining who was
eligible or not.
DR. WOOD: Dr. Clapp?
DR. CLAPP: Does the REALM literacy test
test for comprehension? You can read, but do you
comprehend. So I was wondering if there is a
comprehension component to analyze for--
DR. PARKER: No. The REALM is a list of
66 words. It is a word-recognition, pronunciation,
test. You read the list of words. If you
correctly pronounce the word, it is scored as
correct. It has not measurement at all of either
comprehension in context and there is no gauge
whatsoever of numerancy which is the ability to
understand numerical concepts which are a critical
piece of the understanding needed for acting on
this kind of information. So a stronger screening
would, no doubt, give you more information about
DR. WOOD: So does that mean I would fail
on the pronunciation?
DR. PARKER: I don't know but I will test
DR. WOOD: On the pronunciation.
DR. PARKER: But I am going to use my
instrument and not that one.
DR. WOOD: Any other--Frank?
DR. DAVIDOFF: I guess I am a little bit
confused because it seems to me that we are getting
too different messages here. One of them is the
entirely laudable effort on the part of Merck to
have the target conform to the ATP guidelines to
minimize confusion, to presumably increase the
efficiency and efficacy because it is more
At the same time, we are hearing that,
well, there was an awful lot of slipping in people
self-selecting for that target group. But that is
okay. In fact, it is good because then those
people will also get some benefit.
So, in a way, the latter observation
suggests, well, why have these criteria or why have
many of them because, as Chuck Ganley says, well,
if some of them aren't very important, why put them
Well, I think the reason they are in there
is because of Merck's interest in keeping things
more targeted and more consistent. So I am a bit
hung up here between those two. I would appreciate
anyone's comments, particularly, perhaps, from the
sponsor as to what is really going on here and,
perhaps, reassuring us that this is going to be
going in one direction or the other rather than
sort of like the character in the novel who jumped
on his horse and rode off in all directions.
DR. WOOD: Do you want to respond to that?
DR. HEMWALL: Yes. I think it would be
helpful if we had a few minutes to try to return
back to the center in the sense that people are
thinking very closely to what the FDA analysis did,
which did take that very strict interpretation. If
you missed any of the ten or twelve criteria, you
went down into the bucket of "failed."
Of course, one of the elements was the
doctor interaction. That doctor interaction was
also a key element of the label-comprehension study
and that 1 percent rapidly goes up when people say
they would need to check with their doctor because,
of course, in a label-comprehension study, we had a
bunch of people that didn't know their cholesterol
numbers. This was a mall-intercept study.
But Bob Tipping would like to just take a
few minutes to come back and actually show that
this is, in fact, how the data were analyzed.
Although we took a very strict approach to stay in
line with the NCP guidelines, we looked at that
data in other ways that allowed some leeway around
those guidelines knowing that it is still a
surrogate and we are trying to approximate a
surrogate with our labeling.
MR. TIPPING: I have several comments to
make. I have heard several comments here about our
behavioral data and our comprehension data. Some
of them I agree with and some I think need some
Dr. Ganley has made a few really good
points, I think, in his opening remarks the other
day. He made the point that the health
consequences of the errors must be considered.
Then, later today, he made the point that there are
errors occurring but there has to be some
I think that is exactly what some of the
analyses that we presented tried to do, tried to
put some context around that. It was a full
disclosure. We told you about the safety warnings
but then we tried--and, actually, I believe that
the label performed extraordinarily well both in
the consumer's ability to comprehend it as well as
behave to it.
I will show you some slides in just a
minute on that. The areas where maybe the behavior
was a little bit less was around these very
criteria that we are targeting the population, do
you know all your lipids. What are your
triglycerides? That is where the behavior was a
little bit lower.
I don't think--to respectfully disagree
with what someone on the panel said, I don't think
that is because it is a strong lack of
comprehension. I think people from our
label-comprehension studies understand those
I think it boils down to them making their
own personal assessment of benefit. They don't
have the safety issues. They know that maybe while
they don't know all of the issues on this label
that have to do with the targeting a population, I
don't know what my HDL is but I know my doctor told
me I had a high total cholesterol. In fact,
80 percent of our users knew their total
They decided that, I am going to give this
product a try. I think that our analyses tried to
break that out and it showed you that greater than
90 percent were getting this safety-warning
messages, and that number fell to the 60s for the
I think the FDA analysis, which we don't
argue with the numbers that underlie all of it, but
it was very much a hierarchical approach that
required compliance to each and every one of those
To Dr. Ganley's point, I am not sure that
that approach takes into account the clinical
consequences of behavior around those elements.
So, with that sort of passionate speech to start
DR. WOOD: Dr. Benowitz? Oh; I'm sorry.
Dr. Neill first.
MR. TIPPING: I would like to show you a
DR. WOOD: I'm sorry. I thought you were
MR. TIPPING: I will hurry this along.
DR. WOOD: Be quick.
MR. TIPPING: If we could see Slide 122.
DR. WOOD: Very few slides. Okay?
MR. TIPPING: Okay.
Again, this is to remind the group of a
slide that I showed in my presentation which talks
about behavior around the safety warnings in the
label. They are listed as warnings for the initial
use. You see many of the evaluators with these
conditions and very few, the yellow bars, that are
actually using it. 80 people who came and said, I
have liver disease, only three used.
That, to me, is a lot better than 10
percent behavior around these elements. Twelve
pregnant women; none of them chose to use. This
had nothing to do with a physician interaction that
mitigated this behavior. Those twelve pregnant
women chose not to use the product.
Potentially interaction medications.
There were 152 of our evaluators. Only ten of them
chose to use and there were no--and this gets me to
another point. So that is behavior around this
element, but you have to put it in context. What
is the absolute risk to this group of people?
We have heard that people taking
potentially interacting medications with Mevacor,
maybe the rate of rhabdomyolysis is 1 in 50,000
patient treatment years. So you have to kind of
look at that and say, with that background rate, if
there is this population of people that are at risk
doing that and we keep this many from doing that,
then you have to apply that factor. So the rate
would drop from 1 in 50,000 or 1 in 100,000 patient
years if we take 152 of the 162 that would expose
themselves to that risk out of the equation.
So I think, in interpreting some of the
behavior, I think we have to be careful to put it
in context to the actual extremely low background
rate of the actual adverse experiences that we are
worried about here.
Let me do one more slide. Give me Slide
This slide specifically talks about the
people that came to one of the sites with a history
of muscle pain. The label is very clear and its
message is about that, don't use the drug, talk to
One point I would like to make is that the
label is effective in raising awareness of this
issue because 300 of our evaluators, nearly 10
percent, came and said, "I have had a history of
that." So it is very important. I think the level
is effective in raising that level of awareness.
And it is working, to a large degree, and that 5
out of 6 of this 300 didn't use the product. 53
What is the consequence of that? Well, 13
of the 53 reported some drug-related muscle symptom
during the study and, again, how much did all of
the label messages kind of raise the awareness of
But, then, what is the behavior in this
group of 13? It is a small number of people but 11
of the 13 make the appropriate decision to stop and
stop taking the product.
So I just wanted to show a few of these
slides to say that there is another interpretation
of our behavior looking at specific elements of the
label that are of particular concern and I think we
actually have exceptional behavior.
DR. WOOD: Okay. Dr. Neill.
DR. NEILL: If you are over 45, and you
are exercising, as everybody is that takes this
medication, and you don't have muscle pain, I want
to know who you are because you are not doing the
But, more importantly, I think, among
those users who reported these symptoms and chose
to take the medication anyway, we haven't seen data
regarding the attitudes that inform their decision
to use this despite whether they comprehend or
I feel confident that there may be some
who choose, as a result of this proxy, the box,
which is a proxy for informed consent which, of
course, in a physician's office is detailed,
rigorous and perfect. But I am confident that
people who see this box and use the information on
the box in the process of using it as a proxy for
that informed consent that some of them recognize
those symptoms. They know they have diabetes.
They know they have these other high-risk
conditions and choose this because they can't get
any of the other things because they are not
They can't get any of the other things
because they just don't have insurance this month.
I do think that, in part, some of those attitudes
inform what may of us have as an opinion regarding
the potential public-health benefit. I don't think
that we should let it be lost that, however small
that effect may be or however few those patients
may be, who really should be treated at a higher
dose and really have to see their doctor.
The bottom line is, they don't. If they
get some benefit from this, that is better than
nothing. The question seems to be whether it is
worth the risk to somebody else. Is the risk of
them receiving some small benefit and not dying
this year from their massive heart attack, even
though they have metabolic syndrome and all the
other things for which they have not seen a
physician, and if you have any concern that there
are patients with metabolic syndrome that don't see
physicians, come to my neighborhood.
Walk down the street. I will show you 20
in five minutes. They don't see physicians for
this and are not being treated. I do believe that
there is some benefit for that. So, for me, while
a strict reading of this Question 5 and especially
the detailed analysis that Dr. Shetty presented
yesterday suggests that people do not appropriately
self-select according to every criteria on the
I still believe that patients within the
CUSTOM study have been able to glean the
information that they need to tilt that
risk:benefit equation towards benefit. I admit to
there being some degree of faith in that given that
the benefit to me is not one I can measure for an
individual patient but it is a benefit that accrues
from the use of this medication in the OTC setting
at the public-health level.
