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
Thursday, January 13, 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.
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.
Jonca Bull, M.D.
Charles Ganley, M.D.
John Jenkins, M.D.
Robert Meyer, M.D.
David Orloff, M.D.
Mary Parks, M.D.
Curtis Rosebraugh, M.D.
C O N T E N T S
Call to Order and Opening Remarks,
Alastair Wood, M.D. 5
Conflict of Interest Statement,
LCDR Hilda Scharen, M.S. 9
Welcome and Comments,
Charles Ganley, M.D. 15
Introduction, Regulatory History and Overview
of Current Proposed OTC Program,
Mary Parks, M.D. 24
Edwin Hemwall, Ph.D. 39
Rationale for OTC Lovastatin,
Richard Pasternak, M.D. 46
Mevacor OTC Self Management System,
Jerry Hansen, R.Ph. 72
Actual Use Study Results,
Robert Tipping, M.S. 88
Medical Perspective and Conclusion,
Jerome Cohen, M.D., FACC, FACP 120
Questions from the Committee 135
Reproductive and Fetal Toxicity,
Karen Davis-Bruno, Ph.D. 228
Label Comprehension Study,
Laura Shay, RN, M.S., C-ANP 262
CUSTOM--Actual Use Study,
Daiva Shetty, M.D. 281
Nonprescription Simvastatin in the United Kingdom
Michael Koenig, Ph.D. 302
Questions from the Committee 324
P R O C E E D I N G S
Call to Order and Opening Remarks
DR. WOOD: If everyone would take their
seats, we are almost ready to begin. Well, let me
begin by welcoming you all to this committee to
discuss over-the-counter use of Mevacor. I am
going to begin by asking the committee to introduce
themselves, and I guess we will start on this side,
DR. RYDER: Steven Ryder, from Pfizer
Research, and I am the industry representative on
the Endocrine and Metabolic Advisory Committee.
DR. WOOLF: Paul Woolf, Crozer Chester
DR. BENOWITZ: I am Neal Benowitz,
University of California, San Francisco, internal
medicine, clinical pharmacology and medical
toxicology, and Nonprescription Drugs Advisory
DR. CAPRIO: I am Sonia Caprio, from Yale
University, pediatric endocrinologist.
DR. BLASCHKE: Terry Blaschke, clinical
pharmacology, Stanford University, on the NDAC.
DR. CARPENTER: Thomas Carpenter,
pediatric endocrinology at Yale, and a member of
the Endocrine and Metabolic Advisory Committee.
DR. FOLLMAN: Dean Follman, head of the
statistics group at NIAID, and a member of the
Endocrine and Metabolic Advisory Committee.
DR. DAVIDOFF: I am Frank Davidoff. I am
an internist and Editor Emeritus of Annals of
Internal Medicine. I am on NDAC.
DR. PATTEN: I am Sonia Patten. I am an
anthropoligist on faculty at McAllister College in
St. Paul Minnesota, and I am a consumer
representative on NDAC.
DR. MCCLUNG: I am Mike McClung. I am an
endocrinologist from Portland, Oregon, on the
Endocrine and Metabolic Advisory Committee.
DR. CLYBURN: I am Ben Clyburn. I am an
internist at Medical University of South Carolina,
and I am on the Nonprescription Drugs advisory
DR. MAKRIS: Susan Makris. I am a
toxicologist with the Environmental Protection
Agency, Office of Research and Development.
DR. CLAPP: Leslie Clapp, pediatrician
from Buffalo, New York, a member of NDAC.
DR. SHADE: David Schade, University of
Mexico Endocrine Division, and member of the
Endocrine and Metabolic Advisory Committee.
DR. TAYLOR: I am Robert Taylor. I am a
clinical pharmacologist and internist at Howard
University, Washington, and I am a member of the
DR. SCHAMBELAN: I am Morris Schambelan,
from the University of California in San Francisco.
I am an endocrinologist and a member of the
Endocrine and Metabolic Drug Committee.
DR. WOOD: Alastair Wood, I am a clinical
pharmacologist from Vanderbilt.
LCDR SCHAREN: I am Hilda Scharen and I am
the Executive Secretary for the Nonprescription
Drugs Advisory Committee, with FDA.
DR. TINETTI: I am Mary Tinetti, from Yale
University, Internal Medicine and Geriatrics, and I
am a Nonprescription Drugs Advisory Committee
DR. WATTS: Nelson Watts, endocrinologist
at the University of Cincinnati, and member of the
Endocrine and Metabolic Drugs Advisory Committee.
DR. NEILL: I am Richard Neill. I am a
family physician on faculty at the University of
DR. WIERMAN: I am Maggie Wierman,
endocrinologist, University of Colorado, and I am
on the Endocrine and Metabolic Drug Advisory
MR. SCHULTZ: I am Jim Schultz and I am
just a patient representative.
DR. SNODGRASS: I am Wayne Snodgrass,
clinical pharmacology and medical toxicology and
pediatrics at the University of Texas Medical
Branch, on the NDAC committee.
DR. PARKS: I am Mary Parks. I am Deputy
Director, Division of Metabolic and Endocrinologic
Drug Products, with the FDA.
DR. MEYER: I am Bob Meyer. I am Director
of the Office of Drug Evaluation II, at the FDA.
DR. ROSEBRAUGH: Curt Rosebraugh, Deputy
Director, Division of Over-the-Counter Drug
DR. GANLEY: Charlie Ganley, I am the
Director of Over-the-Counter Drug Products, FDA.
DR. BULL: Good morning. Jonca Bull,
Director of the Office of Drug Evaluation V in the
Office of New Drugs.
Conflict of Interest Statement
LCDR SCHAREN: I am going to read the
conflict of interest statement. The following
announcement addresses the issue of conflict of
interest and is made a part of the record to
preclude even the appearance of such at this
Based on the submitted agenda and all
financial interests reported by the committee
participants, it has been determined that all
interests in firms regulated by the Center for Drug
Evaluation and Research present no potential for an
appearance of a conflict of interest with the
In accordance with 18 USC 208(b)(3), full
waivers have been granted to the following
participants. Please note that the following
consulting and speaking activities waived are
unrelated to Mevacor and its competing products:
Dr. Michael McClung for consulting for the sponsor
and a competitor for which he receives less than
$10,001 per year per firm; Dr. Morris Schambelan
for consulting with a competitor for which he
receives less than $10,001 per year; Dr. Paul Woolf
for consulting with a competitor for which he
receives less than $10,001 per year; Dr. Margaret
Wierman for being a member of the sponsor's and a
competitor's speaker's bureau for which she
receives between $10,001 and $50,000 per year from
the sponsor and less than $10,001 per year from the
competitor; Dr. Nelson Watts for being an advisory
board member for two competitors for which he
receives less than $10,001 per year per firm; Dr.
Neal Benowitz for consulting with a competitor for
which he receives less than $10,001 per year and
his spouse's stock in the sponsor which is sponsor
which is between $5,001 and $25,000 per year.
A copy of the waiver statements may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building.
We would also like to note the Dr. Steven
Ryder is participating in this meeting as a
non-voting industry representative acting on behalf
of regulated industry. His function at this
meeting is to represent industry interest in
general and not any one particular company. Dr.
Ryder is employed by Pfizer.
In the event that the discussions involve
any other products or firms not already on the
agenda for which an FDA participant has a financial
interest, the participants are aware of the need to
exclude themselves from such involvement and their
exclusion will be noted for the record.
With respect to all other participants, we
ask, in the interest of fairness, that they address
any current or previous financial involvement with
any firm whose products they may wish to comment
upon. Thank you.
DR. WOOD: In case any of you missed it,
this is obviously an unusual meeting and I wanted
to begin with summarizing some of the issues here.
We are usually asked on NDAC to consider
the approval of over-the-counter products for the
treatment of symptoms or diseases in patients where
individual patients can identify their symptomatic
problem and self-medicate to treat that problem.
Now, in such a setting the patient can expect that
they will derive benefit, usually symptomatic
relief, from the product that should be obvious to
the patient. Thus, the benefit to an individual
patient should be clear, and the individual
risk-benefit can be assessed both by this advisory
committee and, most importantly, by the patient.
So, they can ask the question how bad is my runny
nose, or how bad is my headache, and does it
justify the risks that are outlined on the package?
The patient can also usually answer the question
did this medicine help, after they have taken it
for some time.
The use of statins OTC is different. Our
justified faith in their efficacy and their
favorable risk-benefit profile is based on
population data showing that populations who
received these drugs and lowered their LDL do
better than similar patients who do not. But
individual patients cannot fully assess their
levels of cardiovascular risk because is not a
symptom, it is a statistical probability.
Additionally, they cannot fully answer the question
did this medicine help that we talked about earlier
since they are practicing preventive medicine.
Thus, in contrast to our usual model,
neither we nor the patient will ever know the
individual patient who benefits from a statin, be
that statin administered to them OTC or by
prescription. But, of course, we always know the
individual patient who suffers an adverse event.
In other words, this represents a new model for OTC
drug use, namely, seeking group benefit while
trying to assess and, of course, minimize
Now, I think understanding that dynamic
should be the overriding issue in our
deliberations. It should inform and direct our
discussions on the decision about the OTC
indications and it was used by the agency in
developing the questions that we will attempt to
These questions are designed to force us
to discussion and to force us to come to some
conclusion on whether the benefits of OTC
lovastatin to the group outweigh the risk to the
individual; whether individuals can identify
themselves as appropriate for therapy; and, very
importantly, conversely, whether we think that
individuals at particular risks can be identified
and excluded from therapy; whether the method of
use, including all the self-screening and other
techniques that we will hear exhaustively, I am
sure, about later are appropriate; and, finally,
whether there are additional measures that we think
are required to maximize the benefit and minimize
the risk to patients from this product.
So, these are unusual issues for us to
debate on NDAC where we usually address symptomatic
treatments, and that is why I wanted to try and set
the stage before we start.
Let's get right to the presentations.
Charlie, do you want to start?
Welcome and Comments
DR. GANLEY: Before starting, I just
wanted to thank the members of both advisory
committees and the invited consultants for taking
time out of busy schedules to participate in this
I would also like to acknowledge the
efforts of the review staffs and project management
staffs of both the Endocrine and OTC Division for
reviewing the information in a relatively short
time and helping to put together this advisory
committee. As always, we greatly appreciate the
efforts of the advisory and consultant staff who
make all the arrangements to conduct these
meetings. I would also like to acknowledge the
efforts of the sponsor to respond to our questions
in the review process in a very timely manner.
I don't think I can be as eloquent as
Alastair in sort of laying out the issue here, but
this is, indeed, a new model for an OTC drug. It
is designed to treat an asymptomatic disease, which
is not typical for OTC drugs. It requires
long-term compliance to obtain a benefit. It
requires laboratory monitoring for the individual
to assess whether they have had a treatment effect
and then some benefit from therapy. But it also
requires a highly motivated individual to decide to
use the product in the first place according to the
product label for a long period of time.
Now, when I think what are the hurdles for
a drug coming to the OTC market, I usually divide
them into two things: what are the issues related
to the drug and what are the issues related to the
disease? Let me just touch on the drug-related
hurdles for OTC marketing.
The first is really that we have to make
some determination of the assessment of the
relative safety of the drug. What we mean by that
usually is what are the events that we are
concerned about. Almost all drugs in the OTC
market can be associated with serious adverse
outcomes and generally we make efforts to try to
minimize those; how often is this likely to occur,
and are there measures that can be taken to help
decrease this occurrence.
For the drug under review for today, there
have been serious adverse events associated with
therapy, particularly the possibility of serious
muscle injury. There are some questions regarding
what the risk is for liver injury. There also are
populations that may be at increased risk for this,
and can those individuals identify that they may be
at increased risk and make a decision whether they
want to use the product? Included in that are
questions regarding underlying liver disease or
individuals who have asymptomatic, undiagnosed
underlying liver disease. Pregnancy or use by
women of childbearing potential is an issue, and
also potential for drug interactions which could
lead to a possibility of increased risk for serious
Now, the disease-related hurdles for OTC
marketing are that there are multiple steps for a
consume to assess their eligibility for
self-selection to use the product. It requires
some monitoring and knowledge of their cholesterol
levels. After initiating therapy, is there some
change in risk, such as the addition of a new
medication, that may necessitate the individual to
make a decision that they should stop the drug or
talk to a physician? Most importantly I think,
individuals need to understand, if they are going
to use this drug, that they really need to take it
for long periods of time to derive some benefit.
You are going to hear a lot today about
consumer behavior studies. Members of the
nonprescription committee, or many of them--we have
some new members today--are quite familiar with
some of the terminology. We are going to make
every effort, and I think Merck will probably make
similar efforts, to try to describe these studies
and what we tried to obtain from them.
The first type of study is a labeling
comprehension study, and these are simply studies
where we attempt to understand whether an
individual can comprehend the information on the
labeling. We use the results to adjust the
labeling prior to an actual use study or prior to
marketing the product. The results from these
studies are not always predictive about behavior in
that the consumer understands the labeling but
their behavior will be different in a real-life
Within the last several years we had an
example of this where we were reviewing a drug that
was clearly associated with significant risk of
drowsiness, and there was clear warning on the
label suggesting that they not drive. In the
labeling comprehension study the individuals
understood this with greater than 90 percent
comprehension but in the actual use study a half to
three-quarters of the individuals drove anyway. I
think what we lose in there is that people still
have their lives and they have to go to work, or
they have to pick up their children, and you don't
get around that by just labeling a product all the
The other type of study is an actual use
study. I am not going to go into great detail. I
think you will hear more about this in Merck's and
FDA's presentations. There are two terms you
should know, one is self-selection. Self-selection
is an individual making a decision whether they are
going to use the product. De-selection is when an
individual has already made a decision to use the
product and they have to decide whether they need
to stop based on a lack of efficacy or the
potential for an adverse event.
The results of consumer behavior
studies--based on literacy and education we really
cannot expect 100 percent success for all the
objectives, and we do develop some hierarchy of
priority in determining what are the most important
things that we are trying to get across. All of us
here will have different thresholds for tolerating
behavior errors. Laura Shay, in this afternoon's
talk, will go into that a little bit. It is really
dependent on the health consequence of the error.
For example, in the case of Mevacor or any other
statin, if an individual develops muscle tenderness
or pain in the muscles we would like them to stop.
If they don't stop they risk potential for serious
injury. In those situations, we would expect
consumers to really understand that concept.
The other question with these types of
studies is that they are not perfect studies. They
are done in settings that are not totally
consistent with how the OTC market works. So,
sometimes it is difficult to extrapolate these data
to an OTC population.
The other thing I want to point out is
that you are going to hear a lot of different
analyses today. The FDA discussion is going to
focus on the "according to label criteria" and
Merck will cover that in addition to multiple other
analyses which I have listed here today. During
the presentations I think it is very important for
the committee to understand what analysis is being
discussed and what the definition of that analysis
is. As far as the committee is concerned, we don't
expect you to remember all these acronyms but we
are going to give you a quiz first thing tomorrow
morning to see if you do remember them!
Who is this product directed to? When you
think about this going into the OTC market the
obvious answer is it is the people with the
criteria on the proposed Mevacor label, but who may
actually use this? It could be any person who fits
the NCEP guidelines for treatment. It could be
simply people who have an interest in their health
and in lowering cholesterol, folks who may eat
cereal because of the potential to decrease your
cholesterol for example, or it could be the United
Other relevant information--OTC drug
advertising is regulated by the FTC, not by FDA.
This is important because advertising will lead
consumers to look into using this product. During
the course of the actual use study, when the study
was advertised, there was some direction given to
consumers that they could call an 800 number and
they should know their cholesterol. But you can
imagine, through advertising without some specific
details as to what you need to know or what the
risk may be, that you could include a much larger
The other issue is the economic
implications of a switch. When considering a drug
for switch, FDA does not take economic
considerations into account during the decision
process. This doesn't just apply to OTC drugs; it
is also applicable to prescription drugs. So, the
cost of the drug is not an issue and insurance
coverage is not an issue.
So, with those remarks, I think I will
send it over to Dr. Parks who is going to give
another introduction and give some past history and
additional comments. Thanks.
Introduction, Regulatory History and
Overview of Current Proposed OTC Program
DR. PARKS: Good morning, Dr. Wood,
members of the advisory committee.
I will be presenting the regulatory
history of Rx to OTC switch for lipid-lowering
drugs. My presentation will also provide you an
overview of previously submitted applications for
nonprescription lipid-lowering drugs, including the
initial Mevacor over-the-counter proposal and its
deficiencies. I will provide an overview of the
current Mevacor application and, finally, I will
present to you areas for consideration on this
The first lipid-lowering drug proposed for
nonprescription use was a bile acid sequestrant.
It was thought to be an ideal candidate for
nonprescription use, at least from a safety
perspective. There were two advisory committee
meetings held on this application and the advisory
committee members concluded otherwise.
As a result of the second 1997 advisory
committee meeting, the FDA issued a guidance to
industry on the over-the-counter treatment of
hypercholesterolemia. That document concluded the
following: that hypercholesterolemia is a chronic,
asymptomatic condition requiring accurate diagnosis
and testing and, therefore, this condition should
remain under the directed care of a healthcare
professional. In short, a recommendation was made
that drug treatments for such a condition not be
In 1999 FDA received two applications
proposing the nonprescription use of a low dose of
two statins. Those statins were lovastatin and
pravastatin, and their applications were presented
at two separate advisory committee meetings in
The medical OTC program back then proposed
the lowest dose of Mevacor for non prescription
use. This dose was 10 mg. The patient population
targeted included men over the age of 40 and
postmenopausal women. Patients could not have a
history of cardiovascular disease, diabetes or
significant hypertension, and they should not be on
prescription lipid-lowering thera[y. The total
cholesterol targeted was 200-240 and LDL
cholesterol of 130 or greater.
The advisory committee members raised
several issues in this application. For efficacy,
it was noted that the sponsor did not incorporate
current treatment guidelines. In particular, no
treatment goals were defined for the consumer. In
addition, clinical benefit could not be
extrapolated from clinical outcomes data for the
proposed dose of 10 mg and for the target
population. Finally, consumer comprehension was
poor in this program, underscoring the complexities
of treating hypercholesterolemia in the
The safety concerns raised at that
advisory committee meeting were not necessarily
unique to lovastatin but are actually found for
other drugs in this class. For muscle, all statins
have been associated with rare cases of
rhabdomyolysis. Lovastatin is metabolized by
cytochrome P450 3A4 isoenzyme. This is the enzyme
involved in metabolism of multiple drugs.
Consequently, they were concerned that
co-administration with potent 3A4 inhibitors might
increase the risk of myopathy.
For hepatic concerns, all statins have
been associated with increases in hepatic enzyme
levels although these laboratory abnormalities
rarely result in serious clinical sequelae.
However, all statin labels recommend baseline liver
testing and for some testing is recommended
periodically after initiation of therapy. The
sponsor had to address how an over-the-counter
product could be marketed when the prescription
label for that product had recommendations for
routine biochemical safety monitoring.
Another issue raised was that clinical
studies for statins excluded patients with
underlying liver abnormalities, either clinically
diagnosed or chemically diagnosed. Consequently,
the safety of statins in patients with undiagnosed
liver disease had not been addressed.
Finally, all statins are labeled as
pregnancy category X drugs. This means that the
drug is contraindicated for use during pregnancy.
Since the July, 2000 advisory committee
meeting, several important events relevant to a
statin over-the-counter program merit discussion.
The first is that the 1997 guidance to industry was
withdrawn in the year 2001 as it was apparent
during the 2000 advisory committee meeting that
there was potential public interest in making
available safe and effective therapies for the
management of hypercholesterolemia in a
Second, and very much an integral part of
the Mevacor over-the-counter program, was the 2001
publication of the National Cholesterol Education
Program ATP III treatment guidelines.
Recommendations made by the NCEP have established
the clinical practice guidelines for managing
dyslipidemia over the past two decades. These
recent guidelines establish new risk categories,
new goals of therapy, and were subsequently updated
in July, 2004 to recommend even lower LDL treatment
goals in patients with very high risk for a
A detailed discussion of the ATP III
guidelines is beyond the scope of today's
presentation, but the publication of these
guidelines has been provided to all members of the
advisory committee in the background packages.
Relevant to this meeting is that the ATP
III guidelines establish new risk categories for
the treatment of dyslipidemia. These risk
categories identify the LDL cholesterol for which
drug therapy should be initiated. It identifies
the LDL cholesterol goal for which drug therapy
should be targeting. There are essentially three
The first includes patients who have
established coronary heart disease or CHD risk
equivalents. These are patients who have diabetes,
peripheral arterial disease or clinical
manifestation of atherosclerosis. These patients
are at high risk for cardiovascular events. Their
10-year risk of having a cardiovascular event
exceeds 20 percent.
The second category includes patients who
have two or more risk factors for heart disease.
The NCEP definition for risk factors includes an
HDL that is less than 40, tobacco smoking,
hypertension, a family history of early coronary
disease and age according to gender. This category
of two or more risk factors is considered
intermediate risk for heart disease.
The third category are the low risk
category patients. These are patients who have no
or only one risk factor for heart disease.
While the next two days we will emphasize
drug therapy for hypercholesterolemia, it should be
noted that the ATP III guidelines are
recommendations on a background of lifestyle
changes. The importance of diet, exercise and
lifestyle modification cannot be emphasized enough
in the management of coronary heart disease.