When somebody wants to fund that study,
let me know. I would be happy to be a P.I. for
DR. WOOD: Dr. Wierman?
DR. WIERMAN: The majority of the focus
and the discussion recently has been in the CUSTOM
study about how well it did to prevent people who
would be at risk for the side-effect profile from
getting the side-effect profile and the absolute
low risk of potential toxicity of the drug.
I was more concerned with the FDA
presentation about how poorly it did in having
people correctly self-select for the target
population. So how well--the data suggested that
the people who this drug is appropriately targeted
for in the appropriate label did not pick it. So
we have talked about how well it did in preventing
people from getting side effects.
But I would like to refocus the question
on was this an adequate evaluation to prove that we
have developed tools to be able to allow the
population to self-select the drug for the
appropriate reason, to take it for the right reason
instead of potential risk.
DR. WOOD: Dr. Benowitz?
DR. BENOWITZ: I think a lot of the issues
that I was going to talk about have been dealt
with. But I guess the question, as asked, doesn't
exactly say, according to the labeled
criteria--because I think the CUSTOM study, as
everyone says, has got a lot of problems,
especially self-selection based on lipids.
But there is evidence that it is pretty
safe, especially if they can deal with the age
issue. And the efficacy, if you do look at a shift
of LDL cholesterol, there is the same shift of
cholesterol in the population as has been seen in
controlled clinical trials with a 25 percent
reduction of LDL cholesterol.
So one could say that that is effective.
I guess I need some guidance as to how to answer
DR. WOOD: I agree. The problem with the
question is, I think, the committee doesn't buy
into the criteria that were used for entry into the
study in totality. Is that fair? We don't buy
that and we actually think it should be more
liberal, just so everybody understands that.
Therefore, we are not enthused by the problems that
occurred in the study because we think that knowing
your triglycerides, while it may be a good thing to
know, it is sort of analogous to somebody knowing
their American Express card off by heart. It may
not help much to get your lunch.
So that, I think, is kind of getting
at--Charlie, you already address that, I think, to
some extent. Do you want to add something?
DR. GANLEY: I think you are getting at a
different issue because I think you are going down
the path a little bit that why even have a label
that has instructions if we can sort of come to the
compromise that anyone who takes this is going to
get a benefit as long as we kick out the people who
may be at increased risk.
I think it goes back to some of your
opening remarks, you know, the population versus
the individual and who needs to be eliminated.
Obviously, the less information you have on the
label which has criteria directing it towards a
certain population, you are going to expand the
population, potentially, if he takes it and is that
But I think, in the context of what our
interest is this study may get based on the
criteria that is in that label right now. That is
what I was trying to get at. If you have it--my
earlier remarks are it is tough. You have all
these layers to go through--Dr. Parker could
probably talk to it better than I can--and that is
just hard to do.
So, if you say that it doesn't make it
but--I don't really think you need to know your HDL
level, or I don't need to know your triglyceride.
That starts peeling away the layers. Dr. Parker
may be able to articulate it better than I can.
But I think, in the context of what our interest
is, we have a label. These were the population.
You may not agree, necessarily, with that
population, but does this study show that they
self-selected well with that.
That is the question. Then you can add
all your caveats, what you think is important, what
is not important, which gets down towards your
DR. PARKER: Just to sort of take up on
that, I think published studies would support that
when messages are layered, the first layer is the
one that is going to be most likely to be
understood and, with each additional layer, which
is another way of defining complexity, you lose
comprehension on the other side.
The challenge here, as I said earlier, is
that the required information is complex. I think
the burden, then, is to say, well, what is the
absolute essential information to know. I would
put beside that--because the need to know is the
term that we use so much, but for the activated
consumer, it is not just need to know. It is need
to do. What do I need to do?
So you have got to sort of put those
side-by-side when you approach the content of
information that needs to be defined. Once you are
absolutely clear on the information that is
essential from a need-to-know, need-to-do
standpoint, then it is a matter of figuring out how
best to communicate that complicated information
and yet it would be great to dumb it down.
But that doesn't work. It is too
complicated to dumb down. There is a set of
information that people need to be able to
understand and act on and there is a way to
communicate it. But it takes rigorous work,
rigorous scientific data, to prove that you have
actually done that.
What I would contend is that there is a
beginning to that process but that process is going
to require the same type of rigor that has been
applied to the other outcome studies that look at
biochemical markers like liver-function test and
like neural-tube defects or whatever it is. It
takes scientific rigor to really figure out what it
is that has got to happen so that we can take
advantage of what we know biochemically or
We have got to have that degree of rigor
in our efforts to communicate it effectively.
DR. GANLEY: I think Dr. Wierman put her
finger on the key question, and that is the
consequences of selection for rather than selection
against because I think it is pretty clear from the
CUSTOM study that the ability to select for being
in the target group was quite variable and fairly
weak, and so on.
I don't' see that as dangerous in the
sense that it is putting people at risk,
necessarily. But I think it does raise the key
question of whether not meeting those criteria
doesn't dilute the efficacy of taking the drug. In
fact, I think that is exactly right. I think that,
in a sense, is the key or a very central question.
Every time you don't meet one or another
of those criteria, the amount of benefit you can
expect from this gets less and less. That, I
think, multiplied times millions of people is an
enormously important question.
DR. WOOD: Any other discussion on this?
Is this a question you need a vote on or have you
got what you need out of this? All right. Then,
if we are ready, any other discussion? Let's have
a discussion about the question. Sorry; go ahead.
DR. SCHAMBELAN: I think the question is
DR. WOOD: Yes; I do, too.
DR. SCHAMBELAN: I think it would be
interesting to come back here in six or seven or
eight years and talk about the poly-pill and not
having any criteria for taking the medication. So
I think people are comfortable because we recognize
that lowering LDL cholesterol probably at any level
across the spectrum of these patients is going to
But that is not what you are asking us.
You want us to know if this self-diagnosis
technique that was used here was adequate to
support a conclusion. I think I agree with Dr.
Woolf, that I think this was not a very good study
in terms of providing that support.
But, as to whether we think it could be
used safely or effectively, I think we have already
addressed that in the earlier discussion. So it
would help if you could either break that question
down or make it something that we can vote on
without having that ambiguity.
DR. WOOD: I agree. I think that is spot
on. It seems to me that the committee has a
comfort level for the use of this drug that goes
beyond the criteria that were used to define that
use study; is that--so that makes it somewhat
difficult to take what looks, then, like a much
more difficult and exact requirement than they
think is reasonable. Is that--
DR. SCHAMBELAN: Yes.
DR. WOOD: Okay. So I am not sure how we
vote exactly on that. Sorry; somebody over wants
DR. McCLUNG: I would like to then beg out
of being included in that last statement of yours
about the committee.
DR. WOOD: Okay.
DR. McCLUNG: I am not comfortable with
the documented efficacy in much lower-risk
populations. Again, sort of in mention, that the
ability in the CUSTOM study of patients to identify
themselves on the appropriate inclusion criteria,
and inclusion criteria were chosen to identify
patients at moderate risk.
26 percent of the individuals made the
right selection on the basis of age and their LDL
level, the two major risk factors that we--and the
way in which they missed the target was that the
patients were younger and the majority of the LDL
misses were that their values were lower, both of
which lower the risk in the population which means
that, despite--I am not arguing that relative risks
won't be equivalent in that population, but the
absolute risk and, thus, the benefit and the
efficacy of therapy is diluted by the decisions
that were made.
The risk remains the same, the risk of
side effects remains the same, in that population
but the benefit with regard to reducing heart
disease is diluted. As that happens in what I
think is probably the best-case scenario in the
CUSTOM study, and once we have direct-to-consumer
marketing in a much broader population, I am not
confident that the behavior is going to be better
in that circumstance, in that scenario, than what
we have observed in the CUSTOM study.
Then we are treating a very low-risk
population where the benefit is modest, to be
generous, and the risk remains the same as was seen
before. So I am not certain I agree with you
DR. WOOD: I think I was saying knowing
your HDL, knowing your triglycerides, probably
doesn't influence that risk very much.
DR. McCLUNG: That's fine. But even if
you take the two important easy, what I would
contend to be the crucial pieces of information,
age and LDL, 74 percent of patients miscategorize
themselves as being candidates for therapy.
DR. WOOD: It is hard to imagine, and
Charlie Ganley has made this point already, how
such a large proportion of patients get their age
wrong and give it right presumably in the entry
form to the screener, because it wasn't that
someone knew their age.
DR. McCLUNG: It doesn't say they got
their age wrong. They knew their age but they made
the wrong decision, by the criteria that were set
DR. WOOD: Why don't we go you, first.
DR. SCHADE: I would just like to say one
thing. I like the CUSTOM study. I think it was a
good study. I think what we are forgetting is
there is there is no control group. I think the de
facto control group that we are all thinking about
is 100 percent correct answer to each question.
The fact is, a control group might be a
fully informed person with medical background,
great experience with lovastatin, et cetera, et
cetera, and, if you have that control group, I am
certain you still wouldn't have 100 percent correct
answers, not if you have to add all the criteria
that are listed.
So I actually think the CUSTOM
study--nobody knows, or at least nobody can tell
me, is what the correct study should have been
relative to the correct answer. In other words,
let's suppose only 10 percent of the people got the
entrance criteria correct. Well, what number
should it have been in the best population that we
could have picked for a control study.
There is no control study. A control
study, of course, is really practically impossible.
So I think this is a descriptive study that gives
us information. We may not like the answer. I
don't think anybody liked the answer that everybody
didn't get every question right. But I am not so
sure that this is a bad study. I think it is
informational. I think it may lead to positive
suggestions on correcting the literature that is
given out and I think that is a positive outcome of
But I don't think we ought to--at least,
personally, I think it is a very interesting study
with a certain outcome. I don't know what should
have been the outcome but I think, basically, it is
going to lead to some positive suggestions. So,
rather than criticizing the company for doing the
study, I think they should be basically applauded
but say, gee, we would like, maybe, some more
information we didn't get from this.
But I don't see a control group for this
study so I don't know what the right answer should
DR. HEMWALL: Thank you. I think I have a
couple of things that can put all of this kind of
in the right perspective and bring together
everybody's remarks here and kind of put people in
the mind set that we were in four years ago when we
set about to define the label population and we
worked with FDA on that. We worked with outside
cardiovascular primary prevention experts.
How do you develop a label that attracts
the population that is consistent with ATP 3. What
we did was we thought kind of conceptually. You
want to drive them down the middle of the highway
and keep them from veering off onto the shoulder.
So you want to make the guideposts very strict,
make sure that they are catching their HDL, we are
doing it in terms of LDL instead of total
cholesterol which most consumers know and we are
asking them to know a lot of other things about
But we are guiding them down a narrow
path. Unfortunately, some people chose to go a
little bit outside that path but that is a good
thing because we want to stay within the spirit and
intent of the guidelines.
What we are dismayed a little bit by is
that we are sort of being criticized or punished by
those that did go a little bit outside the
guidelines. But the interesting thing is, if you
look at all the people in CUSTOM taken together, 70
percent of them met ATP criteria that would qualify
them for lipid-lowering therapy.
Their overall 10-year risk was around 10
percent. In AFCAPS, the 10-year risk, and it is a
slight extrapolation because that was a 5-year
study, but the 10-year risk of the placebo group
for heart CHD was about 6 percent. So we are still
in a range where AFCAPS has demonstrated a benefit
which can be linked to this group, albeit not
directly, but we are in a group that can benefit.
If you take away the restrictions that the
label applies and just look at who was interested
and used the drug, 75 percent of them were in
accordance with ATP 3 criteria. We think that is
pretty good. And, by the way, two-thirds of them
got their lipids tested and came back and followed
through with some of these more difficult elements
to just actually execute let alone know about
yourself or your risk factors.
So we were very pleased with the results
of the study but, taken very strictly, keeping
people down the narrow highway, we did not have
everybody on the highway. Some were driving on the
shoulder, but we kept them out of the ditch and
that is the most important thing.
DR. GANLEY: Alastair, can I just add--I
think the thing is, and maybe just to put it in
another framework, you have this CUSTOM study and
you have these multiple analyses one of which--it
seems--I don't know, but it seems that you are
comfortable with these other analyses where it
defined people as closely benefitted or they fit
So when you look at a net--if you go back
to Dr. Shetty's slide, you get up to 900-and-some
of the 1059. So, if that is what makes you feel
better, then you buy into that analysis. That is
what I think we are trying to get out, because it
says, please describe what analysis influenced you.
That is what is influencing you. You
think that that is a reasonable way to look at
that, potentially. There is the other side where,
well, we want some a little bit stricter. We want
people to follow that. That gets closer to Dr.
Shetty's or if you want to even add on the
physician override. Do you understand what I am
DR. WOOD: Absolutely, but I think we are
also hearing from some of the committee who feel,
as I understand it, uncomfortable with that. So we
need to have that discussion so that we get that
Maybe we should articulate the question,
rather than in terms of results from the CUSTOM
study undefined, and redo this question the way you
just described it so that, as I understand the
question that you are putting out there, is would
you be comfortable with the results of the CUSTOM
study in terms of the people who took the drug and
their likelihood for benefit. Is that the--
DR. GANLEY: To me, it gets still back to
these multiple analyses. If you take it on face
value, you have this very strict interpretation
which gets you a 10 percent. When you start
throwing in these other things where, yeah, well,
they missed a few of these things but they had
this, so that is okay, and you keep adding to that
I think that is really consistent with
what people are saying here. They think that the
population may not be right but they had a comfort
level with how the study was. And that, I think,
gets back to the Merck analysis of, well, when we
look at those people and what their risks were,
they still fit the NCEP/ATP guidelines.
So someone could say, for this study, yes,
because I buy into that very loose interpretation
of the analysis or, no, because I am a little more
strict. That is the question, I think, to be
answered. If you say yes or no, what analysis made
you say that. If you are comfortable with this
alternative analysis where it is closely adhered to
the label for benefit or the ATP guidelines, you
are getting back into this realm, well, I don't
think the population's right but that is okay.
DR. WOOD: So you want us to address that
question because I don't want to--
DR. GANLEY: Yes; I think it is an
important question for us to understand because it
gets to people's hierarchy, too.
DR. WOOD: So the question then, really,
is, are there strict constructionists who feel that
the only analysis is the total analysis, or are
there people who feel more comfortable with an
analysis that looks only at the key risk factors
and how do we break as a committee on that. Is
that what you are--
DR. GANLEY: I don't like to rewrite
questions during the meeting but I think if we just
stick to the question and think, do I fit into this
looser interpretation analysis. Then I am getting
up to 90 percent correct self-selection. Or am I
very strict "look at the label," and I am getting
down to that 10 percent.
That will help you decide what your answer
is. If you are up at 90 percent, that may be--
DR. WOOD: But I am trying to
operationalize this question. So the question
would be that people could answer yes to Part 1 or
no to Part 1 and base that on either a strict
constructionist sort of analysis, so there response
could be, I base on a strict constructionist
analysis. Every criteria has to be counted, or a
looser criteria. Would that be fair?
DR. GANLEY: Yes.
DR. WOOD: I mean, that seems like--I
mean, we have to get answers. Do people understand
our discussion? Let's start with Dr. Snodgrass.
First, is there any further discussion we
should have on that?
DR. WATTS: I think it is a misnomer to
call this self-selection because many of these
people talked to a health professional and, yes,
they made their own decision, but it is not that
they read the thing and they came to the right
conclusion. They needed to get help and help is
not mandated in this scenario.
So I am uncomfortable with the fact that
many of these people needed to access other
resources before they could "self-select."
DR. WOOD: Okay. We will strike "self" in
both places so the appropriate diagnosis and
selection support--how about that? Would that be
Any other discussion? Then let's start
with Dr. Snodgrass.
DR. SNODGRASS: Question 5, I will answer
DR. FINCHAM: No.
DR. WOOD: Wait. There are two questions
we are being asked. Sorry. Back up again. We
want to know--sorry. I think what they want to
DR. SNODGRASS: What were my reasons.
DR. WOOD: --if, if you answer yes or no,
are you basing it on a strict every-criteria
analysis or a looser analysis that only took the
major risk factors. I think that is what
Charley--is that right? Okay. Let's go again.
DR. SNODGRASS: So probably I fit the
stricter group, perhaps. Their specific section is
55 percent, I think, had greater than one risk
condition, used the product but still had relative
contraindications, as an example. To me, the
package information--it has already been discussed.
This is very complex and it is just a complicated
issue. So that fit into this.
I think it turned out something like 69
percent needed more information to really make a
decision based on what was presented to them.
DR. WOOD: Okay. Jack?
DR. FINCHAM: My answer is no, based upon
I don't feel that the CUSTOM study is generalizable
past the participants in that study. I am not
trying to criticize Merck. I am not trying to
criticize the people that conducted the study.
They are not bad people. It is just that this was
a flawed study from the git-go. That is why I say
DR. WOOD: Dr. Schultz?
MR. SCHULTZ: My answer is no. As an
individual, I feel, as Dr. Neill said, how many of
these people actually went to their own physician
or a physician to get to the point where they could
make this informed or self-determination?
DR. WOOD: Dr. Wierman?
DR. WIERMAN: I answer the question no,
with more strict criteria.
DR. NEILL: I answer the question yes and
the only reservation that I have in that answer is
the recognition that, in answering yes, I don't
believe that people have to understand why they are
doing the right thing to do the right thing, A. B,
I do buy into the analysis that suggests that there
is medically acceptable use that falls outside of
the label criteria. The only reservation that I
have about that is a very practical one. As a
prescriber, if this goes over-the-counter, I don't
have great hope that prescription benefit managers
will alter their OTC versus prescription criteria
in a way that will allow me to continue to use
prescription statins in the way that I need to and,
if there is a reason that I want these strict
criteria on the label and on the approval language,
it is so that I don't have to add to the stack of
prior authorizations that I and my patients hate,
and we will have them if these criteria are
loosened because every patient that is on a statin
needs to be on a statin, needs to be on a higher
dose, needs to be on a prescription and will be
made to jump through that hoop first and nobody in
here wants to do that.