In the current program to be discussed
today the sponsor has proposed Mevacor
nonprescription therapy to the following patient
population, a primary prevention population with
less than or equal to 20 percent 10-year risk of
coronary-heart disease without underlying chronic
conditions that would complicate consumer
self-management. The product label proposes a
consumer select a product according to the
following: Males 45 years or older; females 55
years or older. The age cutoff for women is
intended to exclude all women of childbearing
potential in order to avoid inadvertent exposure in
pregnancy. The LDL cholesterol should be between
130 and 170, and consumers should have at least one
of the following, smoking, HDL of less than 40,
family history of early coronary disease and
The intent of this particular product
label is that if a consumer can actually
self-select appropriately on the first criterion,
that is, age according to gender, they
automatically have one risk factor for
coronary-artery disease. If they then can
self-select appropriately on the third criterion,
that is, having at least one of the following, they
will automatically have two or more risk factors
for coronary heart disease. So, the summary here
is that the target population is actually the two
or more risk category that I described in an
earlier slide based on the NCEP guidelines.
The proposed dose for a nonprescription
prescription lovastatin is a fixed daily dose of 20
mg. There is no recommendation to titrate up or
down to meet treatment goals.
The treatment goal defined in this
population is an LDL less of 130, and this is in
accordance with the NCEP guidelines. The NCEP does
define secondary goals for therapy, for example, if
a patient has hypertriglyeceridemia then non-HDL
might be a second goal of therapy. This was not
incorporated into the program, however, it was
recognized that patients would need to actually
have fasting lipid profiles to follow this, and it
is also very complicated for consumers to
understand secondary goals of therapy.
In order for consumers to actually follow
current treatment guidelines, this proposal
requires that they know the following things:
Consumers need to know their baseline cholesterol
values, and they need to know their cholesterol
values while they remain on therapy. Consumers
also need to know their baseline risk and changes
in health status that might alter the risk-benefit
ratio of continuing lovastatin 20 mg.
You will hear from the sponsor momentarily
how their clinical program addresses the
deficiencies noted in the July, 2000 advisory
committee meeting. For efficacy, the sponsor has
summarized the LDL-lowering results of two
previously submitted clinical studies, EXCEL and
AFCAPS. They also summarized LDL-lowering results
from the actual use study submitted specifically
for this NDA. Based on these results, one can
expect on average a 24 percent reduction in LDL
cholesterol with the lovastatin 20 mg dose.
The clinical benefits of lovastatin 20 mg
were extrapolated from the AFCAPS study. This was
a 5-year placebo-controlled outcome study
evaluating lovastatin 20-40 mg daily, and the
primary endpoint was a composite of unstable
angina, nonfatal MI and coronary-heart disease
For safety, the sponsor approached these
issues by re-evaluating the EXCEL and AFCAPS
database. These two studies provided lovastatin
exposure data from close to 10,000 patients. The
sponsor also evaluated their global post-marketing
safety database from marketing until present. This
is approximately 17 years worth of marketing,
providing approximately 27 million patient-years of
exposure. Although not on this slide, the sponsor
has also reviewed clinical trial safety data for a
similar statin, simvastatin.
The conclusions from these databases, at
least for muscle and liver safety concerns, are the
following: The risk of myopathy and rhabdomyolysis
is extremely low; that the 20 mg dose, if labeled
adequately and understood by the consumer, is an
acceptable dose for over-the-counter use. There is
little to no hepatic risk in patients with normal
The safety of lovastatin in patients with
asymptomatic liver disease, including viral
hepatitis, was not addressed in well-designed
prospective studies. However, the sponsor has
submitted an abstract of a study in approximately
40 patients and a retrospective study using
lovastatin and other statins in patients with
baseline elevations in liver enzymes. The results
of these studies and the rationale from the sponsor
as to why these data are sufficient to remove any
recommendation for liver monitoring in a
nonprescription setting will be presented by the
Given the small number of patients
evaluated in one study, the retrospective nature of
the other and the exclusion of patients with
certain liver diseases in that study, the FDA finds
these data problematic and difficult to conclude
that patients with any form of asymptomatic liver
disease can initiate lovastatin without periodic
monitoring, at least based on these data submitted.
With respect to pregnancy safety issues,
preclinical studies were conducted and reviewed
under the prescription NDA. You will hear from Dr.
Karen Davis-Bruno the FDA's conclusion on
preclinical studies submitted to that NDA. This
product will retain its category X labeling based
on the following: First, the FDA's interpretation
of these data and, second, based on agreement or an
understanding between the FDA and the sponsor that
the risk of continuing therapy with lovastatin
during pregnancy outweighs any benefit and the drug
should, therefore, remain contraindicated for use
A greater concern is the use of lovastatin
in women of childbearing potential who may
subsequently become pregnant while on therapy. Dr.
Davis-Bruno's presentation is to provide the
advisory committee members with background
information to assess whether the risk of
inadvertent exposure during the first trimester of
pregnancy has been adequately addressed. This is
particularly relevant as you hear the results of
the actual use study presented by Dr. Daiva Shetty
and the ability of women of childbearing potential
to make appropriate decisions on the purchase and
use of this product.
Over the course of the day and a half, we
ask that you give consideration to the following:
A critical outcome study of nonprescription
lovastatin use is not practical, and an analysis of
AFCAPS/TexCAPS does represent the best available
data to date for some estimate of clinical benefit
associated with over-the-counter lovastatin 20 mg.
However, several caveats of extrapolating
from this database must be kept in mind. The first
is that this was a post hoc analysis and that some
of the comparisons no longer maintain the
comparison of randomized treatment groups. None of
the subgroups elected by the sponsor fully reflect
the over-the-counter population as AFCAPS included
patients who were titrated to 40 mg and were also
treated to a lower LDL cholesterol goal. Finally,
long-term benefit observed with AFCAPS assumes
adherence to therapy in the over-the-counter
We must also remember that over time
changes in individuals' health status may occur.
These changes may result in a change in the risk
classification for a patient such that more
aggressive therapy is needed than what lovastatin
20 mg might achieve.
Many of the safety issues will be
addressed primarily through labeling, and the
effectiveness of this approach is evaluated in one
six-month actual use study. Similar to the
efficacy concerns, the impact of changes in health
status and the use of interacting drugs on the
safety of lovastatin over-the-counter must be
considered, particularly in the long term. This
concludes my presentation. Thank you.
DR. WOOD: Thank you very much. Let's
move straight on to Dr. Hemwall's presentation from
DR. HEMWALL: Advisory committee members,
guests, FDA staff, I am Ed Hemwall, representing
Merck Research Labs and Johnson & Johnson-Merck
Today we will be discussing our new drug
application for nonprescription lovastatin at a
dose of 20 mg a day, with the proposed trade name
of Mevacor Daily, however, throughout today's
discussions and in your written background it is
referred to as Mevacor OTC. The indication we are
proposing for the OTC label is to help lower LDL
"bad" cholesterol, which may prevent a first heart
As Drs. Ganley and Wood have noted, the
concept of an OTC lipid-lowering drug and the
accompanying self-management system that we propose
represents an unparalleled challenge to the
consumer in the OTC world. But it also represents
an unparalleled opportunity to have an impact on an
important public health problem in the United
Your predecessors on these committees
reviewed an earlier version of this proposal, as
described by Dr. Parks, for the 10 mg dose, in
2000, and they concluded that the benefit of the 10
mg dose was not sufficiently established with
regard to cardiovascular risk reduction and,
although the safety in an OTC setting was generally
accepted, there remained many questions, which Dr.
Parks has noted and which we are prepared to
Finally, the ability of the consumer to
appropriately self-diagnose and use the product
required further investigation and that is the
cornerstone of our submission to be discussed
today, the CUSTOM study.
So, as noted, a few weeks after the last
meeting in 2000, in part motivated by those
discussions, FDA did lift the negative guidance
which discouraged development of
cholesterol-lowering drugs for over-the-counter use
and this opened the door for a series of
constructive interactions between FDA and J&J-Merck
for approving the OTC labeling approach and the
designs and the objectives of additional consumer
research studies, which we have done, and we are
very appreciative of the guidance we have received.
Since that time, our development team has
conducted extensive research to establish and test
an improved approach to OTC cholesterol management.
We have had input from the Food and Drug
Administration and outside academic experts in the
field of lipid management and primary prevention of
cardiovascular disease. We have increased the
proposed dose to 20 mg and instituted a treatment
to the LDL cholesterol goal approach for our
primary prevention target population that is
consistent with the most current clinical
guidelines established by the National Cholesterol
We conducted a sophisticated actual use
study, called CUSTOM, in which over 3000 consumers
evaluated this OTC option in a naturalistic OTC
setting, and over 1000 consumers elected to
purchase and use the product for up to 6 months.
All this was part of a comprehensive consumer
education and support program which we will review
with you today.
The overriding question which you have
been asked to contemplate today is can an OTC
option enable consumers to have a greater role in
the prevention of cardiovascular disease? In order
to address the question we will examine the OTC
target population and the labeling eligibility
criteria which allow approximation of that
population. We will look at the role of the
Mevacor self-management system and, importantly,
the role of the healthcare professional in
directing and encouraging achievement of
cholesterol goals and heart-healthy behaviors
through a collaborative care approach. Also, the
ability of consumers to act in general accordance
with the label. The criteria that are on the label
are intended to maximize both benefit and safety in
the OTC environment. And, we will look at the
overall benefit-risk relationship for the
individual and, more importantly, for the
population at large.
Our presentation today will be that
following my brief remarks Dr. Richard Pasternak
will discuss the rationale for OTC availability of
a statin drug in this target population and he will
include an overview of efficacy and safety of
lovastatin. Then, Jerry Hansen will provide some
insights generated from our extensive consumer
research and the development of the OTC
self-management system, which is on display over
there and I invite members of the committee, during
the breaks, to take a look at it and also some of
these exact same materials are in your briefing
documents. After Jerry, we will have Bob Tipping
who will review the results of our actual use
studies, with principal focus on the CUSTOM study
which tested the key elements of the
self-management system. Finally, Dr. Jerry Cohen
will complete our presentation with the perspective
of a preventive cardiologist, and the potential
public health impact of increased access to a
statin in a consumer-friendly lipid management
The following slides outline our
consultants whom we have here with us, with
expertise in several topics, who are here today to
provide additional perspective on some of the
questions which may arise during your deliberations
over the next two days. Rather than read through
the entire list of names, we have provided a
complete list of these experts, in handouts printed
on yellow paper, at your seats.
So, that concludes my introduction. I
would now like to introduce Dr. Richard Pasternak.
Dr. Pasternak is a former member of the National
Cholesterol Education Program guidelines panel and
co-author of several associated publications, and
we are really proud to have him now as part of our
Merck clinical research team. He will review the
rationale behind over-the-counter Mevacor.
Rationale for OTC Lovastatin
DR. PASTERNAK: Thanks, Ed.
Good morning, ladies and gentlemen,
members of both panels, the FDA and guests. I am
Richard Pasternak. Prior to joining Merck this
past September, I spent 22 years at Harvard Medical
School in cardiology and preventive cardiology and
that provided me with the kind of opportunities and
privileges to participate in some of the activities
that Ed Hemwall just mentioned.
Given my own strong and long-term interest
in preventing heart disease, I am delighted to be
here today to share with you the rationale for
consumer access to an over-the-counter statin
option. I believe that Mevacor OTC can further our
current efforts in cardiovascular treatment through
improved collaboration between healthcare
professionals and the consumer, resulting in a
potentially significant expansion of prevention of
heart disease in America. I recognize that this
is, as Dr. Wood pointed out in his opening remarks,
a very novel pathway that is being proposed and
that there a number of important and very tricky
issues to consider in the next two days. But, by
the end, I hope that when you look at the strength
and weight of the evidence you will agree that the
benefit and risk arithmetic strongly favors an
option for consumers to have access to OTC Mevacor.
The rationale I plan to review today is
compelling and straightforward. It begins with the
problem, the enormity of the current cardiovascular
public health burden in the United States today in
which huge treatment gaps continue to exist. Next,
I will outline the proposed Mevacor OTC target
population and the well-known product efficacy and
safety information of lovastatin 20 mg. Finally, I
will conclude by discussing the potential for
Mevacor OTC to actually improve public
cardiovascular health, both directly and
indirectly, through increased consumer awareness
The problem is clear and known to everyone
in this room. Cardiovascular disease is the number
one cause of death and disability in the United
States today. If something is not done it will
continue to be our greatest health problem. The
annual number of coronary heart disease events is
over a million per year, with an accompanying
enormous economic impact.
As shown in the graph at the bottom of
this slide, with our aging population our situation
is only going to continue to worsen. In fact, with
our current system it is projected that over the
next 50 years the incidence of coronary heart
disease will double to nearly 30 million.
It is well-known that reducing cholesterol
is one of the most important actions that we can
undertake to reduce the risk of heart disease, and
I could have chosen a number of different figures
to illustrate this but I have taken this figure
from our ATP III update which depicts a log linear
relationship between LDL cholesterol and the
relative risk of coronary heart disease. There is
a well-known and well-accepted relationship between
lowering LDL and risk reduction, such that for each
one milligram/deciliter change in LDL cholesterol
there is roughly a one percent change in risk. New
information now also tells that the lower the LDL
cholesterol, the lower the relative risk even down
to levels below 70 mg/dL.
So, are we making progress in battling
this disease? Well, despite our knowledge of the
importance of cholesterol reduction, we have not
been very successful at the population level. In
fact, over 15 years of advances in treatment
strategies and guidelines we have produced really
minimal, if any, movement in the average total
cholesterol in the United States population. Our
national public health goals, as outlined in
Healthy People 2000, have not even met a relatively
modest goal. And, current data suggests that the
relatively unambitious goal for Healthy People 2010
is also in jeopardy.
Why? Well, there are many reasons for
this problem. One of the major reasons is that
there are minimum number of individuals actually
being treated with cholesterol-lowering therapy.
In 2000, the NHANES data showed us that while we
were doing a pretty good job of getting individuals
tested for their cholesterol, in fact less than a
third to a fifth of people with elevated
cholesterol levels were actually treated, and here
I don't mean treatment with drug therapy only; this
is treatment with either diet or drug therapy.
This isn't due to lack of available therapy or
insufficiently aggressive guidelines.
In fact, our guidelines recommend that a
great number of individuals should, in fact, be
treated. This figure shows estimates of the number
of Americans recommended for treatment by the ATP
III guidelines. Roughly 25 million people are at
high risk or already have heart disease and are in
need of secondary prevention therapy. There are
also roughly 11-18 million individuals at moderate
risk in need of primary prevention.
Today, less than half the people who
adverse event in the high risk group are actually
being treated, representing a major gap. More
importantly however for our discussions here, an
even smaller number of people who are at moderate
risk are actually being treated, with an estimated
60-70 percent treatment gap.
Most of the focus of prescription therapy
has been, and this is appropriate, for the
secondary prevention group. We certainly propose
that that continues. So, what we do propose today
is for you to consider the addition of an OTC
statin option to help increase appropriate
treatment in the moderate risk primary prevention
group, a group, according to the ATP III
guidelines, in need of more and specific attention.
Now that we understand the problem and
have identified a group in which an OTC option
might play a positive role, it is important to
clearly define a target population that is, one,
consistent with the NCEP guidelines and that, two,
can benefit from over-the-counter statin use.
You have already heard a brief outline of
this from Dr. Parks and time doesn't permit me to
go through ATP III guidelines in detail. You do
have this in your background package. But for
those of you not familiar with the format of the
ATP guideline, let me take a moment to walk through
The horizontal rows here are organized
around four designated risk groups. In fact, the
moderate risk group that Dr. Parks referred to is
really divided into two. Each column then lists
the specific LDL goal; the level of LDL at which
therapeutic lifestyle change is recommended for
initiation; and the level at which drug therapy
should be considered for initiation in each of the
four risk groups.
In keeping with the guidelines, we are
proposing the primary target of OTC should be those
at moderately high risk, with two risk factors and
a 10-20 percent 1-year Framingham risk with LDL
levels greater than 130, thus, qualifying for drug
In addition, however, we believe it is
appropriate to consider OTC treatment for the group
listed as moderate here. In fact, when we on the
NCEP panel recognized the benefit of this group,
the cutoff level for consideration for drug therapy
was driven, in large part, by pharmacoeconomic
considerations. Throughout our presentations today
we will refer to the proposed OTC target
collectively as the moderate risk population.
It is important to understand how this is
actually approached in an OTC label. In
consultation with the FDA, we considered and found
it impractical to have consumers actually calculate
their Framingham 10-year coronary heart disease
risk score, something, unfortunately, most doctors
don't even do. Therefore, our OTC label approach
utilizes a surrogate for the Framingham
calculation. The OTC label includes people with
elevated LDL cholesterol above 130 who have two
risk factors, such as age or family history, and
also includes the NCEP treatment goal of LDL less
It is important to point out that the
proposed OTC label directs treatment within the
context of a comprehensive cholesterol management
approach, not just drug therapy. Consumers are
encouraged to include lifestyle changes such as
diet and exercise before and during use of the
product. The Mevacor OTC program also includes a
comprehensive self-management system to reinforce
these lifestyle changes. Most importantly, the OTC
system was designed not to be solely reliant on
self-care. At the center of the OTC system, as you
will see, there is a collaborative care approach
taken that encourages healthcare professional
The most critical element of OTC
consideration is the proven efficacy and safety of
lovastatin 20 mg. Statins as a class have a
long-standing and, as you have heard,
well-documented history of efficacy and safety.
Literally hundreds of thousands of patients have
been studied in controlled clinical trials, and
hundreds of millions of patient treatment years
have been accumulated in the more than 17 years
since these products have been on the market.
The accepted efficacy and safety of this
class was summarized in a joint statement issued on
behalf of the American College of Cardiology,
American Heart Association and National Heart, Lung
and Blood Institute, in which I was privileged to
participate. I won't read the statement in its
entirety but the key point is that statins, as a
class, have clearly proven benefit and are
extremely safe, with a low frequency of adverse
events in comparison to the very large number of
patients receiving these drugs.
This slide illustrates the depth and
breadth of clinical trial experience with statins
across all risk groups from the very high secondary
prevention at the top of this pyramid where
individuals in the trial had an over 50 percent
10-year risk of heart attack or cardiac death, down
to the bottom of the pyramid, the large primary
prevention base that was studied in the landmark
AFCAPS/TexCAPS trial, a trial which showed benefit
of lovastatin in a patient population all the way
down to roughly a 6 percent 10-year risk of MI or
Importantly, these studies showed that
regardless of the population studied in concomitant
risk, there was a significant and similar magnitude
of relative risk reduction from 25 to 50 percent in
all these studies.
Similarly, other endpoint studies have
also shown that significant relative risk reduction
is also achieved across different levels of
baseline LDL, and I have applied some of the trial
data to the earlier slide that I used. In fact,
with the addition of data from the Heart Protection
Study, which was analyzed after ATP III in 2001, we
see that relative risk reduction and, therefore,
treatment benefit occurs at LDL levels below the
2001 ATP III cutoffs for considering drug therapy.
HPS was, in fact, one of the trials that led to the
Turning to lovastatin specifically, there
is a well documented benefit. There are two major
mega-trials that include over 15,000 patients, as
you have heard. The EXCEL study was a 48-week
efficacy and safety study with up to 80 mg daily of
lovastatin. The AFCAPS was a 5-year outcomes trial
studying lovastatin 20-40 mg in a primary
prevention OTC-like population. At 20 mg LDL
reduction is in the range of 20-25 percent; HDL
increases of 6 percent and concomitant total
cholesterol decreases were seen. Importantly in
the AFCAPS trial, a 37 percent reduction in a first
coronary event was seen in this moderate risk
Here the AFCAPS data is displayed with
respect to its primary endpoint in a relative risk
plot. The first line here represents the total
AFCAPS cohort demonstrating the 37 percent risk
reduction that I just mentioned. Although, as was
pointed out by Dr. Parks, direct measurement of a
benefit in an OTC target population is not
possible, we are able to at least look at subsets
of AFCAPS that allow an estimation or approximation
of how risk reduction in an OTC population might
This next group is such a subgroup. It is
a subset of the total cohort which achieved the OTC
goal of less than 130 mg/dL and, again, a similar
degree of risk reduction is seen.
Seen here is the subset within AFCAPS in
this post hoc analysis that strictly meets the
proposed OTC label eligibility criteria and
received only 20 mg of lovastatin throughout the
five years. Of course, the confidence intervals
are broader because the population is smaller. But
it seems clear that there is a similar risk
reduction that is achieved with 20 mg of lovastatin
in the OTC eligible population as in the entire
cohort. There are homogeneous results across these
Given the proven efficacy of lovastatin,
let's turn our attention to the critical discussion
of the safety of lovastatin. As the first approved
statin in 1987, lovastatin does have extensive
in-market safety experience with, as has been
mentioned, 17 years of data for a total of more
than 27 million patient treatment years.
The clinical data to support safety again
includes AFCAPS and EXCEL with daily doses from
20-80 mg. You will see that there is a wide safety
margin for lovastatin 20 mg with safety data up to
40 mg comparable to placebo.
Let's examine the potential concerns,
first looking at the liver. Lovastatin is
generally safe regarding the liver. We do
recognize that currently all statin labels suggest
baseline and most suggest periodic LFT monitoring.
Our current knowledge regarding liver safety,
however, has evolved. We know that asymptomatic
moderate elevations of liver enzymes are seen with
all statins and, in fact, are seen with virtually
every lipid-lowering agent. The elevations are
dose and potency dependent. They are often
transient and resolve with continuing therapy.
Importantly, there has been no demonstrated
association or causality with permanent liver
disease with statins.
As you have seen in the background
package, we believe that liver enzyme testing is
not necessary and is, therefore, not being proposed
for the 20 mg dose in the OTC label-defined
population. We are clearly prepared to address any
questions from the committee and have experts
available to respond to this important issue.
Looking at the lovastatin clinical data,
this table examines cases of consecutive ALT
elevations exceeding three times the upper limit of
normal. As you can see, LFT abnormalities by this
definition with lovastatin 20 mg are exceedingly
rare in both the EXCEL and the AFCAPS trial, and at
20 mg not statistically significantly different
from what was seen in the placebo groups.