Having said that, I am still answering
DR. WATTS: I would say no. It is hard to
point to the analysis. It would be helpful if we
had a list of the analyses we are supposed to be
considering labeled A, B, C, and D. I an not a
strict constructionist but somewhere short of the
liberal. I am concerned that many people
self-selected or made the determination to take the
drug who didn't have substantial opportunity to
benefit from the drug.
DR. TINETTI: I say no based on two
things. Number one is most people did not do this
by self-selection. They needed help and input.
The other reason I say no is something that sort of
got swept under the rug is how many people who are
presently on prescription medications will no
longer want to take their prescription level, will
go to this lower level, based on what Merck has
told us, that these people prefer to self-medicate.
My concern is that CUSTOM didn't address
all the questions that are necessary.
DR. WOOD: I vote yes, on the more liberal
DR. SCHAMBELAN: I vote no, on the
DR. TAYLOR: I vote no, on the stricter
criteria particularly for the low literacy and the
minority group. I think there are problems
DR. SCHADE: I vote yes, on the more
DR. CLAPP: No. 37 percent of women users
were less than 55 years of age and 69 percent
needed more information. That fact is disturbing
to me because I am not sure whether or not they
actually received this or tended to receive it
because it was a more comfortable box to check.
DR. MAKRIS: No, based on the more
DR. CLYBURN: No, based on the fact that I
think that the low-risk population is not apt to
get a lot of benefit and they would still be
subjected to risk.
DR. McCLUNG: No, based on either the
stricter or the liberal criteria.
DR. PATTEN: No, based on the low
percentage that selected correctly based according
to the two most important criteria, and also no
because of the fact that 37 percent of the women
who were selected were under 55 and 11 percent of
women under the age of 45 selected.
DR. DAVIDOFF: No. I think the strict
constructionist versus loose analysis is looking at
the problem through the wrong end of the telescope.
I think the important point is the potential
efficacy and it seems to me that that was
demonstrated by the CUSTOM study to be quite weak
whether you interpret the choices were made by the
strict or the loose criteria.
DR. FOLLMAN: I would say no. Some of the
things that I found more troubling were the fact
that it seemed about two-thirds of the people were
outside of the intended range meaning they would be
either overdosed or underdosed, that about 10 or 11
percent of the women were less than 44 and that
only one-third of the people got the six-week test,
so they didn't seem to be able to follow the
directions in terms of monitoring their cholesterol
DR. PARKER: No, but I would add that I
think data gleaned from the label comprehension and
the CUSTOM study are a beginning.
DR. CARPENTER: No, based somewhere in
between the conservative and liberal criteria but
primarily being very uncomfortable with the ability
of a generalized population to make appropriate
decisions without the help of physicians in many of
DR. BLASCHKE: Yes, with the caveat that
I, too, am concerned about the percentage of women
of childbearing potential that did take the drug.
DR. BENOWITZ: I would say yes. I share
the points of view about why the age was not
followed. It seems like something that should be
correctable. I do agree that there are some people
who probably took treatment with low benefit
because they were at low risk. But, on balance, I
think that, for the most part, it was safely and
DR. WOOLF: No, because there were too
many people who would have the most moderate
benefit participated and their failure to follow up
with lipids sufficiently, lipid measurements.
DR. WOOD: So 6 yes and 18 no.
The next question addresses the supportive
role of a physician in what has been described as
self-selection or self-diagnosis although Dr.
Neill, I think it was, made the point earlier, or
somebody made the point--Dr. Watts, I guess--that
it is not really self-selection if it is with a
I will read the questions to you. A high
percentage of study subjects in the CUSTOM
actual-use study relied upon a physician for
correct self-selection and/or self diagnosis--at
least said they relied on a physician. I think
that actually should have been in there because we
don't really know that. Do you expect the general
population will have this degree of physician
interaction? Do the CUSTOM actual-use-study
results support a conclusion that individuals can
use lovastatin safely and effectively in the OTC
setting without the guidance of a physician?
Do we have discussion on that?
Apparently we have to correct the vote.
It was 5 yes and 19 no.
DR. BENOWITZ: It was my understanding
that, for Part B, that the guidance of a physician
was intended for certain people.
DR. WOOD: Right. I didn't understand
that question either. My understanding of the
package is that they are going to suggest that
people get a physician involvement if they want it
and, if they get that, that is not a failure.
DR. GANLEY: I think that was more
directed at the population of people who do not
have a physician. It gets back to, you know,
this--I am not disputing that it is good to talk to
a physician but there is a significant proportion
of the population that does not have that choice.
I think that is where we are trying to get at
because Merck's analysis of correct self-selection
was the people who followed the label and then this
Well, if you don't have a physician to
override, what do you do?
DR. WOOD: What was the proportion of
people in the Merck study who didn't have a
DR. GANLEY: I think the important thing,
though, is to understand what is the percentage of
the population that doesn't have a physician and
have access to a physician.
DR. WOOD: No; I understand. But let's
hear what they have.
MR. TIPPING: Of the users in CUSTOM, 57
percent of them at some point in the study had an
interaction with a physician. Now, it is important
to distinguish that from an interaction that
actually had some influence on our judgement of
self-selection behavior. So it is 57 percent with
an interaction, but there were actually 620 of our
1,059 users whose behavior around that initial
decision did not require a physician override.
I guess I would add to that that those are
what we feel are the important criteria, the
warnings. That is where the behavior and the
entire cohort was 90 percent or higher. But, we
don't think it is the right thing to do because we
feel the physician is mentioned in the label and
that is appropriate behavior.
But, if you do look at just that subset
that didn't require that physician override, that
620, it is 82 percent.
DR. WOOD: Let's keep moving here. The
question that you were asked, though, was what
proportion of patients in the study had a
physician. Do we know the answer to that or not?
MR. TIPPING: 57 percent--
DR. WOOD: No; they are the people who saw
a physician. They might have had a physician and
been able to go see a physician if they--I know
that. So 80 percent, Dr. Wierman is pointing out,
had insurance; is that correct?
MR. HANSON: I just want to make sure I
understand the question. It was how many of
DR. WOOD: The question that we are being
asked to answer is do you expect the general
population with this degree of physician
interaction. In determining the answer the answer
to that, I guess, the question devolves to, was the
population you studied fairly representative of the
U.S. population in terms of the people who had
insurance and, therefore, had access to a
So that is what we are trying to get at, I
MR. HANSON: I will just give you the
data. Of the people who were in CUSTOM, 90 percent
had seen a doctor within the past year and that is
certainly higher than the general population which
is consistent with--what we have said is these
people are very involved in their healthcare and
with their doctor.
As far as health insurance, I would have
to look that up but I can get back on that.
DR. WOOD: My recollection was you said 80
MR. HANSON: Yes; 82 percent healthcare,
50 percent had prescription coverage as part of
DR. WOOD: Say it again; I'm sorry.
MR. HANSON: I'm sorry. 82 percent had
health insurance. 50 percent of those had
prescription coverage. I don't know how that
compares to national averages.
DR. WOOD: Okay. It is about the same,
40 million people are supposed to not have health
DR. BENOWITZ: Just another question about
b. It says, "without the guidance of a physician."
But, to me, if there is a pharmacist available or
if there is a knowledgeable 1-800 number, that
would really affect my decision about this I think
a pharmacist could do the same thing, or a
knowledgeable 1-800. So, could we expand this to
some "health provider?"
DR. WOOD: So we will read that as
1-800-doc and a pharmacist.
DR. PARKER: It was very much on that same
point, just that there are so many mentions of the
study personnel and I understand from yesterday
that that is because this was the label used in
CUSTOM and it is not the label that would be used
in actual use, necessarily. But I think that is a
point for clarification and also for understanding.
I think there would be many ordinary
Americans who would not know what study personnel
means. I can tell you they don't know what a
healthcare provider is. We have done that and
taken a close look at that. Physician is more
understood but the notion of who that intermediary
is, if this is the role of an informed
intermediary, being very clear about that.
I still have some concerns about--I guess
the answer yesterday was this notion of the study
personnel would be taken off the label were this
the label to go to market, that it was only tested
for CUSTOM. But I still have some concern about
DR. WOOD: Are we ready to--sorry; Dr.
DR. CLAPP: Does the 69 percent that we
are discussing that consulted with a physician
include from the CUSTOM study the pharmacist or
study personnel or is that just specific for
physicians? I think the data said consulted with a
physician. Did you mean physician or a healthcare
professional as described here?
MR. HANSON: To clarify that, the study
personnel on there was just an artifact of the
clinical study and study personnel actually would
mean pharmacist in the real world, so just replace
the word "pharmacist" for study personnel.