To analyze the potential safety concerns
outside of the clinical trials environment in the
marketplace, we refer to Merck's worldwide adverse
experience system. The WAES database is comprised
of spontaneous reports of adverse events in a
post-marketing experience. It is voluntary
reporting system. Reports are often incomplete and
dependent on the terminology of the reporter and
are not by case definitions. It includes all
reports independent of perceived causality. Of
course, because of the way the data is collected,
it can't provide incidence rates.
From this data set we can see that, as
expected, the number of WAES reports of acute liver
failure associated with lovastatin is very low.
During the more than 27 million patient treatment
years there have been only 25 reported cases of
acute liver failure and upon outside expert review
none of these cases could be clearly attributed to
Turning to muscle safety, while muscle
pain symptoms do occur occasionally, actual muscle
toxicity is extremely rare with low-dose statins.
It occurs with all statins and fibrates, and it
occurs particularly when these two are combined.
Since muscle pain symptoms usually occur prior to
actual muscle toxicity, this potential side effect
is often recognizable by the patients. Patients
recover when the drug is stopped and progression to
rhabdomyolysis is rarely seen at any dose.
Going back to EXCEL and AFCAPS data, this
table displays the frequency of CPK elevations
greater than 10 times the upper limit of normal.
Again, we do not see statistically significant
differences between placebo and lovastatin in
either the 20 mg or the 40 mg doses. Both EXCEL
and AFCAPS show low numbers and a very low rate.
While the definition of myopathy and
rhabdomyolysis is evolving and sometimes confusing
because it is used differently in different
settings, using the definition shown here in these
studies, there is additional data that with low
doses there is no evidence of an increased risk of
rhabdomyolysis. Across both trials there was a
total of three reported cases of rhabdomyolysis for
both 20 mg and 40 mg of lovastatin, one in the
lovastatin-treated group and two in the placebo
group. The one case with lovastatin in AFCAPS
occurred post surgically in a patient being treated
for prostate cancer. The patient had been taken
off lovastatin before surgery.
Post-marketing experience also shows the
rarity of rhabdomyolysis directly related to
low-dose lovastatin. Again, out of 27 million
patient treatment years with lovastatin, there have
been a total of 336 spontaneous reports of
rhabdomyolysis. This equates to a reporting rate
of approximately 1/100,000 patient treatment years,
and 158 of these reports occurred without the use
of a potentially interacting drug, and while not
all reports indicate dose, 41 of the events were
reported to have occurred with lovastatin 20 mg.
As previously stated, the potential for
muscle concerns does increase when lovastatin is
used in combination with certain potentially
interacting drugs. Therefore, the OTC label takes
a conservative approach by instructing consumers to
talk to a doctor or a pharmacist if they are taking
any prescription medication, listing potentially
interacting drugs on the package insert and in
corresponding educational materials. With regard
to these potential drug interactions, strong CYP3A4
inhibitors can increase plasma levels of certain
statins and their active metabolites. But a key
question for you to consider is whether this
increase translates into comparable increases in
symptomatic myopathy at the proposed OTC dose.
The AFCAPS trial, interestingly, actually
helps us address this concern since the study was
conducted before we knew details of the potential
concerns with 3A4 inhibitors and co-administration
in AFCAPS was actually allowed. Even in this kind
of worse-case example we see similar numbers
between groups for musculoskeletal adverse events,
defined either broadly or narrowly, when we compare
lovastatin-treated patients and placebo patients.
Thus, while co-administration of a CYP3A4 inhibitor
may increase the relative risk of adverse events
the absolute risk appears to remain extremely low.
From the spontaneous reports WAES database
we see that there have been 178 reports of
rhabdomyolysis with interacting drugs. Since cases
of co-administration with fibrates, in this case 96
of these 97 were gemfibrizole and cyclosporine, are
likely to be patients for conditions already under
the care of a physician this concern for OTC usage
is primarily with niacin and strong CYP3A4
inhibitors. There are 34 reports of rhabdomyolysis
with niacin and 28 reports with strong CYP3A4
inhibitors. Approximately two-thirds of these
cases include dose information and only 29 of the
total of 178 were reported with the 20 mg use.
Therefore, the data supports the conclusion that
the clinical consequences of drug interactions with
lovastatin 20 mg are unlikely given the strong
clinical trial evidence, given the extensive
in-market use over the last 17 years, and given the
OTC labeling instructions that, as you will see,
are effective in guiding consumers away from
concomitant usage of potentially interacting drugs.
Also regarding safety, as detailed in your
background package, there is the regulatory
pregnancy labeling category for prescription
lovastatin. This has already been noted by Dr.
Parks. Since their initial approval, all statins
have been designated pregnancy category X. This
original classification was due to the non-specific
findings in animals observed at many multiples of
the therapeutic dose. Against this background,
since there is no benefit to treat women with
elevated lipids during the relatively short period
of pregnancy, all statins have been assigned the
category X labeling to contraindicate use in
pregnancy. Even though there has been no clear
signal from animal or human data, the proposed
Mevacor OTC label contains strict warnings of "do
not use if you are pregnant or breast feeding."
There is data supporting the safety of lovastatin
in pregnancy and we are fully prepared to address
any questions from the committee and have experts
available to provide the proper perspective on this
Therefore with respect to both efficacy
and safety, lovastatin has a very strong product
profile in support of OTC use. There is
significant benefit that has been demonstrated for
the proposed OTC population on drug, clearly, both
in terms of cholesterol-lowering efficacy and in
terms of CHD risk reduction. Lovastatin has a very
large safety database demonstrating a wide margin
of safety at the proposed OTC dose. Potential
risks will be further minimized by effective
consumer-friendly labeling and education.
So, even though there is an appropriate
target population in need of treatment and a
positive product profile, is there really a
consumer need for an OTC statin option--a question
you will need to consider carefully? Our research
tells us that there is demand for an OTC option.
In the survey carried out this past year by the
National Lipid Association, the details of which
are also in your background package, they found
that compared to five years ago the majority of
consumers are now making more health decisions on
their own and, importantly, 72 percent of
cholesterol concerned consumers surveyed said they
were interested in learning more about an OTC
In another survey from the National
Consumer League, three out of four consumers at
moderate risk and not taking prescription therapy
said they prefer an OTC option for health
Further proof of this interest can be seen
by the fact that consumers already purchase more
than a billion dollars worth of heart health OTC
products yearly. That includes everything from
supplements like garlic and vitamin E to foods that
claim heart-healthy effects, such as oatmeal and
Finally, as many of you in this room know,
earlier this year the U.K. approved nonprescription
Zocor, simvastatin, 20 mg for over-the-counter
Finally, let's consider how this OTC
option can help address the public cardiovascular
health problem that I outlined for you at the
beginning of my presentation.
Looking at the distribution of total
cholesterol among the U.S. population aged 45 and
greater, we see that, like many biologic functions,
there is a bell-shaped curve. Unfortunately, the
peak of this curve is hovering around an elevated
level clearly greater than the desired cholesterol
level delineated by ATP III.
What we are suggesting is that the Mevacor
OTC option provides us with a unique opportunity to
have an increased focus and consumer involvement in
a comprehensive cholesterol management program that
is ideally capable of achieving a leftward shift of
this curve, in fact, a targeted population approach
to CHD prevention.
To conclude, today we have seen that there
is an enormous and growing cardiovascular public
health problem that has not been adequately
addressed. A key concern is the large moderate
risk population which deserves preventive treatment
but is achieving relatively little focus from our
current medical system. We believe that the weight
of the evidence indicates that this problem can be
improved with Mevacor OTC, a drug that has proven
to be appropriate for OTC from both efficacy and
safety standpoints. There is clearly strong
consumer interest in this OTC option, giving us the
potential to greatly improve public cardiovascular
The key question that remains is can a
consumer appropriately use Mevacor OTC in an OTC
setting? The remainder of the presentation today
will focus on that important question and I would
like to now turn the podium over to Mr. Jerry
Hansen, Vice President of New Product Development
and Consumer Research, to begin the discussion.
Thanks very much for your attention.
Mevacor OTC Self-Management System
MR. HANSEN: Good morning.
Today I will be reviewing the Mevacor OTC
label and self-management system. It is important
to note that the exact label and system I will be
discussing were fully tested in the CUSTOM use
trial which is why it is important to review them
prior to the presentation of the CUSTOM data.
As was stated, the key issue today is
whether consumers can play a greater role in
cholesterol management. To that end, we have
studied over 34,000 consumers over a number of
years in the following areas, consumer
understanding, including attitude and behavior;
label development and comprehension; development of
the self-management system; and the actual use
studies. I will discuss the first three areas and
Bob Tipping will follow me with a review of the use
studies focusing on the CUSTOM use trial.
Our first step in developing the label and
system was to gain an in-depth understanding of
consumers who are likely to take action as a result
of the OTC availability. The demographics of those
interested is fairly representative of the U.S.
population. They are older, which is consistent
with the proposed label, but income, race and
education levels are very similar to U.S. averages.
What is most interesting is that while demographics
are representative, their attitudes and behaviors
regarding their health are very different.
These people are extremely active in their
own health care and believe in the idea of
preventing disease. They are more likely than the
general population to be knowledgeable on health
issues; to diet and exercise; to take aspirin for
heart health; and to take vitamins and supplements.
Despite their high involvement in their
own care, they also have strong relationships with
their doctors. Over 80 percent see their doctor at
least once a year. Over 70 percent have had a
cholesterol test in the past year, and about 80
percent have discussed cholesterol with their
doctor. A good way to characterize those
interested is that they are motivated, health
So, with this high involvement in their
health care and their doctor, why not prescription
therapy versus OTC? Well, an important finding is
that these people have a general reluctance to
prescription therapy and prefer instead to make
lifestyle changes or to use OTC medicines.
Good evidence of this as it directly
relates to OTC statins comes from a recent study
conducted by the National Consumer League. The
sample included people at moderate risk for
coronary heart disease but who were currently
untreated with statin therapy. This chart shows
that there is a strong preference and greater
likelihood of action with OTC. This group is three
times more likely to consider taking an OTC,
recommending it to a family member or friend, and
seeking more information about it than a
This slide outlines the reasons why the
same population prefers OTC. On this graph the OTC
preference is in yellow and the preference for Rx
is in blue. This preference is driven both by
practical reasons, such as better convenience
because it is easier to buy and easier to keep
taking every day but, more important, provides
further attitudinal insights. When asked to
describe a cholesterol prescription user versus an
OTC user, they generally feel that a prescription
is for someone who is sick and that an OTC is for
someone who is healthy like themselves.
So, incorporating this consumer learning,
we designed the Mevacor OTC self-management system
to be far more than just a pill in a box. So, the
label and support program we have developed through
rigorous testing over several years offers support
and education that is unprecedented for an OTC
product. The process we employed included
designing a program that is consistent with
treatment guidelines but is also understandable by
consumers. We incorporated iterative consumer
feedback from those likely to use, and then
developed language and multiple tools to ensure we
effectively communicated key messages. Finally,
the program offers a comprehensive approach to
clinical management, including addressing lifestyle
changes such as diet and exercise.
Healthcare professionals play an important
role in consumers' OTC decision process. Data
shows that for any OTC product, for no matter how
long it has been on the market, consumers usually
consult a healthcare professional before using it.
Nearly 80 percent of consumers say that a doctor's
recommendation is very important in their decision
about whether or not to purchase an OTC for the
first time, and 64 percent say a pharmacist's
recommendation is very important. It is not
surprising then that most consumers interested in
Mevacor OTC will do so in partnership with their
healthcare professional. In fact, over 80 percent
claim they will talk to their doctor before using.
A key element of our program, therefore, is to
facilitate and encourage this interaction.
Because the package label is at the core
of Mevacor OTC, our first step was to create a
label that effectively communicates. The label and
support materials are in your background for your
review and, as Ed stated, the entire system is over
there, at the side of the room, that you can review
The key label messages include an OTC
target consistent with NCEP guidelines. This was
approximated on the label by targeting those with
an LDL between 130 and 170. It is also for men 45
years and older and women 55 years and older. And,
the user should also have one additional risk
factor. These include positive family history,
smoking, low HDL and high blood pressure.
People who have liver disease, are
pregnant or breast feeding, or allergic to
lovastatin should not use the product. There are
also strong messages for those at higher CHD risk
to not use and to see their doctor about possible
prescription therapy. Finally, there are clear
safety warnings about potential drug interactions
and muscle pain.
Again, taking a comprehensive approach to
cholesterol management, the label instructions
include encouraging lifestyle changes and
cholesterol testing. Before using you must have
tried diet and exercise to reduce your cholesterol,
and had a fasting cholesterol test within the past
year. Users are also instructed to test their
cholesterol at six weeks to see if they reach goal.
If they do, they should keep taking Mevacor OTC
daily, test at least once a year and continue to
diet and exercise.
As stated earlier, we believe Mevacor is
not purely self-care but a collaborative
partnership with healthcare professionals. So, the
label strongly encourages this interaction by
telling users to consult with their doctor or their
pharmacist if they have any questions. Examples
include that if someone does not reach their LDL
goal they should talk to their doctor because OTC
may not be enough for them. They should also talk
to their doctor if there is any change in their
health, and talk to their doctor or pharmacist if
they start any new prescription therapy.
Label comprehension testing was conducted
to ensure clear communication. The methodology
included testing in a representative sample and in
low literacy and ethnic subgroups. Again, the
label used was the identical label used in the
CUSTOM trial. The study employed both correct and
correct/acceptable scoring, with acceptable
generally referring to checking with the doctor.
The full results of the label
comprehension studies will be presented by FDA but,
in summary, the label results were very strong,
with over 80 percent or more correct/acceptable for
most measures and 90 percent or more
correct/acceptable for key safety messages. The
label, therefore, is very effective at
communicating key messages across all groups and
also effectively communicates that consumers should
ask their healthcare professional if they have any
So, once we had a clear understanding of
the potential users and had developed an effective
label, we went on to develop the Mevacor
self-management system. The goal of the system was
to provide additional information and tools to
reinforce key label messages and to emphasize
lifestyle changes. In developing the system we
incorporated feedback from external experts,
including professional organizations, key opinion
leaders and consumer behavior specialists. We
learned that consumers like to receive information
in different ways so we offer multiple methods of
delivering information to appeal to these different
learning styles. Importantly, all elements of the
system are part of our proposed NDA labeling and,
therefore, will be required in the marketplace.
Like the label, the system I will describe was also
fully tested in the CUSTOM study.
In the CUSTOM study the self-management
includes three major health components,
pre-purchase, in-store and post-purchase. But
importantly, the program strongly encourages
healthcare interaction through first looking at
The most common way that the consumer will
learn about Mevacor OTC is through advertising. In
this advertising there will be extensive
communication and education, including the
importance of knowing your cholesterol numbers and
highlighting that OTC is not right for everybody.
To help consumers determine if it is right for them
the program will offer eligibility assistance by
directing them to their doctor or pharmacist if
they have any questions. It also offers access to
trained product specialists who will be available,
toll-free, to answer questions about Mevacor and
related services such as cholesterol testing.
The next step a consumer is likely to take
is to visit a store to learn a little more about
the product. So, let's review the in-store
assistance we will provide. In-store assistance
includes extensive support in the pharmacy.
Importantly, we are proposing that Mevacor be sold
as a pharmacy care OTC. To support this, we will
be providing extensive pharmacist and staff
training. We will also provide enhanced retail
communication including interactive tools that will
support the label.
I will now talk about each of these in
more detail. Pharmacy care OTC is a new approach
developed by the American Pharmacists Association
and other key pharmacy groups. The goal here is to
provide expanded support for more novel Rx to OTC
switches by facilitating greater interaction
between pharmacists and consumers.
The features include that manufacturers
will voluntarily distribute the product only in
stores with a pharmacy; that it be available on the
open shelf with current OTC products and not behind
the counter; that pharmacist intervention is not
required but strongly encouraged; and there is an
expansion of supportive services such as
cholesterol testing and counseling.
As I stated, we will be providing
unprecedented in-store education and support for
Mevacor OTC. Here is an example of a novel store
shelf device we have developed and tested. It
highlights two decision processes including
information for first-time buyers primarily, should
you take it, and repeat buyers, with messages
regarding getting to goal. It also offers extra
tools such as tear-pads and eligibility wheels.
These directly support the label but allow people
to answer questions in a more interactive way.
Finally, the shelf communication strongly
encourages dialogue with the pharmacist which
further supports the concept of pharmacy care OTC.
Now we will review post-purchase
assistance. This includes programs and tools to
support the consumer after they purchase the
product and take it to their home.
Post-purchase assistance includes
materials in the package, including an educational
brochure; package insert Q&A; a quick start guide;
and incentives for cholesterol testing.
Regarding cholesterol testing, this is a
very important component of the Mevacor OTC system.
Our toll-free number and our website offer
assistance on obtaining cholesterol numbers and
where to get tested. We will also be offering in
each box a high value coupon toward the six-week
We have learned that doctor-directed
cholesterol testing continues to be where most
consumers prefer to be tested. However, other
testing options are becoming increasingly available
including tests in the retail setting, walk-in
clinics, and at home.
Another important part of post-purchase
assistance is the ongoing adherence program. This
includes a toll-free hotline and website,
educational video and American Heart Association
cookbook, ongoing newsletters, postcards, and
This is how the adherence program works.
It is customized to correspond to the date the user
started taking the product. This ensures that the
message is relevant to them at that point in their
therapy. For example, the first three months focus
on eligibility and treatment to goal, while later
communication focuses on diet, exercise, long-term
adherence and health professional interaction.
While not a requirement, most consumers
interested in Mevacor OTC want to and will partner
with their healthcare professional while using.
Therefore, we have structured the system to
encourage and facilitate this.
To support this interaction, the program
encourages ongoing dialogue concerning any
questions regarding Mevacor OTC including testing
and monitoring. The program also includes a risk
referral program for those who are identified at
higher risk and then directs them to their doctor
for possible prescription therapy.
Here is an example of one of the
doctor/pharmacist tools. In each package will be
two cards, a doctor card and a pharmacist card.
Users can fill out the inside of these cards with
information such as when they started taking
Mevacor and list any other medications they may be
taking. The doctor can then add this information
to the patient chart and the pharmacist to the
So, as I have shown, the Mevacor OTC
self-management system is comprehensive and offers
the tools for a consumer to self-manage their
cholesterol. However, each element of the program
also strongly encourages healthcare professional
interaction as needed.
In summary, those likely to take action as
a result of Mevacor OTC differ from the general
population, with these people being highly
motivated and health conscious. The
self-management system offers multi-faceted and
unprecedented support to reinforce key label
messages and was designed to drive interaction with
healthcare professionals. Both the label and the
support system were submitted as proposed NDA
labeling and, therefore, will be required in the
marketplace. We have further demonstrated the
feasibility of executing this commitment in the
marketplace with key partners including retail,
pharmacy and testing companies.
Finally, if approved, we commit to
extensive post-marketing surveillance to monitor
actual use in the marketplace and we will use this
data to modify our program as necessary. That
concludes my presentation. I know we are scheduled
for a break now.
DR. WOOD: Let's just go straight on to
Robert Tipping's presentation.
MR. HANSEN: Dr. Wood, I do just want to
warn you that this is about 30-40 minutes and gets
DR. WOOD: That is okay.
Actual Use Study Results
MR. TIPPING: Thank you, Jerry and good
morning to members of the advisory committee and
representatives of the FDA.
I am Bob Tipping, a director in the
clinical biostatistics department of Merck Research
Labs. Today I will share with you some of what we
have learned about how consumers use Mevacor OTC
and the self-management system that you have just
The data I will present today addresses
three key questions about consumer behavior: Will
the Mevacor OTC self-management system allow
consumers to make appropriate initial decisions
about the use of the product? Will they be able to
self-manage the potential safety issues over time?
And, will they be able to self-manage their
cholesterol over time and obtain benefit?
To address these questions I will be
showing you data from the large behavioral trial
called CUSTOM, the Consumer Use Study of OTC
Mevacor. It is important to realize that CUSTOM is
a large trial, over 3300 participants and 800,000
data items. Given the time constraints of this
meeting, I will not be able to show you all of the
data. Instead, I will focus on those results that
address the key questions about consumer behavior.
Let me briefly review the CUSTOM study
design. Participants were recruited using TV,
print and radio advertisements. Ads did not
include specific eligibility criteria. The ad
campaign included ads designed to communicate to an
ethnically diverse population and included a
toll-free number for interested individuals to call
for an appointment.
Study sites were set up to simulate an OTC
retail environment. This included a shelf display
and drug package consistent with marketplace plans.
CUSTOM was an all-comers study. All participants,
regardless of their label eligibility, were able to
make a purchase decision. Participants reviewed
the label and the other in-store components of the
system to assess if Mevacor OTC was right for them.
They were allowed to leave and return later if they
felt they needed more information. The option to
purchase a cholesterol test was available. Study
site nurses were trained to act as pharmacists and
could answer questions but did not volunteer
assistance unless asked by the participants.
Interested participants were required to purchase
After making the initial purchase
decision, participants were followed for six months
of self-guided behavior and product use with
minimal intervention. Visits were not scheduled.
Participants returned to the site at their own
initiative to purchase additional drug or a
cholesterol test. Behavior around obtaining a
follow-up cholesterol test following treatment to
the goal messages and new medical conditions and
prescriptions was observed.
Baseline and end of study lipid values
were collected from participants who purchased the
study drug in a way to have minimal impact on
participant decisions. These lipid values allowed
us to assess the lipid-lowering effect of
lovastatin 20 mg a day in an OTC setting.
At the end of the study eligibility
information was collected. Participants were asked
about new prescriptions, new medical conditions and
adverse experiences. Information about diet and
exercise and the reasons for inappropriate
decisions were also collected.
A post-study survey was conducted in a
subset of users to obtain additional information
about specific behaviors.