DR. CLAPP: So when we were talking about
that 69 percent that consulted with a healthcare
professional, do you mean specifically a physician
or are you saying physician/pharmacist?
MR. HANSON: The data from CUSTOM was 57
percent sought a physician and about 30 percent of
the people interacted with the study personnel
which was a mock pharmacist in the study.
DR. WOOD: No, but I don't think that is
the answer she is getting at. 57 percent saw a
physician at some time through the year but it
might have been--
DR. CLAPP: No.
DR. WOOD: Is that not right?
MR. HANSON: Sometime within the
course--the six-month course of the study.
DR. WOOD: That might have been with a
DR. CLAPP: Right.
DR. WOOD: Are we misunderstanding that?
That was my understanding. So you are saying 57
percent of them saw them about this study? I don't
MR. TIPPING: Can I have Slide 158 please?
Just real quick because it gets right to the point.
DR. WOOD: There is an easy answer to
give. Did they see a physician because of this
study or did they see a physician for any--
MR. TIPPING: 57 percent of the users in
CUSTOM and, in this case, these are 57 percent of
the users who saw a physician about Mevacor OTC, so
it wasn't because they went because they feel and
broke their ankle.
DR. CLAPP: When those 69 percent sought
help with making a decision--didn't I see 69
percent sought help in making the decision by
consulting with a healthcare professional prior to
purchasing the medication? Am I misrecalling?
MR. TIPPING: I am not recalling the 69
DR. CLAPP: Or needed more information?
Let me ask you this. What percentage are you
saying consulted with a physician to make their
decision prior to purchasing the medication?
DR. WOOD: Or not purchasing.
DR. SCHAMBELAN: Purchasing or not
purchasing. They might decide either way once they
consulted the physician. I think that is the
number we would like to know.
MR. TIPPING: There were 620 who did not
consult with a physician of our 1,059 so it is
about 430 something.
DR. SCHAMBELAN: And of the people who
decided not to participate, is that based upon a
physician's advice or was that their own decision?
MR. TIPPING: So you are talking about the
over 2,000 who didn't purchase and I think I would
have to go back to the slide, but I believe 19
percent of that group specifically said that they
had talked with a physician before making that
DR. WOOD: Here is the question that Dr.
Clapp was asking, I think, and I still don't think
you have answered it. Are you telling us that 57
percent of the patients who were in that study
consulted a physician about participating in the
study because that is not what I understood you to
say before and that is quite different from--I
mean, that is a devastating number if that is the
MR. TIPPING: 57 percent of the users had
an interaction with a physician about Mevacor OTC.
DR. SCHAMBELAN: Those are the users.
MR. TIPPING: During the study.
DR. WOOD: All right. Do we know what
percentage saw a physician for anything over that
MR. TIPPING: No.
DR. WOOD: So went to their gynecologist
or--we don't know that?
MR. TIPPING: I thought that is what that
57 percent was.
DR. WOOD: No; we were asking them
specifically about interactions having to do with
DR. WOOD: Any further discussion on this?
Do you expect the general population will have this
degree of physician interaction? Dr. Woolf? Try
and do both at the same time because we are rolling
DR. WOOLF: No, I do not expect the
general population to have that kind of interaction
without--the answer to that is no, both a. and b.
DR. BENOWITZ: For Part a., I abstain. I
just don't have enough information to make any
judgment about that. For Part b., I think that if
we expand it to a physician or pharmacist or 1-800
number, I would say yes.
DR. BLASCHKE: Based on what we just
heard, I think the number might go down in Part a.,
so I would probably answer no, that it will
probably go down in terms of physician interaction.
To 6 b., I would answer yes, I think that, again,
with the change that Neal suggested.
DR. CARPENTER: No to both.
DR. PARKER: I would say unknown to the
first and no to the second.
DR. FOLLMAN: I would say no to the first
and the fact that we haven't really studied and we
haven't done a CUSTOM study for this population, we
think it doesn't have access to physicians, I would
have to say no to the second.
DR. DAVIDOFF: I would say no and no.
DR. PATTEN: No to both.
DR. McCLUNG: No to the first and, unless
we believe that interacting with physicians makes
things be worse, then the answer to the second part
DR. CLYBURN: No and no.
DR. MAKRIS: I would say no to both but I
believe that there are probably some things that
could be done to move towards a yes.
DR. CLAPP: No. No.
DR. SCHADE: No. Yes.
DR. TAYLOR: No to both.
DR. SCHAMBELAN: No to both.
DR. WOOD: An unknown, I think, to the
first one and I would say no to the second one if
what we just heard was really true, that 57 percent
of the patients consulted a physician about the
study which is not what I understood the data to
DR. TINETTI: I would say we don't have
enough information for a., and no to b.
DR. WATTS: No to both.
DR. NEILL: Yes and no.
DR. WIERMAN: No and no.
MR. SCHULTZ: Unknown and no.
DR. FINCHAM: Yes and no.
DR. SNODGRASS: No and no.
DR. WOOD: Question No. 7; do the results
regarding self-management--that is, user behavior
after the initiation of treatment--raise any
concerns about the safety and effective use--oh;
before we get to that, I promised we would come
back to quickly list other exclusions that Dr.
Parker and others had outlined, and Dr. Benowitz.
We had alcohol, transplantation. Are there any
others that we wanted to get on the record for that
from the committee? A single word will suffice.
Then let's move on. No. 7; do the results
regarding self-management--that is, user behavior
after the initiation of treatment--raise any
concerns about the safe and effective use of
lovastatin 20 milligrams in the over-the-counter
setting? If yes, what are the concerns? Please
consider in your discussion monitoring LDL-C,
physician interaction, new risk factors or
medication after initiation of therapy.
DR. BENOWITZ: I just want to go back to
something that we have talked about on and off and
that is some indication to the patient about
potential benefits in absolute terms because, while
I am totally supportive of the public-health
benefit, I think someone needs to know that they
need to take a medicine at great cost for a long
period of time for a relatively small individual
benefit. I think that needs to be communicated
DR. WOOD: I agree with that. Any other
discussions? Dr. Clapp?
DR. CLAPP: Is this for the target
population that we are discussing?
DR. WOOD: I guess not. Well, maybe. I
don't know. Do you have a comment? Make it
DR. CLAPP: I think, if it is for the very
narrow focus of the target population, the small
percent that self-selected correctly, then the
answer would be different.
DR. GANLEY: No. For No. 7?
DR. WOOD: Yes.
DR. GANLEY: It is anyone who is in the
study. So, whether you were the target population
or not, it is still a measure of someone's
behavior. So it is trying to get at that.
DR. WOOD: Could we make that--obviously,
there is always concerns. Charlie? Raise any
concerns. Do you really want any concerns of any
DR. GANLEY: Significant.
DR. WOOD: Significant concerns, maybe.
DR. GANLEY: Significant is fine.
DR. DAVIDOFF: I think if I had to single
out any particularly significant concern, it would
be with the first one with the monitoring of LDL-C
because it seems to me that that could potentially
be a really important way to help focus the therapy
so that it was more efficacy rather than less.
I don't remember the exact numbers on
follow up LDL cholesterols, but they were fairly
good. I think it was in the range of 60, 70
percent, or something of the sort. But it seems to
me that that certainly could be seen as the glass
being at least a quarter empty and that that is
something of a concern.
Related to that is the concern that we
haven't heard at all and that is about the accuracy
of cholesterol testing because there is a lot of
mention made of on-site and sort of bedside
cholesterol testing. The last time I looked, the
accuracy of that testing was quite variable. It
might have improved since I last looked, but I
think that that--throw that into the mix and you
really do have a soft spot in the self-management
DR. WOOD: Any other discussion? Neal?
DR. BENOWITZ: Something, just because of
my research that I am curious about, and that is
the smoking business. A lot of smokers stop and
they relapse and they stop and they relapse. So
there is sort of one risk factor that is flapping
back and forth. I am just curious to know how one
self-manages when one has a disappearing and
reappearing risk factor.
DR. WOOD: You are the man. Tell us what
you think, how you feel.
DR. BENOWITZ: I don't have an answer. I
am just curious.
DR. WOOD: Well, then, I doubt that any of
us do. Are we ready to vote on that? Then let's
start with Dr. Snodgrass.
DR. SNODGRASS: The way the question is
worded, I will answer yes and then what are my
concerns. It was 57 percent that had some sort of
physician interaction. I think there are so many
potential other illnesses, disorders, involved in
the population that that is too low a number. That
is one concern I have about this and that is why I
DR. FINCHAM: Yes. And I have concerns
about drug interactions that weren't picked up,
weren't monitored, that there was no way to follow.
MR. SCHULTZ: Yes. And I am concerned
with subsequent adequacy or frequency of the
follow-up testing that would be needed if someone
is going to really keep a close tabs on this.
DR. WIERMAN: Yes. And I am concerned
that the study hasn't demonstrated that we are
there yet in adequate monitoring for efficacy and
DR. NEILL: Yes. Inadequate access to
healthcare for most patients makes this not doable
and the low benefit to patients who inappropriately
self-select when they are at low risk makes this
akin to giving them very expensive supplements when
we have already heard are available to them, they
are already using and aren't a good idea.
DR. WATTS: Yes. I agree with all the
concerns that have been raised and am particularly
concerned that that is going to be money spent for
short-term, make you feel better that you are doing
something but won't have any long-term benefit to
the patient or to the population.
DR. TINETTI: I would say yes and concur
with what has been said so far, and also add that
there is no confidence that these people are going
to recognize when they have new conditions that
develop over time so they no longer meet criteria
DR. WOOD: I would say yes as well. We
have spent a day and a half talking about concerns
so it would be hard to answer that no, I think, at
DR. SCHAMBELAN: I would say yes and add
that the other features of the metabolic syndrome
will continue to appear in this population. We
will gain a pound or two a year and, if they are
not paying attention to that, they are not going to
get the same benefit that they otherwise would
under a physician's care.
DR. TAYLOR: I would say yes because I
think many patients will want a physician
interaction. For some populations, they have no
physician and, therefore, they won't get an LDL
because they are not going to go and buy a
self-testing kit. Those of the population that I
see are lower income and, therefore, compliance
will become an issue.
DR. SCHADE: Did we change the word "any"
to "significant" in that sentence?
DR. WOOD: No; we did not, I don't think.
DR. SCHADE: Does the sentence say "any"
or does it say--
DR. WOOD: It says, "any concerns about
the safe and effective use."
DR. SCHADE: I don't know what I am voting
on. Does it say "raise significant concerns" or
"raise any concerns?"
DR. WOOD: We didn't discuss what
"significant" is so I voted actually just on what
DR. SCHADE: The way, then, I would vote
yes, if it is "any," and no if it is "significant."
DR. WOOD: Right. I probably would too,
but I think--
DR. CLAPP: Yes. And many of the reasons
have been discussed.
DR. MAKRIS: I would say yes. It is not
so much that the study raised specific concerns in
and of itself but, rather, that it wasn't of long
enough duration and didn't really evaluate the
long-term behavior of people to address whether or
not these would be an issue.
DR. CLYBURN: Yes, for the reasons already
DR. McCLUNG: Yes, for the reasons already
DR. PATTEN: Yes, for reasons already
mentioned plus the fact that 270 of 356 people in
the CUSTOM study got a new prescription during the
study and I would be concerned that, if the use of
statins was not on their medical record, they may
neglect to tell their physician at the time they
get a new script and that could present a hazard.
DR. DAVIDOFF: Yes, for many of the
reasons already mentioned.
DR. FOLLMAN: Yes, for the reasons
DR. PARKER: Yes, for the reasons
DR. CARPENTER: Yes. Ditto.
DR. BLASCHKE: Yes, for the reasons
DR. BENOWITZ: Yes, but I would like to
make a pitch for pharmacist involvement because I
think a lot of this could be dealt with if we
really had a system more like the U.K. where we
really had a pharmacist who was involved with the
patient, who was supervising cholesterol
measurements. So I think this is something that
could work but we need a better system. So I would
just try to urge whoever can make these changes to
think about those kind of changes.
DR. WOOLF: Yes, for the reasons
DR. WOOD: 23 yeses, 0 no's.
The final and critical questions; should
Mevacor OTC be marketed OTC. I think we deleted,
"for the proposed population;" is that right? So
the question now reads, should Mevacor OTC be
marketed OTC, period. Then we will get to these
other ones in a moment.
Do we want to have discussion on that? So
take that out, that last part.
DR. SCHAMBELAN: Could you clarify that?
It would include all comers? The box would exist
in the supermarket like Tylenol, you just go ahead
and pick it up? Is that what you are asking us to
DR. WOOD: No. Just should it be marketed
OTC under any circumstances.
DR. SCHAMBELAN: That is what I am saying.
DR. WOOD: No, no, no. Are there
circumstances under which it could be marketed. I
think that is the--
DR. SCHAMBELAN: How would we know what
those circumstances are?
DR. WOOD: I will let the FDA answer that.
DR. ORLOFF: As proposed.
DR. SCHAMBELAN: That is for the targeted
DR. ORLOFF: But it is also with the box
and what you have heard about and everything.
DR. SCHAMBELAN: As proposed. All right.
DR. ORLOFF: And if not, why not? What is
lacking? What is missing? They have proposed
something. Should it be approved or not?
DR. WOOD: Frank?
DR. DAVIDOFF: I just like to make a few
comments in connection with the general question.
I think it is very clear that there is obvious
benefit to this drug. It is an amazingly effective
drug in targeted therapies including secondary
prevention. I understand the interest in moving
ahead to broaden the use to the primary-prevention
My thinking really started out very much
strongly in favor of going on that direction. I
mean, there have been times in my career when I
thought the statins ought to be in the drinking
water. But contrary to Dr. Cohen, my view has
evolved in the opposite direction and I have gotten
progressively more concerned as I looked at the
evidence and got deeper in the subject. I think it
does remain a very tricky question to decide.
I have three main concerns. The first is,
as a number of people have mentioned, the efficacy
for primary prevention, I would argue, is really
not known. We just plain don't know what that
efficacy would be in the actual over-the-counter
setting. But what is almost certain is that it
would be considerably lower than the figures that
are being presented that are derived really
directly from randomized trials which I think is
not an appropriate extrapolation. So that is No.
No. 2 is that primary prevention with
statins is not cost effective, and I will come back
to that in a moment. The third has to do with the
concerns about pregnancy which we have really heard
a lot about.
On the efficacy question, it seems to me
that the key issue here is not what happens to
people's cholesterol level. That is a surrogate
measure and I think everyone pretty much agrees
that what really matters is the absolute risk
reduction for cardiovascular events. Yet we
haven't heard the information presented in terms of
absolute risk reduction.
The closest we have come has been number
needed to treat which is, as pointed out, the
reciprocal of absolute risk reduction. The figure
that has been presented by Merck is an NNT in the
range of 35. You have to treat 35 people for six
years to achieve a 3 percent reduction, absolute
risk reduction, because that is the reciprocal of
But I would raise substantial questions
about that absolute risk reduction for the
following reasons. First, the baseline risk on
which that NNT is based, I would argue, is
unrealistic. We have already seen that very close
to 50 percent of the CUSTOM users were taking
low-dose aspirin. In fact, they showed another
slide in which that 50 percent was amazingly
consistent across all the studies, that, since we
know that aspirin lowers absolute risk by about 30
percent, that means the baseline risk was not what
was being assumed, as near as I can tell, but was
actually somewhat lower.
If you do the numbers, and I think I did
the math right, that means that the absolute risk
reduction would go down to about 2-and-a-half
percent, given the starting baseline risk.
I would also point out that only 40
percent of the CUSTOM users reached a goal of less
than 130 milligrams percent of HDL cholesterol
whereas, in the AFCAPS study, the rate of reaching
that goal was 81 percent. So, to extrapolate from
the AFCAPS numbers in the randomized controlled
setting to over-the-counter use seems to me to be
not appropriate. In fact, I think you have to cut
the efficacy by about half, roughly. So that gets
you down to 1.25 percent absolute risk reduction
given that lesser reaching of goal.
The third point is that compliance is an
issue, as has been discussed. On about 65 percent
of the expected doses were taken in CUSTOM in six
months. The drop off, as we have seen from other
studies, continues over the 12 months at least
beyond that so that figures in the range of 25 to
50 percent adherence over the long term seem to be
much more realistic. After all, as has been
pointed out, there is no incentive to keep taking
the drug because there is no symptom relief and
there is disincentive to continue taking it because
people are paying out of pocket.
In fact, in the AFCAPS study, 99 percent
of the participants had taken 75 percent of their
pills at the end of one year. That is way beyond
what was true even in the six-months CUSTOM study.
So I would argue that, as a reasonably
conservative estimate, that drops the absolute risk
reduction down from 1.25 percent down in the range
of 0.6 which comes out to be a number needed to
treat somewhere in the range of 100 to 200.
Now, having got that far in my thinking, I
decided, well, that is still probably a meaningful
benefit if you multiply that over many millions of
people. That is not a trivial number of
cardiovascular events prevented.
Part of the problem, though, is we really
don't know, and, unfortunately, the opportunity
hasn't been taken advantage of to find out. So,
looked at that way, I think you could argue that
going OTC statins would, in a sense, be a massive
uncontrolled experiment. I just would hope that
someone might actually do the study that gives us
the data so that it wouldn't be an uncontrolled
Without that, I would see this as not a
good model for how the FDA might move into the
over-the-counter area of treating chronic diseases.
DR. WOOD: Let me try and present the
opposite view because I think that is an
interesting perspective. You are saying sort of
that we shouldn't approve something because the
group at the lowest risk will get a relatively
small benefit. So, to argue the counter view which
is a sort of libertarian, I suppose, view, that
sounds awfully paternalistic. I mean, there are
clearly people who are going to derive substantial
benefit--well, who are going to derive benefit
within the group for whom this therapy is targeted.