You have seen this slide a few minutes ago
when Jerry Hansen presented the Mevacor OTC
self-management system. All elements of the system
were evaluated in our CUSTOM trial. The system
emphasizes a collaborative care approach, designed
to support self-management while encouraging
interaction with healthcare professionals. In
fact, we will present data demonstrating that
consumers will seek out these partnerships with
doctors and pharmacists in the OTC setting.
The analysis of behavior evidenced
decisions about the purchase and use of Mevacor
OTC. The analysis carefully considered
interactions with healthcare professionals. The
label contains numerous messages about talking with
your doctor or pharmacist. Information about these
interactions was collected and was an important
factor in determining the appropriateness of use
decisions. We also wanted to document the positive
impact that this system had in creating new and
maintaining existing relationships with healthcare
professionals. Finally, we collected information
from participants about their diet and exercise
habits while on Mevacor OTC.
Turning now from study design to the
CUSTOM study results--
Before we get into actual behavioral
results, it is important to understand how
participants flowed through our study and to
introduce the various populations to be discussed
further into the presentation. In response to
study advertising, over 11,000 individuals called
our toll-free number. Of that group, 3316
scheduled an appointment and traveled to one of the
study sites. This group, called the evaluator
population, reviewed the label and the other
in-store components of the system and made a
decision about the purchase of Mevacor OTC; 2111
people decided not to purchase the drug and a
little over 1200 did choose to purchase. The
purchasers split into two main groups, those who
purchased but did not go on to actually use the
drug and a group that actually began to use the
medication. Finally, there was a subgroup of 398
uses who participated in our post-study survey.
This slide presents a brief overview of
the demographics of the evaluator population, and
59 percent were men. They had a median age of 53
years. As mentioned earlier, the recruitment ads
were designed to reach an ethnically diverse
population and we were pleased to see positive
results from this, as evidenced by a 28 percent
minority participation rate at this stage of the
study. Twelve percent of the evaluator population
was classified as low literacy based on the results
of a validated adult literacy questionnaire called
the REALM test.
Before discussion of behavior, and
specifically behavior that resulted in the
potential for an increased safety risk, it is
important to provide a summary of the actual safety
results from the use of lovastatin 20 mg in an OTC
setting. There was only one serious drug-related
event, an allergic reaction to lovastatin. One
death occurred in the study. A 50 year-old man
died of a stroke that was judged probably not
related to study drug. There were no serious
drug-related muscle or liver events. No new safety
issues were identified and lovastatin was generally
safe and well tolerated by this population in a
simulated OTC environment.
To better understand consumer behavior
regarding the Mevacor OTC label, it is helpful to
think about the label elements as falling into one
of four quadrants. The top and the bottom rows of
this table contain label elements for the initial
and the ongoing use decisions respectively. The
left column consists of specific safety warnings
and the right-hand column contains label benefit
Safety warnings, summarized here, guide
appropriate behavior from consumers with these
conditions or situations so as to minimize the
potential for a safety concern.
Benefit criteria target an appropriate
population based on their age, presence of
additional risk factors and knowledge of their
complete lipid profile including triglycerides and
HDL. As mentioned earlier, these criteria were
written to be readily understood by the consumer
while allowing an approximation of eligibility
according to ATP III treatment guidelines.
It should come as no surprise that many
users in CUSTOM were not 100 percent compliant with
each and every element of this multi-factorial
label. A strict interpretation of the CUSTOM
results along these lines can be viewed as a less
than positive outcome, but if one sees some
distinction between these label elements; if one
believes that a "do not use if you are pregnant"
warning should be evaluated at a different level
than a specific age or lipid value cutoff; if one
believes that people should have the option to make
their own personal benefit assessment, then the
CUSTOM results will demonstrate that consumers can
be capable partners in the management of
cholesterol and heart health.
So, will consumers make appropriate
decisions about starting to use Mevacor OTC?
From the population of 3316 who evaluated
the product, there were 2111 who chose not to
purchase. An additional 64 purchased the product
but made a decision not to begin taking it. There
were 659 people who began to use the product in
compliance with both the label safety warnings and
Taken together, this totals 86 percent of
the population who came to one of the sites and
evaluated the product.
There were an additional 109 participants
who began to use the product despite a label safety
warning that was relevant to them. Let's look at
each of these groups more carefully.
Coming back to the study population slide,
I will next show you data from 2111 non-purchasers
and the 94 purchaser non-users.
This group of evaluators who chose not to
purchase the product provides strong evidence that
the label and the other in-store components of the
system are discouraging inappropriate people from
using the product. Seventy-nine percent of this
group indicated that they were not interested in
buying Mevacor OTC. Nearly two-thirds of this
subgroup stated that they believed Mevacor OTC was
not right for them.
The group of 94 who purchased but did not
go on to actually use the drug includes 64 people
who actually left the site with Mevacor OTC. The
majority cited that "my doctor advised me against
using it," or "I learned it was not right for me"
as a reason for not using the drug. These results
provide strong evidence that the post-purchase
components of the system are further discouraging
inappropriate use of the product.
Returning again to our population slide, I
will next show data from the 1059 people who
actually began to use Mevacor OTC, and remind you
that we are still addressing the first of our three
key questions, will consumers make appropriate
decisions about starting to use Mevacor OTC?
The target behavioral goals established
for the CUSTOM study were based on information from
label comprehension studies. Typically, a level of
80 percent is regarded as a reasonable benchmark
for correct and acceptable answers for each of the
individual label elements. Our pilot comprehension
studies of the CUSTOM label showed that most of the
individual label elements were understood by 80
percent or more of those tested and, most
importantly, the key safety warnings were
understood by more than 90 percent. We know that
label comprehension results do not always predict
behavior, but we decided to apply the same 80
percent benchmark in evaluation of our behavior
data, an even more rigorous test because it
required being correct on all label elements
collectively, not just individual criteria.
Indeed, for the safety criteria 90 percent
of the CUSTOM users demonstrated correct behavior
around all label safety warnings jointly, exceeding
the 80 percent benchmark and consistent with the
label comprehension results for the individual
Correct behavior according to the multiple
label benefit criteria was not as high. It was 66
percent of the users closely adhering to the
benefit criteria. Taken together with the label
comprehension results that exceeded 80 percent for
these elements and the excellent behavior around
the label safety warnings, this suggests that
consumers are understanding the label and are
applying more individual judgment on the benefit
criteria before beginning to use Mevacor OTC.
Looking jointly at all safety and benefit
criteria for the initial decision to use, which was
a prespecified hypothesis of CUSTOM, this
translates to 55 percent of the users behaving in a
fashion consistent with all label elements. This
number is obviously driven by the low adherence to
the label benefit criteria and is roughly the
product of the 90 percent and the 66 percent.
Let's now explore the behavior within each of these
bars more fully.
First, let's look at the safety warnings
directed at the initial use decision. Recall that
90 percent of all users exhibited behavior that
completely met the label safety criteria and 10
percent who did not comply with the label safety
warnings. This 10 percent corresponds to 109 of
Recall, this was an all-comers study.
There was good representation from all of the
safety decision areas among our evaluator
population, the orange bars.
There were very few people with these
conditions who went on to actually use Mevacor OTC
without speaking to a physician. There was no use
by pregnant women. Use by people in the other four
categories was low and there were no serious
drug-related muscle or liver events among them.
The difference between the number of the
evaluators represented in the orange bars with
these conditions and the number who chose to use
Mevacor OTC, the yellow bars, provides strong
evidence that the safety warnings directed at the
initial use decision are effectively discouraging
inappropriate purchase and use of Mevacor OTC.
Now let's look more fully at the benefit
criteria directed at the initial use decision.
These are label elements referring to age, lipids
and CHD risk factors. Recall that 66 percent with
behavior that met or closely met label benefit
criteria and the 34 percent who did not comply with
the benefit criteria--that 34 percent corresponds
to 357 of the user population.
But 72 percent of this group, based on
their risk factors and their 10-year risk for
coronary heart disease, should be considered for
lipid-lowering therapy according to ATP III
guidelines. Let's now look at the specific label
benefit criteria that cause people to fall into
this 34 percent group.
Eighteen percent of users did not know
their complete lipid profile. However, results
from the study-mandated baseline lipid exam
indicated that 93 percent of them had elevated
lipids, a measured LDL at or above 130 or a total
cholesterol of 200 or more. Fifty-one percent of
this group did not know their complete lipid
profile but they did know their total cholesterol
value. This group had a median LDL cholesterol of
165. So, while they did not meet the strict label
criteria, they are still very likely to obtain
benefit from lipid-lowering therapy.
Sixteen percent of the users had
self-reported triglycerides of 200 or higher. The
label advises consumers with triglycerides greater
than or equal to 200 not to use the product unless
directed by a physician. This is to minimize the
potential for use among people with possible
metabolic syndrome since they may require more
personalized medical care. However, results from
the study-mandated baseline lipid exam showed that
92 percent of this subgroup also had elevated
lipids, with a median total cholesterol or 253 and
a median LDL of 146. Nearly three out of four had
self-reported triglycerides less than 400. So,
again, while they did not meet all of our
conservative label criteria, they are still very
likely to obtain benefit from lipid-lowering
Eleven individuals indicated they would
substitute Mevacor OTC for their prescription
cholesterol-lowering medication without consulting
their physician. This represents just one percent
of our user population and a very small percentage
of the 609 evaluators who reported on being on Rx
Finally, there were 70 individuals, or 7
percent of our users, who were at higher CHD risk.
They reported having coronary heart disease, having
had a prior stroke or being diabetic and chose to
use Mevacor OTC without speaking to a physician.
Among the evaluators, there were 570 who
reported having coronary heart disease, a prior
stroke or diabetes. More than 70 percent of this
group chose not to purchase Mevacor OTC.
However, 167 of them did choose to use
Mevacor OTC and 97 of this group did it after
consulting with a physician. That leaves 70 higher
risk users from the earlier slide who began to use
Mevacor OTC without speaking to a doctor.
However, 26 of these 70 did have a
physician interaction at some point during the
study. Combining these 26 with the the 97 who
consulted a physician prior to using Mevacor OTC,
this totals 74 percent of this group who had an
interaction with their doctor prompted by the
Mevacor OTC self-management system.
Finally, it is important to note that 80
percent of this 70 had elevated lipids, and
two-thirds of them were not on lipid-lowering
therapy at the time they chose to start taking
Now let me summarize the results you have
just seen and address the first of our three key
questions, will consumers make appropriate
decisions about starting to use Mevacor OTC? From
our population of evaluators, there were 2111 who
evaluated and chose not to purchase. An additional
64 purchased the product but made a subsequent
decision not to begin taking it. Finally, there
were 659 people who began to use the product in
compliance with both the label safety warnings and
the benefit criteria. Taken together, this
represents 86 percent of the population that came
to one of the study sites and evaluated the
product. There were an additional 109
participants, representing just 3 percent of all
those who evaluated the product, who began to use
Mevacor OTC despite a label safety warning that was
relevant to them. The behavior of these 109
individuals created the potential for an increased
safety risk, however, there were no serious
drug-related muscle or liver events among
them--good evidence that consumers can select to
use Mevacor OTC appropriately.
Returning to the key questions, I will now
address both the second and the third questions
together for a moment since they are both directed
at the ongoing use decisions. While decisions
about initial use are important, even more
important are decisions regarding ongoing use
because only those who use the product long-term
are going to gain a clinical benefit or place
themselves at a potential safety risk.
Will the system allow consumers to
self-manage the potential safety risks over time?
From our population of 1059 users, there were 366
who actually experienced a new medical condition or
got a new prescription, thus providing an
opportunity to evaluate behavior regarding the
label safety warnings for ongoing use. Of these
366, 94 percent made a decision about ongoing use
of Mevacor that was consistent with the label.
Only 6 percent made a decision that was
inconsistent with safety warnings directed at
ongoing use decisions.
Will the system allow consumers to
self-manage their cholesterol over time and obtain
a benefit? Again, from our population of users, 74
percent obtained a follow-up cholesterol test or
had discontinued Mevacor OTC prior to the six-week
time point directed in the label. Of those users
who did get a follow-up test, three out of four
followed the label directives regarding the LDL
goal. Finally, there was an impressive 21 percent
reduction in LDL.
Again, based on label comprehension study
results, we evaluated decisions about ongoing use
against the prespecified 75 percent benchmark.
CUSTOM demonstrated behavior around all
label safety warnings for ongoing use jointly to be
94 percent. As with the safety warnings for the
initial use decision, this exceeded the target
benchmark and was consistent with label
comprehension results for the individual label
As with the initial use decision, fewer
adhered to the label benefit criteria, with 53
percent of the user population closely adhering to
benefit criteria for ongoing use decisions. Taken
together with the comprehension results for the
label benefit elements and the excellent behavior
around the label safety warnings, this again
suggests that consumers are understanding the label
and are making their own personal benefit
assessment for the continued use of Mevacor OTC.
Combining all safety benefit elements for
the ongoing use decision together which, again, was
a prespecified hypothesis of CUSTOM, we see that 50
percent of the users behaved in a fashion
consistent with each and every label element.
Again, this is no surprise given the results from
the label benefit criteria, and is the product of
the 94 percent and the 53 percent.
Now let's explore behavior within each of
these bars more fully. First, let's look
specifically at the safety warnings directed at the
ongoing use decision. Here is the 94 percent
exhibiting behavior that completely met the label
safety criteria, and the six percent who did not
comply with the label safety warnings. That six
percent corresponds to 21 individuals from the user
There were 693 of the user population who
did not experience a new medical condition or get a
new prescription during the study. That leaves 366
who did experience a new medical condition or a new
prescription and exhibited a behavior that could be
evaluated against the label safety warnings for
ongoing use. The three bars to the right represent
the number of users with each of these events.
And 270 of the 366 reported a new
prescription during the study. Only two were for a
potentially interacting medication where the person
did not inform their physician about taking Mevacor
OTC as directed on the label; 161 reported a new
medical condition while in the study and only three
of these were of concern. As discussed earlier,
there was the individual who had a stroke and died
before he could reveal to his physician that he was
taking Mevacor OTC. One individual was diagnosed
with coronary-artery disease and did not inform her
physician about the use of Mevacor OTC, and one
individual was diagnosed with diabetes and, again,
failed to inform his physician about use of Mevacor
OTC. Sixty-three reported an unexplained muscle
pain during the course of the study. All but 16
discontinued Mevacor OTC or spoke with a physician
Now let me summarize the results you have
just seen that address the second of our three key
questions, will consumers be able to self-manage
the potential safety risks over time? From the
population of 1059 users, there were 693 who did
not experience a new medical condition or get a new
prescription during the study. An additional 345
experienced and event and made a decision about
ongoing use that was consistent with the label
safety warnings. Taken together, this represents
98 percent of the user population. There were 21
participants, representing just two percent, of all
those who used the product who continued to use
Mevacor OTC despite a label safety warning that was
relevant to them. The behavior of these 21
individuals creates the potential for an increased
safety risk, however again, there were no serious
drug-related muscle or liver adverse events among
them--good evidence that consumers can manage
potential safety risks over time.
Turning now to the third and final of the
key questions, will the system allow consumers to
self-manage their cholesterol over time and obtain
a benefit? This question addresses behavior around
label benefit criteria directed at ongoing use
decisions. These are label elements directing
consumers to get a follow-up cholesterol test at
six weeks and comply with the LDL goal message.
And, 666 of our 1059 users, representing
63 percent, obtained a cholesterol test during the
study. An additional 11 percent discontinued the
study, many for an appropriate reason, before the
six-week time point directed in the label. This
totals 74 percent of our user population making an
appropriate decision about getting a follow-up
Looking specifically at the 666
individuals or the 63 percent of the users who got
a follow-up cholesterol test, 75 percent of this
group followed label directives regarding the LDL
goal message. This was largely composed of
individuals who achieved an LDL less than 130 and
made the decision to continue using Mevacor OTC.
Addressing another component of the third
question, how did the results of CUSTOM, an
uncontrolled, open-label study, compare to what is
known about the lipid-lowering effects of 20 mg of
lovastatin in controlled clinical trials?
In the CUSTOM trial a 25 percent reduction
in LDL was observed in a subset of individuals who
indicated they were fasting both at the baseline
and end of study measurements. Looking at the
entire study cohort, regardless of fasting status,
a 21 percent reduction in LDL was observed. These
results compare very favorably with the large
controlled clinical trials, AFCAPS and EXCEL, both
showing a 24 percent reduction in LDL with the 20
mg dose of lovastatin.
Turning now to data about consumer who
persisted with medication, before I present the
results let me remind you that CUSTOM was not
designed to be a persistence study. In fact, one
of the goals of CUSTOM and of the Mevacor OTC label
is to correctly influence people who shouldn't be
taking the product to stop taking it. With that in
mind, let's look at the CUSTOM persistence data.
Sixty-two percent of the user population
were persistent with therapy through six months of
the study. An additional 17 percent discontinued
Mevacor OTC for an appropriate reason, such as not
reaching an LDL goal, being advised by their
doctor, or learning that Mevacor OTC was not right
for them. Taking these together, 79 percent of our
user population made an appropriate persistence
decision regarding Mevacor OTC. This is consistent
with results from an earlier use trial of
lovastatin 10 mg. In that study 72 percent were
continuing with medication at six months and 49
percent were still on therapy at 18 months. These
numbers compare very favorably to what we know
about persistence with prescription statins.
Finally, what do we know about the
self-management system and its ability to direct
consumers to make appropriate decisions about diet
and exercise habits? A MEDFICTS dietary assessment
questionnaire was given to the user population at
baseline and at the end of the study. This
validated instrument provides a score to determine
if an individual is on an AHA step-one diet or the
more restrictive AHA step-two diet. Not only did
more individuals move to the stricter step-two diet
by the end of our study, but the number of users
who are not on either of the AHA diets decreased
from 17 percent to 11 percent.
Now let me summarize the results you have
just seen that address the third of our three key
questions, will the system allow consumers to
self-manage their cholesterol over time and obtain
From our population of 1059 users, 74
percent obtained a follow-up cholesterol test or
discontinued taking Mevacor OTC prior to the time
directed on the label. Of those users who did get
a follow-up test, 75 percent of them followed the
label directives regarding the LDL goal. Finally,
there was an impressive 21 percent reduction in LDL
cholesterol--again, good evidence that consumers
can manage their cholesterol over time and obtain a
Moving now to an important question about
the ability of the system to promote consumer
interaction with healthcare professionals, CUSTOM
provides information from a variety of groups to
address this question.
Of the people who evaluated the product at
the site but chose not to purchase, 22 percent of
them reported that they did, in fact, talk to their
doctor before making this decision. Physician
interactions were reported by 57 percent of our
user population at some time during the study and,
finally, as I mentioned earlier, nearly three out
of every four of our higher CHD risk users had an
interaction with a doctor as a result of this
In conclusion, the Mevacor OTC
self-management system discourages inappropriate
use of the product.
The majority of consumers who choose to
use Mevacor OTC will be appropriate for
self-management. They will gain a clinical
benefit, as evidenced by substantial LDL
reductions, and most importantly, will be at
minimal safety risk.
Lastly, beyond the direct pharmacologic
effect of the medication, the Mevacor system will
have important public health benefits that include
an increased level of interaction with healthcare
providers and a general improvement in heart health
awareness and behavior. That concludes my
presentation. Thank you for your attention. I
think it might be time for a break now?
DR. WOOD: Right. It sounded like a plea,
right! Why don't we take a break and be back,
ready to start, at 10:15?
DR. WOOD: We will just wait one more
minute so people can take their seats.
Medical Perspective and Conclusions
DR. COHEN: Mr. Chairman, members of the
committee, representatives of the FDA, my name is
Jerry Cohen, and I am a full-time academician and
cardiologist at St. Louis University. I spent
nearly my entire career in preventive cardiology.
I want to start off by telling you that a
number of years ago, when I first heard about the
possibility of OTC statins, I was skeptical about
the notion and I had many questions. I am sure my
initial skepticism and the questions I had then are
similar to ones that you may have today. Your key
questions probably include something like the ones
that are shown on this slide.
First, is there really a need for an OTC
option? Can't we just do a better job of what we
are already doing, using the current treatment
model? Secondly, is Mevacor 20 mg really safe
enough for OTC use? Third, can consumers manage
cholesterol effectively with an OTC product?
Fourth, will OTC therapy divert consumers from a
physician's care and from heart-healthy lifestyle
practices? Finally, why should we do this? What
is the overall benefit-risk ratio of Mevacor OTC?
These are all important questions and you
have just seen compelling data that addressed each
of these questions individually. But in the end,
for me, it was the totality of the evidence taken
together which clearly convinced me that OTC
lovastatin therapy poses not only a minimal and
acceptable risk, but also, as we will see, has the
potential to provide an enormous public health
benefit. In other words, there is a highly
favorable benefit-risk ratio. So, let's review the
The first question is shown here again on
this slide. Is there really a need for an OTC
statin option? Well, conversely, we might ask why
not solve our problem by putting more effort into
the current system of physician and patient
education and build an even greater awareness of
the cholesterol problem and the benefits of Rx
therapy? And, why not just continue to get more
aggressive with our national guidelines?
This is a slide you have already seen and,
as you have heard, despite our best efforts and the
creation of the National Cholesterol Education
Program 20 years ago, we have not made much
progress, particularly in the moderate risk primary
prevention group. As Dick Pasternak has shown us,
cardiovascular disease is still by far our nation's
number one killer and a huge treatment gap exists,
somewhere between 6-15 million Americans. With the
aging of our population, this will only get larger
in the near future.
While there are a lot of reasons for the
treatment gap, the major relevant factor to our
discussion today is that many untreated people are
reluctant to take prescription therapy. As you saw
earlier, with the availability of OTC statins many
of these same people are more likely to take
positive action with an OTC product.