One of the attractions of over-the-counter
availability is that individuals have the right and
opportunity to make that judgement of what risk
benefit and what cost benefit specifically they are
prepared to assume. It seems to me that there is a
difference between, for instance, deciding whether
a health plan is going to pay for something and
deciding whether a drug should be available to
individuals to make that decision for themselves.
So, while it is fine to go through
multiple iterations saying, well, people with an
LDL of only fill-in-the-blank take this, the
benefit will only be X. For people with an LDL
that is substantially higher than that and choose
to take it and choose to pay for it themselves and
decide that that benefit is worth it to them, that
is their decision which is a different paradigm
from society paying for it out of their healthcare
So it does seem to me that that analysis,
while the usual one we do, number needed to treat
of whatever, is one that is applied to a population
where the population, as a whole, is paying for it.
Here, we are in a different situation.
Individuals are making that judgment and in a way
that we make that judgment every day. Some people
decide to put smoke detectors in their homes and
some decide not, or whatever the analysis is.
So I am sort of left uncomfortable, I must
say, listening to that analysis, saying, well, we
are not going to approve a drug for
over-the-counter use because some patients who
might derive relatively little benefit would take
it and, for them, it might not, in our view, be
worthwhile but, on the other hand, in their view,
it might be, and, similarly, there are other
patients out there who might derive benefit but
they should not have the opportunity to do that.
It is sort of like if you look at where
physicians LDL is, it is probably at least as low
as the guidelines, probably down at 70 for many if
they are on statin. So I am not sure that is the
DR. DAVIDOFF: You didn't let me finish.
DR. WOOD: Okay. Sorry; I thought I had.
DR. DAVIDOFF: I am hoping that what I
have to say that I didn't get to say yet will,
perhaps, make a difference in your view because I
would continue by saying that, as the potential
benefit shrinks and, again, as has already been
pointed out, the relative balance between benefits
and risks also shift. It shifts in the direction
of being a bit more concerned of, are we getting
the bang for buck relative to the potential risks.
I think, if the only issue is is having to
treat 100 people for six years in the face of the
apparent relatively rare serious side effects, I
would agree with you, that I think that that is
probably in favor of going ahead.
But I haven't finished. The other issue
that I think is highly relevant is the issue of
cost effectiveness. By that, I am not talking
again about just purely financial and economic
issues but cost effectiveness which is a kind of a
bridging concept between resource use and clinical
The basis of my thinking about that was an
article that was published in Annals of Internal
Medicine in the Year 2000. The lead author is
Prosser but the senior author was Milt Weinstein
who wrote the book on cost effectiveness. The
article is Cost Effectiveness of Cholesterol
Lowering Therapy According to Selected Patient
The reason that I think that that is
relevant is not because I want to focus on dollars,
per se, but on this ratio of cost effectiveness.
Their conclusion was, after looking at extensively
across various categories of age, gender and other
risk factors, was that, in their words, "Primary
prevention is not cost effective. It costs
anywhere from $62,000 to $1.4 million per
quality-adjusted life year for primary prevention,"
depending on which group you are looking at.
In contrast, and this is the important
point, the cost effectiveness for secondary
prevention, which is effectively what happens in
the prescription situation, is $1,800 to $40,000.
So, in effect, the cost effectiveness of primary
prevention versus secondary prevention is between 1
and 2 orders of magnitude less cost effective.
Those calculations are based on efficacy
from randomized trials not from the efficacy of the
much less efficient situation that would occur in
over-the-counter treatment, $50,000 per
quality-adjusted life years, a commonly used
benchmark for cost effectiveness which is why they
came to the conclusion they did.
I think it is also helpful to consider, by
way of comparison, the cost effectiveness of
something much more tangible and that is--the
example they use is single-vessel angioplasty for
severe angina, the cost effectiveness of which is
$10,000 per quality-adjusted life year.
So I think that that does have to be
weighted into the balance. Is this kind of
expenditure, whether it is out of pocket or from
insurance carriers, it is still money being spent
for healthcare. Is that a good use of money in
this area of healthcare. I think that does have to
be weighed into the equation.
DR. SCHWARTZ: Dr. Wood, I am Sandy
Schwartz from the University of Pennsylvania. We
didn't talk about cost effectiveness at all because
we were told cost wasn't going to be an issue. But
there are a couple of important--
DR. WOOD: I think we are going to have to
just keep going at this stage because we are
getting close to the end. We haven't presented
that. But we are close to the time out so I am
going to have to cut you off.
DR. WATTS: I want to make two points.
One is that it has been alluded to but not really
focused on that the leap from prescription status
to over-the-counter status is a big one. It seems
awfully attractive to have an intermediate category
as they do in the U.K. and I would urge the agency
to explore some possibility of creating a
behind-the-counter, because I would feel much more
comfortable having these discussions if there was
some sort of sea-wall between next step and the
DR. FINCHAM: I couldn't agree more. My
vote would be completely different if that was the
DR. WATTS: I don't think my vote would be
different because I am concerned, too, and the
second point to make is that this sets a precedent
that would then need to extend to other drugs in
this class and other drugs for the management of
chronic silent diseases.
I am not comfortable at this point,
certainly not with the data that has been
presented, but it is hard for me to conceive of
adequate data that I would feel comfortable in
looking at antihypertensives for over-the-counter
use, even though blood pressure assessment is
probably more widely available than cholesterol
testing, or for anti-diabetic drugs for
over-the-counter use, even though
self-blood-glucose testing is available and
I am concerned that the precedent to move
this to a non-prescription category, be it a behind
the counter or in front of the counter, has really
serious ramifications that go beyond the decision
for this particular compound.
DR. WOOD: Any other discussion? Are we
ready to vote on this? I have forgotten where we
started last time.
MR. SCHULTZ: If I might add something.
DR. WOOD: I'm sorry. Dr. Schultz? I beg
MR. SCHULTZ: Along the lines of the last
speaker, I would like to say if there is any way
for this committee to offer that suggestion to FDA
as part of our deliberation, I think it would be a
very fine thing to do.
DR. WOOD: Okay. Thanks. I have
forgotten which side we started on last time. So
we will start with Dr. Woolf?
DR. WOOLF: I vote no. I don't think that
the support system is out there for patients,
potential patients, to make an adequate assessment.
We have no data that, even if there were pharmacist
in place, that that would be an adequate backup,
not to mention the fact that there would be lots of
patients who could be buying the product when the
pharmacist is no longer on site. What does that
person do? Does that get folded up and taken away?
Does that person buy the product and come back to
speak to the pharmacist another time or not speak
So, for all the reasons that we have
discussed over the last two hours, plus I don't
think that the backup system to make an informed
decision is there. So I vote no.
DR. BENOWITZ: Let me say first that I am
in favor, in general, of the idea of
nonprescription lovastatin, however, not for the
system as proposed. I see five things that need to
be dealt with specifically.
One, I think there needs to be an accurate
benefit description so people can really make
judgments about if they are going to buy it, which
I agree with you, Alastair, that people should have
the right to do that. They should know what the
benefits are that they are paying for.
I think there needs to be better
protection in terms of pregnancy risk. I think
there really needs to be better care available in
terms of pharmacist care or someone to ensure that
there is better follow up.
I think there needs to be an interaction
between the FDA and whoever regulates marketing so
that it is marketed in a fair and balanced way. I
think we need to be sure that when generic OTC's
come, that they are brought into the same system.
DR. WOOD: So is that a yes or a no?
DR. BENOWITZ: It is a no.
DR. BLASCHKE: Well, to balance that, I
feel exactly the same way as Neal does but, since
we have to give a categorical answer, I will say a
categorical yes with all of the caveats that Neal
has just mentioned. My concerns are exactly the
same, the pregnancy issue, the issue of what the
patient really knows about what he or she is buying
in terms of the benefits, the importance of the
involvement of the pharmacist, et cetera. But, as
a categorical answer, I will say yes.
DR. CARPENTER: I say no. I do agree with
Neal's comments as well. I would welcome and would
push exploration for a p-level designation or
something analogous to the p-level designation in
the U.K. I think it is worth mentioning that this
is an extremely difficult question at hand because,
unlike most of our tasks in these committees, we
are not really simply evaluating the product here.
We are being asked to deal with an entire policy
and philosophy of healthcare.
I think the no's are couched in the fact
that the way this whole system is packaged for us
at present is quite uncomfortable for the reasons
DR. PARKER: No, based on the fact that I
don't think the presented studies support that
people can adequately self-select and manage
without an informed intermediary and also because I
don't feel that the current proposed labeling fits
with the FDA regulation that it be likely to be
read and understood by the ordinary individual
including individuals of low comprehension.
My third concern relates to the cat out of
the box once marketing takes over.
DR. FOLLMAN: I would vote no. My main
concern has to do with the fact that I don't view
we have had really evidence in terms of events
benefits done for this. The studies that have been
done have compared statins to nothing. I think the
proper comparison is statins in a prescriptions,
statins in a over-the-counter world. I just don't
know which way that would come out. I don't have
any evidence. So that is my main reason for voting
I have a few comments on the label. One
is that I think it is important to require annual
cholesterol testing, at least put that on the
label. The label also suggests that those who
don't reach goal at 6 weeks should just stop taking
Mevacor and, by the way, also see a physician. I
think it is important that they should see a
physician if they start because the treatment isn't
effective enough for them.