The next question is of utmost importance,
is Mevacor 20 mg truly safe enough for OTC use?
I believe the answer is clearly yes.
Mevacor has an excellent and proven safety profile,
especially at this low dose. We are not talking
about a newly developed or newly released compound.
We are not awaiting the results of another study.
Lovastatin, as the first FDA-approved statin, has a
proven track record of safety with more than 17
years in market experience. This equates to more
than 27 million patient-years of treatment. As we
have seen, Mevacor has a safety profile reasonably
similar to placebo at up to twice the proposed OTC
If the product is safe at this dose, is
cholesterol too complex for consumers to accomplish
on their own? After all, high cholesterol is a
chronic, asymptomatic condition and it has been
said that this is somehow different from the way
OTC products are presently used by consumers.
First, let me say that the treatment of
chronic asymptomatic conditions is not a new
concept for OTC products. Consumers have been
taking OTC products for such conditions for many
years. In fact, over 35 million Americans are
currently using calcium supplements every day to
prevent osteoporosis. Approximately 26 million
people use low-dose aspirin for heart health, with
a quarter of those doing so on their own. This is
an interesting observation given the fact that both
aspirin and Mevacor have proven cardiac benefits,
and both are among the standards of care. Yet, the
risk of having a serious adverse event with
low-dose aspirin is actually greater than it is
with lovastatin 20 mg.
Perhaps the most relevant example to the
discussion today is that over 14 million Americans
are currently using heart health supplements, many
of which are of questionable safety and
benefit--questionable safety and benefit. So, if
the concept of OTC therapy for chronic asymptomatic
conditions isn't new, how strong is the evidence
that consumers can self-manage their cholesterol?
This slide reminds us of the key data that
we just saw from the CUSTOM study, as well as the
data from two previous actual use studies with OTC
lovastatin. There is a strong consistency in the
findings here. A vast majority, about 90 percent,
had pretreatment total cholesterol values of
greater than 200 mg/dL. Only a small minority were
already taking a statin at the time of the OTC
purchase. Most importantly, consumers did very
well with regard to our concerns about safety.
With safety labeling in mind, between 90-97 percent
appropriately selected the product. In addition,
about two-thirds appropriately selected, in
accordance with the labeling, for benefits.
Now, not everyone behaves strictly in
accordance with the label, but these data represent
what is likely to happen in the real world, and
that is what this OTC study, the CUSTOM study, was
all about, getting a real-world experience. What
is remarkable here is the consistency of the data
which, I might add, supports prior observations
showing that the large majority of consumers do
appropriately self-select for management of their
But how does this compare to the current
state of prescription care when looking at the
results of statin therapy? When considering the
benefits of an OTC statin, all of the parameters
shown on this slide--obtaining cholesterol goal,
appropriate persistence with therapy, and an
average LDL cholesterol reduction--are, at the very
least, comparable to, if not better than what was
seen in the Rx population.
This may be surprising, or perhaps not so,
when considering the fact that self-selected OTC
users are different from and may be more health
conscious and motivated than many prescription
users. Whatever the reason, we can clearly see the
most important bottom-line outcomes which are the
key determinants of coronary heart disease
prevention. Persistence of therapy and the
magnitude of the LDL cholesterol reduction compare
very favorably to the prescription experience.
But no matter how appropriately consumers
manage this condition, it is not intended to be a
substitute for or to take the place of traditional
health care. So, we must ask will OTC divert
consumers from physician care and from
heart-healthy lifestyle practices? It is an
important question. And, it is important for us to
remember that the Mevacor OTC program was designed
to do just the opposite. It was designed to
encourage consumer interaction with their
healthcare providers in order to receive
appropriate therapy, whether that therapy be OTC
for those at moderate risk or prescription
medication for those at higher risk.
This slide shows the system worked. Not
only did the majority of users, as shown in the
middle bar graph, consult healthcare professionals
about their OTC use, 22 percent of the people who
didn't even purchase the product consulted a
physician or doctor or a healthcare provider as a
result of the OTC program. Also of considerable
importance, three out of four higher risk consumers
interacted with their healthcare providers as a
result of the OTC experience. These data clearly
demonstrate that Mevacor OTC is not an isolated
self-care product but is complementary care which
encourages interaction with healthcare
As shown in this slide, consumers do not
get complacent about their heart-healthy behaviors
as a result of taking Mevacor OTC. More than 90
percent maintained or improved their heart-healthy
lifestyles of diet and exercise, confirming that
Mevacor OTC did not distract consumers from these
important interventions. Any of you who saw the
headline story today in "USA Today" about the new
diet guidelines can see that diet and exercise are
being emphasized more than ever.
So, I think we can say that there is a
clear need for OTC statins. There is an acceptable
safety profile and there is demonstrated
appropriate and effective consumer behavior without
diversion from other heart-healthy practices. But
in the final analysis what is most important,
considering all OTC users--all--is the overall
In answering this question let us first
see how Mevacor OTC can narrow treatment gaps. OTC
can directly increase the number of moderate risk
individuals treated. Although these are rough
estimates, our analysis shows that an approximate
4-5 million moderate risk individuals will likely
seek OTC treatment. Thus, by focusing on this
moderate risk group, the treatment gap
In addition, not estimated here, we also
know that there will be some moderate risk
individuals who will be seen by their physicians
and put on prescription therapy as a result of
heightened awareness of their cholesterol problem
stemming from the OTC program.
Likewise, in the high risk group there
will be an estimated 1-2 million people who will
communicate with their doctors and possibly be put
on prescription therapy as a result of the OTC
program. Finally, in terms of this bar graph, we
also know from the CUSTOM data that, while not
ideal, there will be some usage of the OTC product
in this higher risk group. What are the
consequences of such use? Compared to otherwise
taking no action, which surveys suggest is the
usual outcome, I would submit to you that this is a
favorable result--a very important recognition.
The overall effect of OTC statin
availability is narrowing of the treatment gaps for
both the moderate and higher risk groups. Now, OTC
statin therapy is not a panacea for the entire
treatment gap and it will not fix all the problems.
But it is also very compatible with our current
efforts which may be increased in terms of the
effectiveness of Rx and any subsequent change in
the guidelines. These are not mutually exclusive
types of intervention. However, as shown, it will
substantially reduce the size of the gap by
reaching a portion of the at-risk population which
is not currently being reached.
Now I would like to consider the
population shift in the distribution of LDL
cholesterol which will occur as a result of OTC
Mevacor. This slide displays the distribution of
baseline LDL values, shown here in blue, among the
The overlay, now shown in yellow, shows
the end of study, and this is the CUSTOM actual use
data, with LDL levels achieved. Together, they
clearly demonstrate the classic leftward shift in
the LDL distribution. This is a direct effect of
Mevacor OTC. Given the strong positive graded and
continuous relationship between LDL cholesterol and
risk, as was shown by Dick Pasternak in an earlier
slide, this means that nearly all users will
potentially benefit by a reduction in coronary
heart disease risk. Think of that!
It is of interest to note that this goal
of shifting the population curve is not a new
concept. In fact, over ten years ago the expert
panel of the National Cholesterol Education
Program, Dick Carleton's panel, published these
curves that show the potential complementary and
additive benefits of an increased focus on primary
prevention to our current treatment efforts.
The blue line here is the cholesterol
distribution at that time which has not changed
much since 1991. The yellow dotted line projects
the effects of treatment per the then existing ATP
guidelines if they were widely applied. And, the
orange dashed line shows how the complementary
effect of a 10 percent decrease in cholesterol
further shifts the curve, and this is similar to
what we have just observed with OTC Mevacor in the
CUSTOM data set that I showed you with the blue and
yellow bar graphs.
Finally, and most important, is the
projected overall benefit of Mevacor OTC.
Utilizing the CUSTOM risk distribution and assuming
a conservative coronary risk reduction of 25
percent--AFCAPS/TexCAPS actually showed a 37
percent overall reduction--for every one million
consumers taking the product, we can expect to
prevent between 25,000 and 35,000 coronary events
over the next ten years. Given the strong safety
profile, the overall benefit-risk ratio is clearly
It was in recognition of this fact that
our colleagues in the U.K. approved the use of an
OTC statin last year. They got it; they saw the
benefit in terms of the benefit-risk ratio being
highly favorable. The time is ripe for this
important OTC option to be available to consumers
in the United States. Many consumers are
concerned, informed and motivated and are already
active in terms of their own health care. We
should provide them with better and safer options
than what is currently available to them OTC. With
aging of our population, now is the most opportune
time to make possible an OTC stain option.
In closing, we have asked ourselves many
questions that at first glance seem new and
potentially challenging. But when we look at the
strength and totality of the evidence we also see
that we have a great opportunity for reducing the
burden of cardiovascular disease.
Mr. Chairman, members of the committee, my
hope is that today we can look at the totality of
the evidence and recommend approval of Mevacor OTC
to reduce the huge burden of cardiovascular disease
in the United States. The challenge is before us,
but so too is the opportunity. Thank you for your
Questions from the Committee
DR. WOOD: Thank you, and thanks to the
sponsor for sticking so well to the time. Let's
take about 30 minutes of questions from the
committee, or less if we run out, and then we will
move on to the first of the FDA presentations after
that and before lunch. Questions from the
DR. BENOWITZ: I actually have a lot of
questions but I will just start with one to let
other people have a chance. One of the issues that
is really important for over-the-counter
medications is the patient's capacity to understand
benefits versus risks. This is something that we
deal with in practicing medicine as well, and one
of the things that is always an issue is when you
talk about relative risk changes in primary
You may be talking about a 35 percent
reduction of risk, but looking at the data that are
presented, it really is looking at a 2 percent or
2.5 percent change in absolute risk over six years.
Nowhere do you really talk about absolute changes
in risk, and I think that is an important question
for a patient. They have to know that 25 people
have to take this medicine for six years, at a
minimum, to prevent one event. It is true that
there is great population benefit, but when we are
talking about individuals there needs to be some
consideration to give an individual the information
to make a benefit-risk appraisal. You did talk
about absolute risk for safety issues, but you
didn't talk about absolute benefits.
So, I would just like to hear someone
address the question of how do we really give the
patient the proper information to make an
intelligent risk-benefit analysis.
DR. WOOD: Who wants to take that?
DR. HEMWALL: I will at least start. I
guess what you are asking is to somehow also
include in our education and support materials more
explanations of what really is meant by a reduction
in risk for heart disease. In this case we are
talking in the realm of 25-50 percent, depending on
which study you look at and the patient population.
That is certainly possible. In fact, that would be
something we would be more than willing to put in
the right perspective for patients so they would
understand that, and make that as part of their
DR. WOOD: I think what he is asking is if
you have a similar percent reduction in relative
risk across different populations, the absolute
risk will be reduced differently in the lower risk
group. Is that what you are getting at, Neal?
DR. BENOWITZ: Exactly. In secondary
prevention it is easier because the absolute
benefit is great. But the debates in primary
prevention have always been the small absolute risk
DR. WOOD: I think that is the question.
DR. PASTERNAK: Just to amplify it--thanks
for the question and it is an important question.
There are a couple of responses to that. First of
all, people make those choices--low risk or
moderate risk people make those choices every day
when they decide to go running, when they go on a
diet, when they take an aspirin. So, people are
capable at some level of making that kind of
Second of all, as Dr. Cohen showed at the
very end, we think there really is a substantial
benefit to this population, and the number needed
to treat--and we can discuss whether the right
number is 28, 38 or 48--is actually a fairly
favorable number in terms of preventing an event.
It is comparable to the number that is needed to
treat that is seen in some of the secondary
Finally, you are correct that I focused on
relative risk, but my principal aim in discussing
that was not to obscure the low absolute risk but
to make it clear to everyone that the relative risk
reduction is consistent across a wide variety of
populations, a wide level of risks. It has been
said by some that there is no benefit to this and I
think understanding and comparing relative risks is
a way to get at understanding that.
DR. WOOD: Dr. Woolf?
DR. WOOLF: I have a question for Mr.
Hansen. You have a very elaborate display that
will be in the pharmacy for the patient to decide
to go on Mevacor OTC or not. Are there other
models that have been previously used in the
pharmaceutical industry that have helped to guide
the patient to the appropriate or inappropriate use
of a drug? If so, what are they?
MR. HANSEN: To be honest, this is
unprecedented, and this program that we have put
together has gone to more lengths to help the
consumer out, both with the healthcare professional
and to do it on their own, than anybody has done in
I think the example of the one that got
the closest was smoking cessation products. It was
mandated in their NDA that they did have support
materials. There were audio tapes available and
there was a support program that they could enroll
in, and enrollment in that was fairly high.
I think the other precedent with smoking
cessation is that there was a commitment that
smoking cessation products not be sold in
convenience stores, and that commitment--even
though it was ten years ago--is still being upheld
today. So, in essence, those two are the closest
but obviously we are breaking some new ground.
DR. WOOD: Dr. McClung?
DR. MCCLUNG: I want to come back to the
issue about the absolute risk and benefit. The
absolute risk numbers have a time element, or at
least the number needed to treat has a time element
in it. We have been told about the two percent
reduction in absolute risk and the retrospective
population that would have met the criteria for
OTC, but that was over a five-year interval of
time. And, the absolute risk for the side effects
was described in the CUSTOM study over a six-month
interval of time.
If I have done my math correctly, if there
is a 2 percent reduction in absolute risk over 5
years, that is 0.2 percent over half a year. And,
we are told that the incidence of muscle symptoms
in the CUSTOM study was 60/1000 patients or 0.6
percent, and that 16 of those patients had muscle
symptoms and continued therapy, which is an
incidence of 0.16 percent, not very different from
the absolute benefit that would be derived.
So, I concur strongly that we ought to
make sure that we communicate what the absolute
risk and the absolute benefit is, and to put it in
the context that not only physicians can
understand, which is often not the case, but
certainly to put it in a perspective that patients
DR. WOOD: Dr. Watts?
DR. WATTS: I would like a little more
information about the patient interactions in the
CUSTOM trial, or the subject interactions. In the
reading material I think there was mention about
the time involved, but I would like a better
explanation of how much time each individual spent
trying to master the material in the package
insert, and also a little more information about
the circumstances at the testing center. We were
told that there was a display set up, but we are
not told whether that really matches the
surroundings that a patient or prospective buyer
would be in with competing products, other people
passing through, distractors that might interfere
with their attention span to the material they are
expected to master.
DR. WOOD: Does somebody want to respond
DR. HEMWALL: Well, I understand your
question to be along the lines of how realistic was
the pharmacy setup in the CUSTOM study at the study
sites. There were, in fact, store front settings
in strip malls. They were set up to appear as if
they were operating pharmacies but, of course, when
one walked in, it was clear that they were not an
operating pharmacy but they had simulated shelf
setups and the consumer was asked to actually go
and evaluate the material as if it were on the
shelf with mock other products next to it. But it
was not a fully functioning pharmacy.
Although we have done other studies in
pharmacies, some of the questions that we tried to
answer in these various studies caused us to do
different things in design and this was clearly a
self-selection and then an ongoing use study.
Therefore, we elected not to do this particular
study in working pharmacies. But we did try to
mimic that experience. But in all of these
studies--and I think FDA recognizes tha--you can
only get so close to creating the true, natural
environment when you are also doing a study that is
conducted under IND with all the appropriate
regulations that go along with that.
DR. WATTS: The other part of the question
was the amount of time the average subject spent
reading or trying to comprehend the package insert
DR. HEMWALL: We did not record that
amount of time. Again, they had as much time as
they wanted. They not only had the package to look
at on the shelf with the shelf display--the same
one that is shown here--and interact with those
materials but there are tear-pads that they could
remove, go home and get further information. So,
in fact, a lot of people, as Bob Tipping explained,
actually went home and came back later, either
after having consulted with a physician or gotten
their number somehow and returned. So, in some
cases the amount of time they had to consider the
product was several days. In other cases they made
the decision within several minutes and probably,
you know, an entire range within that.
DR. WOOD: Dr Tinetti?
DR. TINETTI: My question relates to
discussions that have taken place concerning the
safety and benefit in an elderly population, which
I will define as greater than 75, given the little
data that exists in your studies. As I looked at
it, in the AFCAPS/TexCAPS, the exclusion criteria
was age over 73. The average age was upper 50s to
lower 60s. It looked like in the actual use study
there were also very few very elderly people. So,
without evidence of either benefit or safety in
this age group, how comfortable do you feel?
Particularly, these people have multiple
co-existing conditions. It is clear they are a
target audience for you because it was mentioned
several times this morning that the aging
population is one of the important reasons to push
forward with this.
And a related question, I haven't heard
much discussion, or in the materials, about the
softer, if you will, more subjective adverse
outcomes related to statins that always anecdotally
have been discussed--depressive symptoms, mild
cognitive changes. I was just wondering what
discussions and concerns have been raised in those
DR. PASTERNAK: Well, both those questions
are important. You are correct, in the
AFCAPS/TexCAPS trial most elderly were not
included. I think our answer to that is that if
one looks across all of the clinical trials at
subgroups such as they exist, the elderly group has
a result that is consistent in terms of relative
risk, often greater in terms of absolute risk
reduction than younger groups.
The two trials that addressed the most
elderly include PROSPER, a study of pravastatin,
and the Heart Protection Study, a study of
simvastatin. They were specifically designed to
look at that question and in those, including the
age groups you just mentioned, there was a highly
statistically significant benefit that was
homogeneous with the results in other groups.
So, I think that the weight of the
evidence for statins in the elderly is that
relative risk is consistent and the absolute risk
is often even greater because the absolute risk in
that population is very high.
I am not quite sure of the answer to the
other question. Others on the panel might wish to
respond but, you know, statins have been looked at
for a long, long time now. One of the points of
our ACA/AHA/NHLBI statement in 2002 was to try and
review all of these other notions that statins
might somehow be doing something else that people
need to worry about, whether it is something
important like cancer or other less important
issues. As you probably know, there are also those
who are arguing on the other side, that they are
useful. I think most of those observational kinds
of looks have not borne out in either direction and
we have to stay focused on what we know these
DR. WOOD: Frank?
DR. DAVIDOFF: Yes, I am having
considerable difficulty interpreting the CUSTOM
study, as interesting as it is, because it seems to
make the assumption about user eligibility based on
several criteria that are on the product label and
that are widely accepted, but it does not take into
account other primary prevention strategies that
are easily available to people and are widely used,
in particular low-dose aspirin.
So, I will limit my question to that,
which is were data collected on how many people
were taking low-dose aspirin in the CUSTOM study?
Because from what we have seen of the data with
low-dose aspirin, it reduces risk over the longer
term by just about the same amount that statins
would in a primary prevention setting. Albeit,
aspirin does have certainly its own risk profile,
which is another issue, I just have difficulty
knowing what the actual risk and, therefore, what
the actual benefit would be for people who enter
this trial or who took OTC statins in the
marketplace because we really don't have an idea of
what their risk status is if we don't know if they
were taking low-dose aspirin.
As a related sub-question, are there data
on potential marginal benefit for taking statins in
addition to low-dose aspirin? Because there may
be, in which case that would be encouraging, but
there may not be.
DR. HEMWALL: There are a lot of questions
within that one question. Yes, we do have the
information on who took low-dose aspirin in CUSTOM
and we can get to that in a minute. But I think
the larger question revolves around the concomitant
use or the additional benefit with regard to taking
low-dose aspirin and a statin. I would like to
introduce Dr. Tony Gotto, who is willing and able
to comment on that particular topic.
DR. GOTTO: I am Tony Gotto, from Weill
Medical College. We recorded the participants in
AFCAPS/TexCAPS who were taking aspirin. We didn't
differentiate between whether it was low dose or
regular aspirin, but just aspirin use. In
virtually all of the secondary prevention trials
with statins there has been a high use of aspirin,
in the CARE study about 80 percent, and that is
about typical for the secondary prevention studies.
There was significant aspirin use in AFCAPS/TexCAPS
as well. This group was very active physically and
there was a major emphasis on lifestyle changes for
all of the participants in this study with group
sessions, and we hammered away at diet and
exercise, and these were very health conscious
individuals. I think they certainly qualitatively
reminded me of the description of the typical OTC
patient. But all of the statin trials have shown a
benefit on top of aspirin use, on top of beta
blocker use, ACE inhibitor and various other things
that are controlled for. And, low-dose aspirin has
not been approved by FDA yet, has it, for primary
DR. PEARSON: I would like to comment. I
am Tom Pearson, from the University of Rochester.
I had the opportunity to chair the American Heart
Association primary prevention writing group which
endorsed the use of low-dose aspirin for the
primary prevention of heart disease.
Part of the issue directly related to the
question is that, in fact, in January was presented
an analysis looking at randomized, controlled
trials of a statin, pravastatin, with the
observational arm of aspirin use. This was
presented as part of a presentation to the FDA
advisory group on metabolics. The suggestion is
that there is at least an additive effect and very
possibly a synergistic effect which you could, in
fact, bring into a variety of mechanisms to explain
that. But it is at least additive, and some of our
statistical friends would suggest it is even
DR. WOOD: Thanks.
DR. SCHAMBELAN: My question gets back to
the self-management system and the specific issue
of the pharmacy interaction. Is the plan not to
market this OTC product in convenience stores and
supermarkets in which there is not a pharmacy? Is
that going to be specifically interdicted? It
seems like a lot of educational materials would not
be available in that kind of a setting, and that is
certainly where a lot of OTC products are sold.
MR. HANSEN: Yes, we are clearly
recommending that this be sold in stores with a
pharmacy only and no other outlets.
DR. WOOD: Dr. Snodgrass?
DR. SNODGRASS: I will just ask one
question. It relates to the risk-benefit ratio
considerations and that is, what is the risk of not
being evaluated by a physician? That is basically
my question. I realize they attempt to involve
healthcare professionals in this but it seems to me
that there are a number of causes of so-called
secondary dyslipidemias, besides diabetes and
thyroid, obstructive liver disease and renal
failure. I don't know that patients who will have
some of these conditions or some degrees of them
will be aware of this. I think there is also the
issue that those persons in your study who knew
enough to know about their cholesterol may, of
course, have had some interaction with their
physicians so you may have selected away from those
who would less likely have this knowledge.
DR. WOOD: Someone want to take that?
DR. COHEN: Yes, thank you for the
question. I can understand the first part of it
but help me if I am not answering quite the
question that you asked afterwards.
If we look at the benefits of this program
overall, it really necessitates, in terms of proper
use, that the person knows something about himself
or herself with regard to the label. Indeed, the
CUSTOM study showed exactly that. So, someone who
has never seen a physician, who doesn't know their
blood pressure--they know whether they smoke, they
know their age and they could qualify just on that,
and the family history, and not have any other
medical knowledge except that they don't know their
lipids which, of course, is part of the labeling
So, I think in this situation if someone
took it without knowing what their cholesterol is,
again, you would have to come back to a high enough
risk patient who would benefit regardless of what
that was. And, we can pick a number, whether it is
higher or lower or exactly what we would expect as
an average, and this might happen over a period of
time with other people being involved and not
knowing their cholesterol.
If you shift their curve to the left, then
I think we will see, as Dick Pasternak showed on
his slide, a reduction in risk estimates based on
the LDL reduction that will be achieved using the
Mevacor OTC product. The issue is, is the safety
there for that person who is unknown, and I think
from the data that we have seen here this morning
that the safety is there. So, that benefit-risk
ratio for that person who has not seen a physician,
who has not been evaluated is still favorable I
think. Certainly, hopefully, he or she will see a
physician more likely because of the result of
reading the label, being in the program,
recognizing the importance of knowing these data
and getting follow-up than they would have perhaps
otherwise. Does that address your question?
DR. WOOD: Can I just follow-up on that
question? It seems to me that there is an
underlying assumption that is somewhat untested and
probably wrong. That is, the comparison for OTC
lovastatin that should be made is one against
physician care which is 100 percent perfect--
--and that is what I mean by probably
wrong. How do we know it is probably wrong? Well,
the first way we know it is wrong is that almost
the only way that someone can get a cholesterol
measured in this country is by going to a
physician. So, almost by definition and going back
to Dr. Snodgrass' question, the population that you
have studied has to be a population of patients who
have failed to receive adequate cholesterol control
in spite of being seen by a physician.
Then, the second part of the question
relates to toxicity and following the warnings.
Again there is an unspoken assumption, which is
also I think probably wrong, and that is that if
patients, indeed, saw a physician the warnings
would be clearly followed explicitly and
absolutely. And, we know from lots of data--you
know, just think of three drugs that have been
withdrawn, Bacyol, Resulin and cisapride--in each
of these cases there were explicit warnings on the
drug label and in each of these cases, and in the
case of Resulin particularly, we know that only a
tiny percentage of patients were following the
specific monitoring warnings that were out there.
So, I was a bit surprised that you all didn't
address that in the presentation.
DR. COHEN: Well, let me just come back to
your first point, and that is that these are
patients who may have seen a physician and the
physician didn't act appropriately. We don't know
that. In fact, the physician may have acted quite
appropriately in the sense that they assessed the
risk, they recognized high cholesterol, and perhaps
wanted to recommend an Rx therapy. What is unique
about this population is that it is an OTC-driven
type of population where they say, you know, Rx is
for a sick guy. I am a healthy person. I am
concerned that my cholesterol is too high. I will
continue doing whatever, including buying other
So, I think these people may be in the
system. They may be seeing their physician and we
have data to show that. But, in fact, I think they
are, for whatever reason, not following through in
terms of an Rx or not getting an Rx in the first
place, perhaps related outcome the healthcare
DR. WOOD: There is another response.
DR. HEMWALL: I do want to acknowledge
your comments, Dr. Wood. In fact, we are not
trying to compare to the healthcare system here. I
think in one of the earlier slides that Dr. Cohen
showed, we did pretty well according to what is
currently in the literature about management of
statin therapy, certainly not worse.
DR. WOOD: I just wanted to be polite!
DR. FOLLMAN: Yes, I would like to discuss
the issue of potential under-dosing with the
over-the-counter strategy for Mevacor. First, Dr.
Cohen had a slide, I think it was 181, which showed
the distribution of baseline LDL levels. I have a
copy of that here, and I was counting up the
percentages greater than 170 and it looks like
about a third of the patients in the CUSTOM study,
with all the scrutiny, etc. that was involved in
that study, had LDL levels which are not in
accordance with the label and they would probably
be better off being seen by a doctor and getting
optimal statin dosing and therapy. So, there is
this concern about potential under-dosing at the
point of purchase.
Another thing has to do with the potential
under-dosing over time. So, if you look at the
label at the back of the box or some of these
brochures, etc. that you have, there isn't really
mention made, as far as I could tell, of the
importance of getting LDL tests, say, every year.
So, the way this is being marketed or proposed is
chronic treatment. So, you just keep using it
presumably forever. So, for a person like that who
is going to continue to use it and not recognize
that his LDL is creeping up past 170-200, or
something, seems to me an error of omission in the
So, two issues about under-dosing, one at
the time of purchase and then concern about upward
drift which won't be recognized by the label, or
encouraged to be discovered by the label.
DR. PASTERNAK: Dr. Hemwall is going to
have a comment about the last part of that with
respect to the label, but we obviously would have
loved it if everybody who had an LDL over 170 had
more potent LDL-lowering than was available from 20
mg of lovastatin. But, remember, these are people
who didn't get any other therapy.
I have heard a lot, not only in the
context of thinking about this but kind of on the
street, about the potential under-dosing with 20 mg
of lovastatin. Remember a couple of things. First
of all, there is this 1:1 relationship that for
every milligram/deciliter LDL lowering there is one
percent change in risk. So, while it is not the
optimal risk lowering that a very large dose of a
very potent statin in a very high risk population
will achieve, remember, we saw on the average 20-25
percent LDL lowering and that is associated with a
substantial relative risk reduction of roughly 25
percent. So, it is true that greater degrees of
risk reduction are possible, but this is still a
very impressive degree of risk reduction and
certainly comparable with the kinds of things
people try to do every day to improve their risk.
In terms of the LDL test, I think it is
the same sort of comment. We would have been
delighted if everybody had behaved appropriately--a
comment that is kind of consistent with Dr. Wood's
a moment ago. When in other settings we have
tested how physicians do with respect to LDL
monitoring, there is that same problem. So, it is
not optimal. It is not optimal in this population
and it is not optimal in the standard of care these
DR. HEMWALL: I just wanted to make sure
we gave a complete response to the question with
regard to the messages that are in our materials
for ongoing monitoring not only of your
cholesterol--and the label specifically says if you
have reached goal get your cholesterol tested once
a year--but it also says that one should be on the
lookout for any change in their health condition
and that they should see their doctor for any
change in those conditions. We actually measured
that in CUSTOM. We had people, as Bob Tipping
pointed out, develop diabetes that didn't go to
their doctor during the course of the CUSTOM study.
Another feature of the support and
management system is the ongoing communication that
goes on well beyond, into the future, where they
will be receiving communications and regular
messages within the materials. I urge you all to
look at the materials that are in the box that we
provided for you. Also the newsletters that come
on a periodic basis when one opts into the program
all encourage that retesting and the continual need
to reevaluate your health status and the need to
see a doctor.
DR. WOOD: Dr. Watts?
DR. WATTS: The success of the program is
in large part dependent on the patient's accurate
knowledge of their cholesterol level to know
whether they are appropriate to initiate their
therapy, and their follow-up cholesterol level to
know whether they are reaching goals. What I
haven't gotten a clear picture of, though it may
have been woven into all this, is information about
the validity of patient self-reports of their lipid
results, both for the initial assessment of whether
they are appropriate candidates for OTC Mevacor and
for subsequent studies to know whether they are
MR. HANSEN: This is going to be a tag
team because I am going to first start with the
general population knowledge of cholesterol numbers
and the ranges because that is important if this
product is approved in the general market. Then
Bob Tipping will come up and show you exactly the
people in CUSTOM who did know their numbers and how
accurate were they in those self-reported numbers
because we did test at the end of the study. So,
if I could have slide 1938?
This is in the general population. We did
the study this year, and it shows a couple of
things. First of all, awareness of total
cholesterol numbers was virtually 100 percent and
that is why it is not on the chart. Then, what you
will see is the subfractions of LDL, HDL and
There are a couple of things on the chart,
first of all, the knowledge of these terms--and
this is just knowledge of the terms--has increased
over time but it is certainly higher for total
cholesterol than the subfractions but we are making
Now I would like to go to slide 1943
because this is getting closer to home. This is
actually do people know their own values?
This, again, is on an ongoing basis and we
will show you trends. So, this is total
cholesterol and can people describe their own
cholesterol? For the most part, their total
cholesterol--over 90 percent can describe it. Only
28 percent can give you a specific number but 91
percent can describe it as either being high,
borderline high or normal.
If you go to the next slide, you will see
that there is a drop-off on LDL but still pretty
good numbers. Less know their specific number but,
again, they have heard from their doctor or know
for themselves and they can describe it as either
being high, borderline high or normal.
Now, the real key question is how did
people in CUSTOM who said they knew their range do
compared to their actual values, and Bob Tipping
will show that.
DR. WOOD: Well, the other question, going
back to my point, is presuming they heard from
their doctor that that is normal, that may not fit
with the criteria from the panels. Do we know
that? Do we actually know that when a patient says
their cholesterol and their LDL is normal that that
means that they don't fit the treatment criteria as
dictated by the various recommendations?
MR. HANSEN: If we don't answer your
question we will come back, but I think what Bob is
going to show is that people were able to describe
either their exact number or whether it was in a
range of either normal, high or low. Then we went
back and looked at those numbers and he will tell
you how well they were able to match those up. I
think that will get to your question but, if not, I
MR. TIPPING: Thanks, Jerry. Before I
describe some numbers for you, let me just remind
you a little bit of the design where behavioral
decisions were based on an individual self-reported
value but we did obtain the baseline actual
measured values so we were able to address the
question of what is the accuracy or the validity of
With our user population, we had 660
individuals who reported that they knew their value
and then we were actually able to obtain the
baseline value, and for 76 percent of them those
two values agreed with regard to the ranges
DR. WOOD: Dr. Schade?
DR. SCHADE: Yes, I have a question. I am
having trouble finding the information, and it may
be me, but my question is about diabetes. I
understand this may not be the direct population
being targeted but they actually represent a huge
risk for atherosclerosis, but as I understood it
from the presentation earlier this morning, the
labeling or the package insert is going to state
that if you have diabetes you should not take this
drug. Is that right or am I confused about that?
How are you actually handling a case when a patient
knows they have diabetes?
DR. HEMWALL: Yes, that is one of the
messages right in the main part of the label, that
you are not to take the drug if you have diabetes,
without first checking with your doctor. So, it is
not a contraindication but it is a statement that
says that you need to talk to your doctor if you
have diabetes. In fact, we hope that if they find
out that they do, they may need more comprehensive
care than simply an OTC.
DR. SCHADE: Yes, that would be of concern
to me only because I can see a rush of patients
coming in, pointing to me, saying that they cannot
take this statin and, by definition, other statins.
It would be worrisome to the patient as well. I am
concerned about that.
DR. HEMWALL: Well, that is a good
concern, and I would want to take that into
consideration with the team as far as perhaps even
putting more of that information in the educational
materials about the importance of having your
lipids treated and to see your physician. It is
not that it is a bad thing if you are a diabetic to
take a statin, but more that you should be doing it
in collaboration with your physician.
DR. SCHADE: Yes, I think some more
explanation is needed because most of my patients
who have diabetes read something and they
immediately think it contains sugar, or something,
because all these cold medicines and everything
else contain that same statement and I get lots of
calls when a patient gets a cold--can I take this,
this and this? And, inappropriately, they end up
not taking something that would help them.
DR. HEMWALL: That is good advice. We
would want to factor that into our materials.
DR. WOOD: That is a good point. Dr.
DR. CARPENTER: Going back to your earlier
description of a lot of this process, challenging
or raising new approaches to how we structure the
paradigm of practicing preventive medicine, I
consider that a great deal of obstacles and certain
patients' access to various medications is cost. I
just wondered if anyone has speculated whether
insurance coverage for statins would change with an
over-the-counter designation and if that would have
any impact on getting this to the people of concern
in contrast to using it as a prescription.
DR. WOOD: Well, it may well do but I
think it is probably not the remit of the committee
to address the financial issues, however
controversial that might be, unless the FDA wants
us to address that.
DR. MEYER: I would say it is to the
degree that the issue of the overall benefit to the
population has been raised, which also isn't
strictly our purview. I think it might be
interesting to hear the answer to the question.
DR. WOOD: To rephrase the question, will
it be covered under insurance? Is that the
DR. CARPENTER: Is there any information
to indicate that with a change to over-the-counter
status it would substantially affect availability
because of lack of insurance coverage?
DR. WOOD: And I would extend the
question, and would it result in other statins
being taken off coverage for Rx?
MR. HANSEN: This was a key concern of
ours because the goal of our program was to
actually get people into the system and get on
either OTC or prescription therapy if possible.
So, we actually went out and did a study, an
independent study with Towers Parent that was
published in The Journal of Managed Care Pharmacy,
in November, and the results were pretty
interesting. We had a good representation of most
of the large managed care organizations and they
have covered over 100 million lives, and the
findings were that they view cholesterol as very
different than they do allergy or heartburn, like
with the recent switches of Claritin and Prilosec,
that cholesterol is for more serious treatment.
They also recognized, as we showed in the treatment
gap, that most of the treatment today is with the
high risk people with higher dose statins. So,
they really don't feel like they would be capable
of down-shifting or downstreaming those consumers
because that would be bad medicine and, in fact,
they may be liable for that. So, we do not see any
evidence that there will be any major changes in
The only balanced statement I will give to
that, however, is that if a person did come in and
they were appropriate for the OTC label and were
not on prescription lowering at the time, managed
care said, hey, there is not a problem. As long as
they are appropriate for OTC, they can try that
product and if they don't get to goal, certainly,
we would put them on prescription therapy--so, a
clear delineation between the person who is on an
Rx today. No, we are not touching those people.
In the future, if they fit the OTC profile,
DR. SCHWARTZ: Sandy Schwarts, University
of Pennsylvania. I have been advisor to some of
the PBMs and to some of the medical insurers
regarding Medicare coverage decisions. You have to
be careful. They make their own coverage
decisions. But I think it is safe to say that an
OTC preparation would not be covered by current
plans, but also that it almost certainly would not
affect the other current statins on therapy because
of the dosing differential for treatment targets.
For example, even PPIs, people who require higher
doses of PPIs can still get coverage under almost
every insurance plan in the country while you can
get low-dose PPIs over-the-counter.
DR. WOOD: Dr. Neill?
DR. NEILL: I have a couple of questions.
Several of the speakers have mentioned the
treatment gap for these moderate risk patients, and
I am interested in data, if you have it, that looks
at all 11,000 callers, of whom 3300 were evaluated,
and in those groups how many were treatment
eligible and how many were already on treatment pre
and post CUSTOM? In other words, I am looking for
evidence of efficacy that this self-management
program does what you suggest that it would do when
it is OTC in this CUSTOM study. Then I have a
second question after that.
DR. HEMWALL: Well, the first answer is
fairly simple. We did not collect that kind of
information from the callers regarding their
demographics or the type of information that you
are looking for.
DR. NEILL: As a family doctor that takes
these phone calls when advertisements end up on
television, I am anxious to know for those 7000 or
6000 patients that did not present to be evaluated,
what was the enticement for the 3000 that did, and
what was the dissuasion for those that did not?
DR. HEMWALL: Well, again, this may be in
part an artifact of doing a study where you don't
have a pharmacy in your local neighborhood which
would carry the product in the real world. So, in
the seven geographic areas in which we conducted
the study, each had two sites. Here, in the
Washington Beltway area, we had a site I believe in
the Silver Spring area and one up--there is a
northern side and a southern side and I can't
remember the exact cities. We can get that.
But the point was that a lot of people
realized, once they made the phone call, that they
might have to either travel to a study site or they
decided that there was something that was
inconvenient for them and they didn't want to
participate. They weren't given very much
information, as per FDA working with us on the
protocol--not to explain to them a lot about the
study, other than that it was, indeed, a study; it
was not something were you were actually purchasing
a retail product. Although they were also told
that they would have to purchase the product and
that may have dissuaded a lot of people who thought
they were going to get free medicine.
DR. WOOD: You have a second question?
DR. NEILL: I will hold it till later.
DR. WOOD: Dr. Clyburn?
DR. CLYBURN: We heard a lot about the OTC
population and how they are interested in
prevention and not necessarily wanting to
acknowledge that they have any chronic illness like
hyperlipidemia. Are we going to facilitate their
denying that they have hypertension, obesity and
hyperglycemia by putting medicines over the counter
to treat hyperlipidemia?
DR. WOOD: It sounds like perfection is
the enemy of the good, right?
DR. HEMWALL: I am not really sure I
understand the question. Could you repeat it,
DR. CLYBURN: We spent a lot of time
hearing about the OTC population being different
than the regular population, and that they are
unwilling or don't want to acknowledge any chronic
illness, are more interested in prevention. Are we
going to make them feel good about themselves with
over-the-counter medications and allow them to deny
DR. HEMWALL: No, I don't think that is
the case but I think Jerry Hansen, who has done an
awful lot of the consumer research and has a better
understanding, may be able to address that
MR. HANSEN: This is a tough question
because it has kind of emotional behavioral
insights involved with it. So, I am not exactly
accurate but I think I can say, after talking to
30,000 consumers over the past seven years, I can
probably get pretty close. Hypertension and
diabetes are viewed very differently by a consumer
than is high cholesterol. I think you have
probably all seen that in your practices.
The burden that high cholesterol has that
those other ones don't is that diet and exercise is
usually tried first and if you don't succeed, that
is considered a failure by the patient and
oftentimes by the doctor as well. So, this is a
situation where the patient really doesn't want to
admit they failed or admit that they are sick and
would like to try an intermediate step in between,
whereas we don't see that with hypertension or some
of the more serious conditions like diabetes.
DR. WOOD: Dr. Clapp?
DR. CLAPP: My interest is in the labeling
of the product with regards to women who are under
55. Apparently, the reason that it has a pregnancy
X categorization is because of the risk to the
fetus to women of childbearing age. In this
regard, the product is being marketed for women who
are over 55. I am not sure if there is clarity on
the package with regards to the reasons that women
under 55 should not take the medication. Since
that doesn't seem to be addressed, should that be
listed in terms of "do not use if you are a woman
of childbearing age," rather than a woman who is
pregnant or lactating.
DR. HEMWALL: Yes, I think we can probably
add additional language to the label in that
regard, but it is important to recognize that the
reason that this drug is category X is because
there is no benefit to treating a woman during the
short term of pregnancy for lipid lowering, and
there is an equation which goes into category X.
And, if there is no benefit whatsoever, then even a
small amount of risk renders it to be
contraindicated and that is why the statins are
category X, because there is no benefit to treating
high lipids during pregnancy.
But the labeling question is a good one.
In fact, other OTCs have already adopted that. As
you well know or many of you may well know, the
NSAID category of drugs, which encompasses quite a
few of the OTC products, do have concerns about
disruptions in the pregnancy or harm to the fetus
with regard to inhibition of prostaglandin
synthetase and all over-the-counter NSAIDs carry
specific labeling warnings about not using the
product in the third trimester with that exact type
of language which you suggest. So, certainly,
there is room to strengthen the message in the
Mevacor label beyond just do not use if you are
pregnant or breast feeding.
DR. CLAPP: Then my question to you is
additionally that if the reason for under 55 is
because of concern of pregnancy--
DR. HEMWALL: No, the 55 is according to
the NCEP guidelines as a risk factor. One of the
risk factors is age for heart disease, 55 for women
and 45 for men. The paradigm is know your lipids,
between 130 and 170, and have two additional risk
factors, and you automatically have one of those
risk factors by having the age for men or women.
DR. CLAPP: So, then teasing out the risk
to the unborn fetus, should there be something
specifically noting that women of childbearing age
should avoid this medicine because of the risk to
the fetus, unless they are prescribed the
medication by a physician?
DR. HEMWALL: I think the message would be
more along the lines of if you are planning on
becoming pregnant you should not be taking this
drug. The data that we have so far, and we would
be happy to go into much more detail, is that the
risk to the fetus, as seen in clinical outcomes, is
very much similar to what would normally be a
category C drug but, in fact, if a woman is
inadvertently exposed in an unintended pregnancy
the risk to the fetus is very small.
DR. WOOD: Could I make a suggestion--this
is obviously a very important topic--but that we
hold this until after the next presentation which
is going to address this directly, and then we can
come back to it in detail if we want? Dr. Parker?
DR. PARKER: My question is about the
label comprehension study. My question is whether
or not it is adequate. My understanding is that
there were 696 patients and that over half of them
were under the age of 45, and less than 10 percent
of them were over 65. I guess I have a little
trouble with that. If the purpose of the label
comprehension study is to assess whether or not the
label is adequately comprehended, the target
population for users is really small in that. So,
I would like someone to address that.
I understand from the slide presented that
looked pretty good, greater than or equal to 80
percent had acceptable responses on the measures.
What about those that were incorrect, and was that
data used in redeveloping the label so that it was
more adequately understood? How was the data from
the label comprehension used in CUSTOM?
DR. WOOD: Somebody want to address that?
MS. LEVY: My name is Stephanie Levy, and
I run the label comprehension studies. If you
could just ask me your questions one by one, I will
be happy to try to answer them.