And, as has been mentioned, I think, the
fact that the CUSTOM study had 10 percent of the
women less than 44 years of age is also of concern.
DR. DAVIDOFF: I would say no. But I
would also say that I think Merck deserves a huge
amount of credit for moving this issue forward or
at least trying to do so. I hope that they don't
give up their efforts and also that the FDA joins
in the effort to try to actually develop an OTC
approach that is more demonstrably effective and
cost effective and then all measures that could
move it in that direction ought to be looked into
including behind-the-counter kind of dispensing,
improved labeling, et cetera because I think it is
the right thing to do. But I don't think we are
DR. PATTEN: I vote no. This is based on
results from the CUSTOM study that have already
been discussed. It is also based on the fact that
the way our healthcare system is currently
configured, we do not have the option that the
British have. I think that is an option that
should be considered. I don't that the idea of
pharmacy-care OTC that we heard addressed this
morning really gets at that issue. There are many
labeling problems that have already been mentioned.
One that passed me by until just a few minutes ago;
if, indeed, age is the first criterion that people
should use to decide if this medication is
appropriate or not, then age should be on the front
of the package. If you are a female, 55 or over,
if you are a male, 45 or over, should be right
there for people to see.
DR. McCLUNG: No, but not because of the
concern about the effectiveness of the drug, but
because of the strategy that is outlined, my
uncertainty about the ability of prospective
patients to adequately assess their needs for
choosing to take the therapy.
Secondly for the reasons outlined
eloquently by Dr. Davidoff about the concern about
low-risk patients being treated. Lastly, the
uncertainty about whether this strategy is actually
better than a physician-based approach that has the
same amount of educational and motivational support
that this program would have from the marketing
DR. CLYBURN: No. I have no doubts that
statins are safe and effective within the target
population. My concerns are more with the
self-selection process and I would support a
behind-the-counter, over-the-counter, option.
DR. MAKRIS: No, based upon concerns about
the current proposal as it was presented. I think
there are a lot of opportunities to improve it or
to move forward in some of the directions that have
been outlined by this group today. I see that
there is a real need for this type of marketing,
perhaps in the future, but I don't believe that
this particular proposal addresses all of the
concerns that have been raised.
DR. CLAPP: I think that the
behind-the-counter option would be a perfect
solution to this dilemma. Mevacor seems to be
crucial in heart health and a great drug for it.
But, unfortunately, because of the nature of the
marketing, I think that it puts the
risk:benefit--it shifts the risk:benefit ratio with
the other considerations that we have described.
But, as Dr. McClung mentioned, I think if
Merck could give the same level of aggressive
marketing to physicians for re-education for them
and, perhaps, pose Merck 20 milligrams in the same
realm as a vitamin or aspirin or something that is
a kind of salubrious solution that doesn't seem as
pharmacological to the patient consumer as another
prescription medicine that is 40 milligrams,
perhaps posing it as an optional medicine for
people because, then, they can conceive that they
made a choice.
You could, perhaps, have the same
public-health benefit to the consumer and then have
the ability to target those who need more than the
So I applaud Merck for their attempts at
putting this forward and I see that the CUSTOM
study was a good attempt. It gave us a lot of
information as to how to perceive and, perhaps,
better construe a study for the future. I am
hoping that they won't drop this effort and I am
hoping that the FDA will have some solution for the
future of changing access to over-the-counter
medicines to behind-the-counter, as they do in U.K.
But I also hope that Merck will consider
aggressive physician education for this matter
because I think, in the interim, the public would
benefit from the 20-milligram Mevacor.
DR. SCHADE: I vote yes.
DR. WOOD: Hang on. We didn't get a vote.
Did we get a vote?
DR. CLAPP: No.
DR. WOOD: Thank you.
DR. SCHADE: I vote yes for the overriding
reason that there are millions of Americans in this
country with no health insurance and absolutely no
access to a statin except, of course, to fly to
Britain. I think that these people deserve the
right to lower their risk and prevent
cardiovascular disease. Until we provide something
over-the-counter at a significantly reduced price
and not having to get a physician's prescription,
we are going to continue to have this huge burden,
particularly in the uninsured. I think there is an
overwhelming urge, or should be an overwhelming
movement, to make absolutely important medications
available to noninsured individuals in this country
because, as I think everybody knows, the healthcare
system is not going to be fixed by tomorrow.
So I vote yes.
DR. TAYLOR: I would vote no. I think we
have some serious infrastructure problems in
implementing the current proposal. I do think we
have to do something about the gap in those
individuals being treated. I do think that there
are a group of individuals that do need more
health-professional intervention and they would not
be able to operate effectively in this system.
Perhaps, integrating it into a more
systemic way into the healthcare system, systems
that are being proposed for the future might be a
way to do that. But this proposal, I think, does
not do it. Pharmacy behind-the-counter would,
however, generate some enthusiasm.
DR. SCHAMBELAN: I vote no for many of the
reasons that have just been articulated,
particularly around the issue of approval as
proposed. I don't think this meets the criteria,
at least to satisfy me. I also feel that the idea
of a behind-the-counter access such as will be
studied in the U.K. might well be an answer.
I think Dr. Follman asked for a
city-by-city comparison. I think we may have a
chance for a country-by-country comparison to see
how this does in an OTC setting and, maybe in a
year or so, we will have some data that we can look
DR. WOOD: I vote yes on the basis that
the drug is safe and effective for use without the
intervention of a doctor in the target population
that it was designed to look at. I am less
impressed with the arguments about cost
effectiveness in that I think people should have
the right to spend their money as they wish.
They do need to have a clear understanding
of the likely benefit that they, themselves, may
derive from the product and that currently isn't on
the label but should be and the opportunity to
calculate that should be there.
The reality is that the vast majority of
these patients we receiving no therapy right now
and should be. I think the idea that we should
deny these patients therapy is disturbing to me.
So I would also agree with Neal Benowitz and Terry
Blaschke and what Dr. Schade said, and not repeat
it again, but even though one of them voted no, I
think these are arguments for approving the drug
for over-the-counter use.
DR. TINETTI: I vote no. I am very
strongly supportive of moving in the direction of
self-management but I don't think we have heard,
over the last two days, the evidence to support
that the overall benefit either to the population
or the individuals will be better with it
over-the-counter than its present situation. I
encourage Merck and the FDA to move towards the
kind of study and evidence that can help address
that question because I think it is a very
DR. WATTS: I vote no. I am convinced
that Mevacor 20 milligrams is safe and effective in
the target population but it is a moving target and
I am not convinced that patients who fall outside
that target are properly channeled to where they
should be if they fail to reach goal or new
conditions develop. I am not at all convinced that
patients can self-select for the target population,
that considerable support from health professionals
is needed and that is why it is a prescription
DR. NEILL: I vote no. The answer to the
lack of insured patients in this country isn't a
piecemeal thing like this. It has to be much more
global. In addition, while I respect the right of
people to be able to choose to spend their money
the way that they wish to, in fact, for the
fraction that have some insurance in this country,
what we are talking about is how my tax dollars are
going to be spent. That is going to be altered
dramatically by a choice like this not just in
terms of how or whether cholesterol-lowering
medicines become available over-the-counter but how
we manage and defined OTC conditions.
We have spent very little time talking
around the edges of that but that is a huge, huge
issue that should not be discussed sideways but
DR. WIERMAN: I vote no.
MR. SCHULTZ: I vote no on the basis that
self-selection does not produce a likelihood of
continued use if there isn't some intervention with
professional medical personnel and should be that
DR. FINCHAM: I vote no. The Institute of
Medicine, crossing the quality chasm that was
referred to in the sponsor's document, they talk
about communication, coordination and integration
of care on Page 49. That would be missing in this
process as it is proposed in the United States.
The British system would remove and
questions and qualms I have about this being
significant. I think it is a tragedy. You don't
have to fly to the U.K. You can drive to Nogales
or any other city in Mexico and buy this easily
without any of this.
So I encourage the FDA and I certainly
encourage Merck to continue this process but I have
to vote no now.
DR. SNODGRASS: I vote no. Many of the
reasons have already been stated quite well by many
others. I would strongly encourage Merck as well
as working with the FDA but continue to address
this issue. It is clear that it has some real
potential on a lot of levels. But I just think the
overall benefit:risk ratio is still not there.
I would like to make one small statement
about the pharmacy issue. I think that is a good
idea and it could advance this considerably. But,
even that, I think, in the United States context,
would have to be looked at very carefully with
regard to numbers of pharmacists, the depth and
quality of their training to deal with this with
regard to the actual patient benefit.
DR. WOOD: Great. So the vote is 20 no
and 3 yes. I think we have answered all the other
questions so I don't think we need to proceed from
that. It is 3 o'clock and I think that is the end.
DR. MEYER: I simply wanted to thank the
committee for the two days. I think this has been
a very thoughtful discussion. We have gotten a lot
out of it from your participation and thank you
[Whereupon, at 3:00 p.m., the meeting was
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