DR. PARKER: Could you address the
adequacy of the study, number one--696 patients,
less than half of them in the target age--excuse
me, half of the participants in the label
comprehension study were under the age of 45.
MS. LEVY: Yes, we designed this study in
conjunction with advice from FDA. It was designed
to be a representative sample. However, we did
feel it was important to supplement for low
literacy groups, but it was felt to be important to
include people who were not in the target group to
confirm that they were not appropriate to use the
product as well. In terms of women under 55, we
did have 254 women in the study of that age group.
DR. PARKER: So, 255 [sic] women that
would not be users of the drug were tested on their
ability to comprehend the label. Is that correct?
MS. LEVY: That is right, because
comprehension is supposed to test among the people
who can use the product, do they recognize that,
and among those who can't use the product, can they
recognize that as well.
DR. PARKER: What was the performance on
the label comprehension study of understanding your
eligibility based on your age alone?
MS. LEVY: I can show you information that
shows the self-selection among that group of women,
but we don't have data that links that that is the
reason but, certainly, we have self-selection among
that group of women, if you would like to see it.
DR. WOOD: I think the question is, is
there an age-related difference in the
comprehension study. Is that the question?
DR. PARKER: Did these people understand
the label well enough to be able to decide whether
or not they are age eligible?
MS. LEVY: Could I have slide 1751,
These are the self-selection scores, both
men and women in the different age groups. We
looked at correct/acceptable scores and also
correct and acceptable separately. You can see
among the women under 55 years old, and there were
254 of them, 92 percent got a correct or acceptable
score; 76 percent completely correct saying that
they could not use the product.
DR. PARKER: Thank you.
DR. WOOD: I know we have more people who
want to ask questions. I just want to be sure I
have covered everybody at least once. Is there
anyone who has not had a chance to ask a question
and wants to ask one that I missed?
Then let's go to Dr. McClung.
DR. MCCLUNG: I want to come back to the
differentiation--this is an easy question, by the
way, that has a specific answer--in the jargon we
have heard today, the OTC versus the Rx guys, one
of the strong justifications for having Mevacor be
over-the-counter is that patients would accept an
OTC medication more than a prescription medication.
Let me ask exactly how that question was asked
where you got those answers. Was is asked "would
you prefer to have a prescription or
over-the-counter remedy for your heart health
program?" Or, was the question asked "if
lovastatin was available over-the-counter and by
prescription, would it make a difference in your
selection on the basis of lovastatin availability
in those two ways?"
If you compare a prescription drug and an
OTC drug, you have described that people who want
OTC things don't want to see themselves as sick.
The other distinction is that patients see
over-the-counter preparations as being natural and
safer in some ways than chemical prescription type
drugs. So, to compare prescription drugs with
over-the-counter preparations like vitamin E isn't
quite the same as comparing the acceptance of a
specific product, in this case lovastatin, and a
prescription versus in an over-the-counter
circumstance. So, can you describe actually how
you asked the question to derive the data that you
presented to argue that over-the-counter
availability would increase the interest among
those who might choose to take it?
MR. HANSEN: Yes, let's look specifically
at slide 58 if that answers the question. I
believe it has the exact wording of the question.
So, what the National Consumer League did,
because this was a concern of theirs as well and
they wanted to understand what is the magic of OTC,
they went out and asked people who were untreated,
either at potential or known moderate risk to
themselves, which of the products you would more
likely take action with.
The further description of this was that
they are exactly the same product, exactly the same
dose. The only thing that differs here is the
distribution of the product. So, here are the
results that you see, which one would you rather
consider taking? Again, this was 20 mg Mevacor or
the equivalent, whether it is OTC or Rx. You can
see that 3:1 they would much more likely take
action with an OTC than a prescription, which is
the basis for our being resistant to Rx versus OTC.
So, that is exactly how the question was worded and
exactly how it was put into perspective, that this
is exactly the same drug, the only thing that
differs is how you get it.
DR. MCCLUNG: Does that assume that the
cost is the same? Many people with prescription
drugs are paying $15 for an Rx drug and they are
paying whatever it is for an over-the-counter, so
did that make any financial assumptions?
MR. HANSEN: I can't remember whether in
this exact survey they did put a price around it or
not. We have had other surveys however where we
put a price range, and we have certainly not
finalized the price for Mevacor, but in the range
of 75 cents to a dollar a day, just to put it into
perspective. And the numbers you see there are
very consistent across studies, that people, in
that price range for an OTC, would prefer--at least
the person we are targeting, would prefer to try
OTC first versus Rx.
DR. WOOD: Dr. Woolf?
DR. WOOLF: To me, the CUSTOM study is a
pivotal study so I would like to get some more
information about exactly how it was conducted,
sort of the nuts and bolts.
In the simulated pharmacy, what was the
role of the nurse/pharmacist? Did this individual
provide guidance if asked; provide guidance without
being asked? What exactly did this person do?
Secondly, what was the cost to the
participant for the drug, and how does the cost
compare to what it is likely to cost in the
marketplace if it were approved for
MR. TIPPING: Your question was in the
CUSTOM study design what was the role of the study
site nurse that was acting as a pharmacist, and
what was the cost of the medication. The study
site nurse was there to answer questions but was
specifically instructed not to volunteer any
information. So, the participants could interact
with them in a couple of fashions. They could ask
a specific question about the label and they would
get an answer to that specific question. Or, they
could initiate, of their own accord, a full
eligibility--is this product right for me? At that
point the nurse would take them through all the
The second part of your question had to do
with the cost of the product. It was $15 a box.
DR. WOOLF: And how does that likely
compare to what it would be if it were marketed?
MR. HANSEN: Again, we haven't finalized
the price. It is certainly within the range of
what we charge in the marketplace.
DR. WOOD: Dr. Watts?
DR. WATTS: We have heard a lot of
information about the patients who self-selected to
use Mevacor OTC, but I don't recall hearing much
about the patients who decided not to use Mevacor
OTC, and that information might be helpful in
getting some idea of how effective this approach
would be in making inroads to this treatment gap.
So, I would like to know, if possible, what
percentage of those who chose not to take the drug
would have been candidates for the drug, that is,
the proper age, the proper LDL cholesterol and
other risk factors.
DR. HEMWALL: While we are getting that
slide, I think Bob is going to have an answer for
you, but we don't have as complete information on
the people that were evaluators as we do on the
people that were users. We have some information
on some evaluators who went through an eligibility
assessment but our information is less complete on
them just because that was the way that we were
able to maintain hands-off on making sure they made
the decisions on their own.
MR. TIPPING: Thank you for that question.
It had to do with the people who didn't purchase
the product. Right? If I could have the slide
that we just talked about?
I am glad to get that question because we
feel that this is a very important group too. If
you recall from my presentation, there were over
2000 of these individuals who took the time to come
to the site and do an evaluation of the product and
then chose not to purchase.
They broke out in this fashion: 438
indicated that they needed more information and
they left the site and didn't come back. There
were 1673 of the 2111 who decided not to purchase.
Of that group, applying all the label criteria--age
and everything--98 percent of them were ineligible.
In fact, if you come down a little bit more, there
is 64 percent that is a subset of the 1673 and it
is an important subset because they specifically
said they don't think Mevacor OTC is right for
them. So, in this subset virtually each of them
was found to be ineligible by some component of the
DR. WOOD: Dr. Taylor?
DR. TAYLOR: For your product to be
effective over the long haul, a high degree of
compliance is needed and you have shown in your
CUSTOM that you did get some fair results. I am
curious, did the individuals know that they were in
a study? For example, did they sign a consent
The second question is were they provided
any incentives for returning to improve their
MR. TIPPING: Yes, your question was did
the participants in CUSTOM have to sign a consent
form. That was the first part of your question.
The answer to that is yes, but only after they had
gone through the process and made a purchase
Your second question I think had to do
DR. TAYLOR: To return; follow-up
MR. TIPPING: No, there were no
DR. TAYLOR: For example, travel stipends,
MR. TIPPING: Only at the end of the study
after all the decision processes had been made,
there was reimbursement for travel. But during the
whole course of the study as behaviors were being
observed there were no incentives to return to the
site. I would also remind you that they had to
come back and actually purchase the drug, or if
they needed a test or wanted a test, purchase the
test. So, no real incentives to encourage--
DR. TAYLOR: But they received something
at the end as a sort of end of study incentive?
MR. TIPPING: At the end of the study they
were reimbursed for their expenses for traveling
back and forth to the sites. There was no
knowledge that that was coming during the course of
DR. WOOD: That wasn't in the consent
form? That is hard to believe. So, they just got
a Christmas present at the end and that was
astonishing to them?
Presumably, just while we are thinking
about that, the people who didn't show up and
dropped out presumably didn't get the payments?
Which is the question which I think is being
addressed by Dr. Taylor, one of them.
MR. STRUBLE: My name is Bill Struble. I
am part of the clinical team at Merck. To answer
your question about compensation, the advertising
for the study did indicate that they would be
reimbursed for time and travel, as well as the
consent form. It was designed not to be a
sufficient amount to be an inducement or an
incentive, and that was done in conjunction with
the institutional review board. They didn't get
that money until the end of the study, as Bob had
DR. TAYLOR: Did they know how much they
were going to get at the end of the study?
MR. STRUBLE: We told them what the amount
would be when they returned at the end of the
DR. TAYLOR: And on average, how much was
that? Do you remember?
MR. STRUBLE: Pardon?
DR. TAYLOR: On average, how much was
MR. STRUBLE: They were to receive $35 per
visit and $75 at the end of the study because we
had an extensive list of questionnaires that they
had to go through at the end of the study. What
you have to keep in mind is that they were
responsible for paying for their medication, as
well as purchasing the cholesterol tests, and we
considered that when we decided what the
reimbursement should be because there is also time
and travel expenses that were involved in that.
MR. TAYLOR: The other question I had was
what percent of your participants that were users
DR. HEMWALL: We have that answer. It
will take a minute to get it.
DR. WOOD: Why don't we move on to the
next question and then you can come back to that?
DR. HEMWALL: The answer is 43 percent.
DR. WOOD: Let's go on to Dr. Neill.
DR. NEILL: Currently, the ATP III
guidelines recommend that anybody that has an
elevated LDL be evaluated for secondary causes of
dyslipidemia before treatment, and if those causes
exist they be treated, and if they are still not at
target that treatment be initiated to get them to
target. Am I hearing that the ATP IV guidelines
will remove that requirement or recommendation?
This is clearly only a guideline.
DR. PASTERNAK: Yes, it is clearly only a
guideline, and as far as I know, there is no ATP IV
planned yet, unless somebody in the room knows
something I don't know. Remember, the label
enjoins the user to seek the attention of their
doctor at some point, and suggests that they have
to have their LDL cholesterol measured.
DR. NEILL: I am going to interrupt
briefly because I actually looked at the box that
was used in the study and there is nothing on the
exterior of the box anywhere that suggests that you
need to see a physician to be evaluated for
secondary causes of dyslipidemia. Now, I am
presuming, because they have another LDL, that at
some point that has happened but that is a
presumption that appears to have been made based on
the fact that a consumer can walk into a pharmacy
and know their LDL. I don't know whether that is a
valid presumption to make, but the question is only
peripherally related to that. It is more related
to whether or not that is something that we believe
is necessary and, if so, is there some way that
that is included within this self-management
package that exists that I haven't looked at yet?
DR. PASTERNAK: Someone else on our team
may remember some of the details of it, but we
certainly do recognize that there are secondary
causes of hyperlipidemia and that a physician needs
to consider that for patients.
DR. HEMWALL: Again, I think it is all
about the overall program that was intended to get
consumers to their physicians, and these are
primary prevention people that are otherwise in
good health but they are warned in the label
against having diabetes and also, as you probably
noticed, if their triglycerides are above 200 they
should not be taking the product if they don't talk
to a physician.
So, there are a number of touch points
which allow the consumer to recognize that they
need to talk to a physician but it is not the same,
obviously, as being worked up completely for high
lipids, and may not be what actually happens in
medical practice as well.
DR. NEILL: I may be missing this but I
don't see any of those things on the exterior of
the package, and I haven't heard with they are in
the self-management materials that are available
for consumers before they make the purchase. Now,
I have new bifocals and that could be a big part of
DR. HEMWALL: I am looking at the label
and it says do not use unless directed by your
doctor, if you have very high LDL cholesterol, that
is, above 171; if you have high triglycerides,
above 200; or if you have a health HDL, good
cholesterol, above 60. Also, do not use if you
have had a stroke, diabetes--
DR. NEILL: I have found it.
DR. HEMWALL: Okay, and this is expanded
upon within the materials, of course, to give more
context to all that information. Referring to one
of the earlier questions, we are not saying you
shouldn't use a statin if you have these conditions
but you should see a doctor first.
Also, I want to correct a statement we
gave a little earlier about insurance coverage.
That 43 percent number was for people who had
prescription coverage, not just health insurance,
and 82 percent had health insurance.
DR. WOOD: Frank?
DR. DAVIDOFF: Yes, I am interested in the
apparent difference between the apparent
requirements for approval of an over-the-counter
drug, that might be used by many millions of people
on an over-the-counter basis, versus the
information or evidence requirements for that same
drug to be given to a much smaller number of people
in a prescription setting. Because it appears that
here, if a decision is made to go forward with OTC
lovastatin, it would be on the basis of a single
non-randomized, non-controlled, short-term study
with no major clinical endpoints but, rather, a
surrogate variable measured.
That prompted me to start thinking about
the opportunity that industry had here to actually
provide a landmark study. This is a historic
opportunity. If an OTC drug for chronic use for
primary prevention is to go forward, there would be
the opportunity to demonstrate that it was, indeed,
the statin that was having the benefit. Because I
can envision a scenario in which there was a
placebo arm in the CUSTOM study but, because there
is such a strong interaction with physicians, there
might have been at least as much, or perhaps almost
as much benefit from having been interactive with
physicians and it may not have been the drug at all
that really produced much of the primary preventive
benefit. I would like to ask the question why a
placebo arm was not included.
DR. HEMWALL: Well, first let me address
one of your comments where you said this would be
available to a much wider group of people. I don't
think that the OTC population could ever come close
to the Rx population that is currently receiving
But having said that, the question that
you are asking about the placebo control and the
level of rigor that is required for an OTC switch
is quite different from that required for the
original approval of a drug as a new chemical
entity, and I think our colleagues from the FDA
would be willing to speak on that. This is the
standard for OTC drugs to actually show consumer
behavior in the hands of the consumers, and in
these observational studies typically placebos are
not used because they are open-label and the
consumer knows what they are getting.
Also, I might add that we have done three
earlier studies of this same type of actual use in
our first application so that we do have quite a
range of data, using different studies designs,
with very consistent results, as shown by Dr. Cohen
in one of his later slides.
DR. DAVIDOFF: But if I may, the day a
drug like this goes over-the-counter it is
available to the entire U.S. population, much more
than the limited and targeted population that is
available by prescription. So, I think that that
is a substantial difference.
The other point is that we really don't
know the efficacy of an over-the-counter statin
over six years or five years in an over-the-counter
situation. Even if we did know that, we wouldn't
know how much of that was attributable to the drug
being available over-the-counter and how much of it
was due to the interaction with physicians. The
CUSTOM study is actually a rather complex
intervention study. The intervention consists of
more than just the drug.
DR. HEMWALL: That is absolutely right.
That is exactly what the program is intended to do,
to be more than just a drug, but to create that
level of education and awareness among the
consumers that use it to get them to interact with
the healthcare system as well, whether it be a
pharmacist or doctor, and that is what we actually
intended to show with CUSTOM.
Keep in mind that, despite the limitations
of the open label, we did have a 21 percent
reduction in cholesterol across the entire
population of those that fasted at both baseline
and at the end of the study, and an overall 24
percent which is very consistent with the placebo,
DR. DAVIDOFF: If I may, that is in the
group in whom you did manage to measure both at the
beginning and at the end. It doesn't take into
account the larger denominator of people who would
be likely to take this in an open over-the-counter
situation. Furthermore, we don't know how long
that lasted because they weren't followed for five
or six years. So, I would repeat that we do not
know the efficacy. It is probably not zero but I
don't think it is 20 percent.
DR. WOOD: Frank, just to follow-up on
that, I am having some difficulty following that.
Isn't that also true for every Rx study that we do?
I mean, you know, we study ACE inhibitors in heart
failure and we extrapolate that to the entire
population with heart failure and make conclusions
from that. I am struggling to understand what the
difference is here, particularly when you have such
a large database of efficacy, real efficacy not
sort of symptomatic efficacy.
DR. DAVIDOFF: Yes, but that efficacy
begins to melt away when you take into account
long-term adherence; when you take into account the
degree of risk to start with. This is a much lower
risk population than the prescription drug risk
group. And that is true for all primary prevention
studies. I repeat, I don't think it would be zero
but I think to rely on efficacy data and to make
direct extrapolation from efficacy data from the
randomized trials to the over-the-counter
situation, even including data from CUSTOM--I have
some difficulty with it. That is really all I am
DR. WOOD: Dr. Patten hasn't spoken.
DR. PATTEN: Yes, I would like to ask a
question about the AFCAPS/TexCAPS cohort in the
post hoc analysis. We are given figures for the
size of the cohort and we are given the initial
gender breakdown, with 5608 men and 997 women, but
we are not given a gender breakdown after that.
So, I would be interested to know if enough women
made it into subpopulations 2 and 3, where event
rates were examined, so that we know that gender is
or is not a factor here in the event rate.
DR. HEMWALL: In the complete AFCAPS
cohort there were about 900 women and the same
magnitude of risk reduction was seen although it
did not reach statistical significance. So, if you
were to slice that further into the OTC cohort,
then you would also not see the same level of
statistical significance but the magnitude of risk
reduction was similar. We have an expert here on
women's cardiovascular issues who can address more
completely the role of risk reduction in women,
which may in some cases be different, if you would
like to hear some discussions along those lines if
that is part of your overall question.
DR. PATTEN: It is.
DR. HEMWALL: I will introduce Dr. Sandra
DR. LEWIS: Sandra Lewis. You know, women
are different and women have been included in many
of our trials. I was the lead investigator of the
subset looking at the CARE study which looked at a
group of women who had had a heart attack but had
total cholesterols less than 240. At that time we
were not treating patients who had total
cholesterols less than 240, independent of risk.
So, this was a secondary prevention trial, and the
women in the CARE trial actually had a more
significant reduction in myocardial infarctions,
stroke, risk of cardiac death, bypass surgery,
angioplasty. There are women included in many of
our secondary prevention trials and also in some of
the primary prevention trials. The risk reduction
across the board is very similar to the men
although, because of numbers, they may not reach
statistical significance because of small numbers.
And we need to get more women into these studies.
I think particularly the differences
between a woman's perception about cardiovascular
disease is really key to this OTC question. Women
look at responsibility for having developed heart
disease as having done something bad, and they are
very anxious to be proactive about their health,
patient centered responsibility. So, for a woman
to have the option to take a product that is going
to make her heart healthy, instead of being told
that she has an illness, is a really positive
thing. We have an epidemic of cardiovascular
disease in this country. We have decreased our
mortality rate for men. So I see this as a
tremendous opportunity for a very special group of
women that would take the opportunity to benefit.
DR. WOOD: We have two more questions, Dr.
McClung and then Dr. Follman, unless there is
DR. MCCLUNG: Let me ask you briefly about
the muscle complication of statins. Is there a
relationship between time of exposure and the
probability of experiencing muscle problems? That
is, is there a susceptible cohort that is more apt
to develop the problem early in exposure or does
the risk increase exponentially with long exposure,
or is the risk simply linear with time?
DR. WOOD: Maybe I can answer that for
you. From the Baycol database, many of the people
there developed rhabdomyolysis very quickly when
they were switched from one drug to another, and
many of them virtually within a few days or weeks
when they were switched. The reason that may be a
relevant database is that the incidence there was
much higher than has been with any other drugs.
Now, for this one I don't know.
DR. MCCLUNG: But is that quite the same
thing? Switching from one drug to another could be
a difference in drug. But if a patient is on a
drug that is known to cause that, is the
probability of experiencing the problem in the
first six months of exposure different than in
their third or fourth year of exposure?
DR. WORTMANN: My name is Robert Wortmann.
I am from the University of Oklahoma. I didn't
hear the last part of your question. The first I
think had to do with when do people who develop
muscle complications from statins do that? Is it
linear with time or is it sudden? And, it is all
over the map. There is no consistent pattern with
statins that are still available. Some can get it
right away; others after weeks; others after
months; others after years. Cerivastatin was a
different compound than those that are still
available. It is metabolized differently and I
think it had reasons why it developed more rapidly.
There was a second part to the question?
DR. MCCLUNG: No, I just restated it in a
clearer way the second time.
DR. ORLOFF: Let me just make a comment
from the FDA side, that it is the impression from
everything we know about statins that there is no
cumulative dose-related toxicity, and I think that
is what Dr. McClung is asking. There are a lot of
unknown factors that go into the development of
myopathy but it does not appear to be related to
duration of use per se.
DR. WOOD: Dr. Follman, you have the last
question unless someone else has something.
DR. FOLLMAN: Thanks. I just wanted to
expand on what Dr. Davidoff was talking about
earlier. I am new to the over-the-counter world
and I think things are different here than in the
prescription world. So, if we are evaluating the
evidence for a prescription drug we compare placebo
to the treatment. That is because in the real
world the drug isn't available to anyone so it is
proper, I think, to compare, say, a statin to
nothing, say, in 1988. This is a different world
now when we are considering the over-the-counter
use of Mevacor. Statins are currently available so
I think the question in my mind is not whether
statins work compared to nothing, but how would
statins in an over-the-counter world compare to the
way statins work in the current prescription world.
So, the numbers of efficacy that we have
heard quoted, say, the number needed to treat 25,
48 or whatever, is for the statin versus nothing
comparison. I think the relevant comparison is how
would they work in a prescription world compared to
an over-the-counter world. We don't really have
evidence of that directly here. But, in my mind,
the ideal thought experiment would be to randomize,
say, cities to the current prescription world or to
an over-the-counter world and then see what the
cardiovascular event rates would be comparing city
to city. I realize that is not doable whatsoever,
but I think that gets at the idea of, you know, you
can't compare statins versus nothing; you have to
compare statins to some partial use of statins.
If this is approved, there will be some
people who take Mevacor over-the-counter who would
have used prescription statins if we didn't approve
it and they might get better treatment. So, I
think there is not really direct evidence on this
comparison that I am interested in, prescription
versus over-the-counter as opposed to statin versus
Interestingly, in the packets that you
gave us there was what I would probably term sort
of an approximation to this thought experiment I
just mentioned, which is the lipid-lowering
component of ALLHAT where they randomized about
10,000 patients to either a fixed dose of
pravastatin 40 mg versus usual care. So, you can
think of the fixed dose of pravastatin as sort of
an over-the-counter world and then the usual care
as a prescription world because in that trial
people on the usual care arm got prescription
statin as they felt it was necessary. During the
course of that trial about 30 percent of the people
in the usual care arm ended up on a statin, and
overall there was no difference in CHD event rates
between the usual care and the fixed dose of
pravastatin arms in this long trial with a lot of
So, to me that is somewhat relevant to
this. It is a different drug, and so on. It is
not a pure comparison with the prescription world
to the over-the-counter world but it seems to be
the closest approximation and the most evidence
that we have available. I think it is not very
promising for an over-the-counter statin if you
take ALLHAT seriously as an approximation for this
DR. WOOD: Didn't ALLHAT show that there
was no difference between the arms?
DR. FOLLMAN: Right.
DR. WOOD: So that would seem positive.
DR. PASTERNAK: I would like to respond
just to the ALLHAT issue. I had the opportunity to
write the editorial discussing the ALLHAT results,
and the title of my editorial is consistent with
the comment I am about to make, which is "Less is
Less." The important part to understand about
ALLHAT is that the delta LDL, the difference
between the treatment group and the control group
at the end of the study was about 12 percent total
The other important point to consider for
ALLHAT is that if one looks at the point estimate,
yes, it is correct that it was not statistically
significant, it was a negative study. But the
point estimate of risk reduction fits exactly along
this log linear line. That is, the group had about
a 10 percent risk reduction because the sample size
wasn't statistically significant.
So, our point and my point in that
editorial was--and I think it is important to think
of this in the context of the individual who is
getting treatment--that there is risk reduction
associated with LDL lowering. For those
individuals who get a 20-25 percent LDL lowering,
as we have shown will happen with 20 mg of
lovastatin, their risk will be lowered by 25
percent. It gets very complicated comparing one
study to another, and I think it is important to
view ALLHAT as fitting in the context, not as a
study which proves that that particular statin or
that particular way of administering a statin
DR. FOLLMAN: I guess I would just
say--you know, you mentioned that in that trial
there is a delta LDL of about 11 percent or so, and
I am wondering would that be the delta LDL or
something even smaller in a prescription versus
over-the-counter world. The issue to me would be
would we be improving the public health with
over-the-counter Mevacor compared to the usual
prescription world we have now?
DR. WOOD: That may need at some point
some comment from the over-the-counter people to
explain the criteria for approving an
over-the-counter drug I guess. But that could wait
until after lunch. Dr. Caprio had a question.
DR. CAPRIO: I have a question. Given the
increasing prevalence of non-alcoholic fatty liver
in our population, I haven't seen anything
recommending testing for NFTs prior to starting
this. This is quite concerning because we are
seeing patients with very high ALT.
DR. HEMWALL: That is an excellent
question, and we actually have a fairly
comprehensive answer to that question. It may not
be that we want to start off on that discussion
right now. I will ask Dr. Wood.
DR. WOOD: I think I agree.
DR. HEMWALL: But we do want to come back
DR. WOOD: So, why don't you think about
that over lunch and we can start with that when we
get back from lunch? How about that? Is that
okay with you?
DR. CAPRIO: Yes.
DR. WOOD: Neal?
DR. BENOWITZ: I have two very specific
clinical pharmacology questions and I just want to
follow up. I know we talked a lot about this on
the compliance issue. One is that there was a
statement in the brochure that we got about renal
disease and changes in lovastatin metabolism, that
that would be contraindicated. I didn't see that
in the package insert stuff.
The second thing is that these are health
conscious people, taking dietary supplements and I
didn't see anything about interaction with dietary
supplements, like St. John's wort and things like
The compliance issue--just thinking back,
I have had a lot of experience with smoking
products over-the-counter and there are two
important issues that I think we have to think
about. One is that even for short term, even for
three-month OTC instruction, compliance is
terrible. Most people stop taking it after a few
weeks. The more you comply, the better you do and
I am very concerned that this six-month trial will
not reflect the six years that it takes for a
number needed to treat at 40.
The other thing is the cost issue. Cost
is a big question. That has certainly been raised
with the smoking products. If we did these
calculations right, four boxes at $15 a box is 33
cents a pill versus the projected 75 cents to a
dollar pill which would also enhance compliance in
a six-month trial. So, I think I need some
reassurance that people are not going to be just
throwing away their money by taking the pill
intermittently or taking it in a way that is not
going to benefit them. So, those three questions.
DR. HEMWALL: I heard a question on
labeling warning or statement on renal disease. As
of our understanding, there is no concern with
renal disease with the 20 mg dose. We haven't put
that in the label but that is something that is
often seen in OTC drug labels and, certainly, if
there were data to support it and FDA were in
agreement we would consider putting that in.
I want to answer a couple of those
questions about compliance over the long term. I
think we do have some good data. It is certainly
not five- or six-year data but this is data that is
fairly unique for an OTC drug. Could I have the
slide that shows the 076 results?
This is a study that we did with 10 mg in
our earlier program. Although the dose is
different, I think it is important to see the
compliance that goes over an 18-month period. The
top line shows the number of pills being taken over
the time frame, representing the percentage of
people that were 75-100 percent compliant over this
time frame. Then, the bottom line shows the actual
number of people that stayed on drug during that
So, you can see that after about 18 months
we have about 50 percent still taking OTC Mevacor
under the simulated conditions of an actual use
trial. These numbers actually compare very
favorably to what is seen in the prescription
environment, and the numbers are in fact, in some
cases, dramatically worse than this. These numbers
are perhaps most consistent with what is seen in
patients that are taking a statin for secondary
prevention after having had their first coronary.
But the numbers for people in primary prevention
are much lower than this, probably falling off to
about 30, 35 percent, and those data are in our
background package in your materials.
The other thing to point out is that there
is a strong precedent with over-the-counter aspirin
which people take every day fairly easily and
simply without any concern. We have very good data
from the aspirin manufacturers on compliance over
the long term. So, we think that that is also
typical of users who might use a product like this,
the heart-healthy, motivated consumer, which would
again show that they would have higher compliance
levels possibly than their prescription
DR. WOOD: Was there someone else who
wanted to comment?
DR. HEMWALL: This is just a review of all
the studies that have looked at compliance with
statins over different time periods. Of course,
even these studies only go out to two years at
most, where the persistence rates vary from 25
percent to 64 percent, and then looking at the
three Mevacor studies that we have so far for six
months and one for 12, and it doesn't have the full
18 months on this slide for the 076 study. Those
are the numbers that compare to what is published
for prescription statins.
DR. WOOD: Any other comments?
In that case, I have to do the usual
bureaucratic stuff. In the spirit of the Federal
Advisory Committee Act and its Sunshine Amendment,
the committee should refrain from discussing this
topic during lunch, any other breaks or this
evening. Please save your discussion for the open
forum of the meeting. I am told on good authority
that it is all right to ask a waitress if this is a
low cholesterol lunch and it is all right to look
for an asterisk on the menu! Let's try and be back
at 1:15 and we will start promptly at that point
with the liver function test discussion.
[Whereupon, at 12:15 p.m., the proceedings
were recessed for lunch until 1:15 p.m.]
A F T E R N O O N P R O C E E D I N G S
DR. WOOD: As I promised before we broke
for lunch, we are going to give the first few
minutes to the sponsor to present some of the liver
data. So, if the sponsor is ready, let's get
DR. HEMWALL: Thank you, Dr. Wood. We had
a question before the break about liver function
monitoring and I want to see if I have the question
right. It is looking at people that might have
undiagnosed liver disease that would take the
product without having a baseline test.
DR. WOOD: I think there were two
questions. One was excluding people who might have
liver disease and I guess unasked there, but
relevant, is whether these people are truly at
greater risk for developing liver disease after
they take the product. Then the second question I
think was related to whether there was a real risk
of liver disease from this product at this dose, at
least that was my understanding of the question.
Is that right? Okay, the questioner acknowledges
MR. HEMWALL: We will start by introducing
Dr. Paul Watkins who will address this from the
perspective that he has in the academic frame.
DR. WATKINS: Paul Watkins, University of
North Carolina. I guess I will address the second
question first. That would make sense to me. The
question is can statins at this
dose--lovastatin--cause significant liver injury?
That is the question that I heard.
The sponsor has provided a lot of data in
the packet about this. The original concern about
statins as being potentially liver toxic came out
of preclinical studies which showed that in certain
animal species that drugs, and lovastatin in
particular, caused hepatocellular necrosis. Then,
when the drug proceeded into man, there were
observed LFT elevations, alanine aminotransferase
elevations. So, a reasonable assumption was that
severe live toxicity was a problem.
However, in the last five years there has
been a re-thinking of the issue. In the
preclinical models, you can actually reverse the
toxicity by nutritional supplementation and
mevalonate, suggesting that this is a pharmacologic
action related to the cholesterol-lowering
property. Furthermore, in man, in all the clinical
trials that have been done, there really has not
been a signal for clinically significant liver
disease relative to placebo arms. And, in the
post-marketing reports, although there have been
reports of severe liver injury, including acute
liver failure, the incidence has not been
distinguishable from the anticipated background
after 27 million patient-years. So, the true risk
of severe liver disease is extremely low and
indistinguishable from the anticipated background
incidence of idiopathic liver injury.
I am sure there is data the company could
show to back that up if there are any specific
questions, but the consensus is that liver
monitoring is not useful during treatment with the
drug. As I say, I don't think that is in
contention. The question is are there
subpopulations where there may be a higher true
risk of significant liver injury, and preexisting
liver disease is the question raised.
That has been addressed, and in the
sponsor's book there are the study results of
Chalasoni et al., at the University of Indiana,
that looked in a large database at patients who had
abnormal liver tests, abnormal serum ALT, and were
started on statins, followed for six months and
compared it to a larger population of people who
have chronic liver disease, elevated ALT, and did
not go on statins, and found no difference in the
incidence of mild and severe ALT elevations between
the two groups.
I understand there is a larger study being
done at Kaiser right now by the company that has
preliminary data that supports the same observation
that the incidence of ALT elevations is not
increased in patients who have preexisting liver
But I think the fact is we know that
patients who have preexisting liver disease do not
have a very significant risk certainly of having
severe liver injury when going on lovastatin from
the post-marketing experience. That is because
about one-third of patients who have hyperlipidemia
have fatty liver somewhere in that spectrum. And
two percent or up to two percent of the American
population has chronic viral hepatitis. And, what
the Chalasoni paper showed us was that physicians
who dutifully measure baseline ALT will still start
some of those patients on statins in spite of an
As Dr. Wood pointed out, physician
compliance with monitoring for liver events is
notoriously poor, and in the Chalasoni experience
only about 50 percent of patients had a baseline
check at all. So, given this enormous background
of chronic liver disease in the population and the
incomplete and poor nature of monitoring, I think
it is reasonable to assume that in the 27 million
patient-years there are many million that reflect
people with underlying liver disease and, in spite
of that, there is this remarkable track record of
safety where you really cannot distinguish a signal
above the anticipated noise.
So, in summary, there will be people
undoubtedly who don't read the label or don't know
they have preexisting liver disease who would go on
and take the drug. But it is my opinion, and I
know Keith Tolman's as well, that the risk in terms
of liver injury is very small for those
DR. WOOD: Dr. Caprio, does that help?
DR. HEMWALL: I wanted to follow-up with
something that Dr. Watkins mentioned, and this is
the Kaiser Permanente study. I also wanted to make
sure that the committee is aware that there is an
application in review by FDA to relax the liver
function monitoring requirements in the lovastatin
Rx label to be more consistent with the idea that
an OTC might be available that does not require
liver function monitoring.
One of the key questions at hand where the
data are still fairly sparse, although the
Chalasoni study was just mentioned, is the concern
about people that do have undiagnosed liver disease
and what would happen to them if they took a statin
without having a baseline liver function test.
And, there is a study that is under way where the
results have come in that we have only been able to
share preliminarily with FDA, but they have been
kind enough to allow us to share that with the
committee today. But keep in mind that the FDA
have not actually reviewed all of this data and
given us their own input on it. Can I have the
This is in the Kaiser Permanente database
where we looked at two different patient cohorts,
those that were exposed to lovastatin with evidence
of liver abnormalities; those who were unexposed,
patients with the same level of evidence of liver
abnormalities but who did not take lovastatin, and
then examining lab inpatient and outpatient
databases used in the exact same way for both
cohorts. Next slide.
The disease inclusions covered virtually
any type of etiology that would result in liver
disease so that we are covering all the bases where
we have, in fact, been a little weak in that in the
Chalasoni study, done in Indiana University. We do
have patients with viral hepatitis. So, the
retrospective chart review as done and we found the
There were approximately 7000 patients
exposed to lovastatin with liver disease, and we
used Hy's Rule as the endpoint which is multiple
lab abnormalities in a well-defined and accepted
outcome endpoint for liver disease. And, the total
person-days of people exposed to lovastatin in this
group was, as you can see, over two million, with
an incidence rate of 2.6/10,000 proceeding to
having more advanced liver disease as defined by
Hy's Rule. In the control group there are about
37,000 individuals who did not receive lovastatin
but had liver disease and were followed to reach an
outcome defined by Hy's Rule, and there were 626
patients who had that outcome. That makes an
incidence rate of 11/10,000 person-days. So, the
incidence rate with those exposed to lovastatin is
actually statistically lower than it is with those
not taking lovastatin, and we won't draw any
conclusions from that and we will let FDA review
the entire study, and also the various cuts of the
data that are still forthcoming. But I thought it
would be important for the committee to know that
this study has been done and at least the
preliminary numbers are looking very strong in
favor of the liver safety of lovastatin even in
people that have preexisting liver disease.
DR. WOOD: Unless there are any burning
questions, let's move on. Dr. Davis-Bruno?
Reproductive and Fetal Toxicity
DR. DAVIS-BRUNO: My name is Karen
I am a supervisory pharmacologist in the
Division of Metabolic and Endocrine Drugs. I have
been asked today to provide you with an overview of
the lovastatin nonclinical or animal developmental
As a means of introduction, what I will
first do is provide an overview of pregnancy
category labeling in accordance with the Code of
Federal Regulations, or the CFR. Then I will
discuss CDER's interpretation of the lovastatin
developmental data which supports the current
pregnancy category labeling. Then I will move on
to a discussion of CDER's interpretation of the
I should add that Merck has submitted an
extensive amount of developmental data, over
roughly a 24-year period which represents roughly
40 such types of studies. So, in the interest of
time constraints, I certainly can't go into details
of every single one of those studies but, instead,
what I will do is provide a broad overview of
CDER's analysis of that submitted data. As I
mentioned, the data is subject to interpretation
and I will try to point out areas where our
interpretation differs from that of Merck's.
One of the differences in data analysis
between the sponsor and CDER is in the definition
of maternal toxicity. This has implications in
determining the clinical relevance of these animal
findings that were observed, and I will spend a
good deal of time discussing that.
Lastly, I will briefly define CDER's
interpretation of the drug-related fetal and
neonatal findings, which include fetal and neonatal
mortality; developmental delays and skeletal
The Code of Federal Regulations, or the
CFR, specifies pregnancy category labeling for drug
products. This slide summarizes the various
categories in order of increasing human concern,
from A down to X.
It is noteworthy that the determination of
a specific category depends not only on the human
data but also the animal data that is available,
and certainly the relative risk-benefit ratio that
is perceived. So, for example, pregnancy
categories A and B, which you see at the top of the
slide, are reserved for cases where there is no
perceived human risk.
Category C, which is shown in the middle
of the slide, is reserved for cases where there is
no human data although there may be animal data
that demonstrates a fetal risk. However, the
important point to make is that the risk-benefit
ratio is acceptable for the indicated use.
Category D applies to cases where there is
human fetal risk based on actual human studies or
on post-marketing data, but in these cases the
benefit outweighs the risk. Examples of these type
products would be products that are used to treat a
life-threatening type indication.
Last is pregnancy category X in which the
product is contraindicated for use during pregnancy
in pregnant women because there is a human and/or
animal series of data that indicate a fetal risk.
But in this case, it differs from the other
categories in that the risk-benefit ratio is
unacceptable. That is, the risk outweighs the
Since its approval for marketing in 1987,
Mevacor has been labeled as a pregnancy category X,
as are all the statins. The rationale for the
current pregnancy labeling is summarized on this
There are no well-controlled studies in
pregnant women for Mevacor. There are, however,
some post-marketing reports of fetal adverse
effects on live births. In these cases exposure
has been established and it appears to occur within
the first trimester. However, the caveat is that
it is limited data so the cause and effect cannot
be demonstrated. However, there clearly are
findings and this would certainly not allay our
The animal studies, which I will explore
in some detail, show fetal and neonatal adverse
effects in the absence of maternal toxicity. This
is an important distinction because it is felt that
the findings in the absence of maternal toxicity
are those that are potentially relevant because a
responsible physician is not going to dose up to
the point of maternal toxicity.
I should state that both CDER and Merck
agree that there is no benefit to temporarily
treating pregnant women. Therefore, we both agree
with the contraindication during pregnancy.
For those of you who may not be familiar
with developmental study designs, I will briefly
review these in this current slide. Standard
reproductive and developmental evaluations are done
in accordance with ICH guidelines S5A, which is a
guidance to industry. Generally, these study
designs fall into one of three categories. I also
want to point out that this is considered the
minimum for product registration and Merck has
clearly, over a 24-year period, submitted a
substantial number of these types of studies which
exceed the minimum.
For the purpose of discussion just to
describe these types of studies, the traditional
segment 1 study which you may be familiar with is
really a fertility/early embryonic developmental
study. It is performed usually in one species,
usually a rat. The exposure is performed prior to
and during mating in either males or females. In
females the exposure continues from mating through
The segment 2 studies are set up to asses
embryo-fetal development. They are usually done in
two species, both rat and rabbit. In this case,
exposures are done during organogenesis.
The segment 3 studies, which are peri- and
postnatal developmental studies, are usually
performed in one species, usually the rat.
Exposure occurs from implantation to the end of
This slide summarizes Merck's
interpretation of their reproductive and
developmental data. Specifically, they denote that
the developmental toxicity seen consists of rat
skeletal anomalies which occur at maternally toxic
oral doses, those doses that either equal or exceed
400 mg/kg/day. This is a very high exposure dose.
Moreover, they determined that the
skeletal anomalies are a direct function of fetal
nutritional deficits which are the result of
reduced maternal food consumption and maternal body
weight. These factors are a function of maternal
toxicity, specifically for forestomach
inflammation, which can become progressive leading
to hyperplasia of the squamous epithelium. Merck
hypothesizes that the forestomach inflammation is
due to a local up-regulation of HMG CoA reductase
in the rat forestomach. Moreover, the rat
forestomach is an organ specific to the rat.
Humans just don't have this organ.
They believe that the histopathology is
reversible by co-administration of mevalonate. I
should note that the actual studies that show HMG
CoA reductase up-regulation were performed in
hepatocytes, not in forestomach.
Merck feels that these particular skeletal
findings are probably not clinically relevant
because they occur in a rat specific organ, as I
mentioned, and they occur at a significant exposure
multiple compared to the proposed 20 mg clinical
OTC lovastatin dose. CDER doesn't necessarily
disagree with this interpretation of these findings
that are extremely high exposures, but we believe
that this interpretation is only part of the story.
One of the differences in interpretation
of the data involves the definition of maternal
toxicity. According to Merck, maternal toxicity
occurs at an exceedingly high dose, at or above 400
mg/kg/day given to rats by oral administration, and
it results in the forestomach hyperplasia that I
mentioned. But if you actually go back and look at
the data, you find that at exposures less than this
dose--so between 100 and 400 mg/kg/day--given to
rat dams by an oral route during pregnancy, you see
that there are maternal decreases in body weight
gain of roughly 10 percent and you see decreased
Moreover, when you look at the studies
that administered lovastatin to the rats during
pregnancy by a different route, by a subcutaneous
route in order to avoid the forestomach toxicity,
you still see maternal toxicity in that you still
see maternal mortality and you also see decreased
body weight gain.
This suggested to us that perhaps a more
conservative maternal no-effect level, no
observable adverse effect level, which is what
NOAEL is, could be established at an 80 mg/kg dose
which represented about a 60-fold exposure relative
to the proposed 20 mg clinical dose.
What we did is, having established this
NOAEL effect level, we went back and reviewed the
reproductive and developmental data from 1980 and
looked to see if there were any fetal or neonatal
findings at these doses and below. What we found
was that there were fetal and neonatal findings
that were observed in fertility, embryo-fetal
studies through postnatal developmental study
designs. The results of this analysis are briefly
summarized in your briefing document. In the
interest of time, I can't go through those
specifics. But the results are summarized on the
This summarizes fetal and neonatal
findings at clinically relevant exposures. So, at
exposures in rats less than or equal to five times
the therapeutic exposure--and what I mean by
therapeutic exposure is the exposure that you would
achieve following a 20 mg clinical lovastatin
dose--you still see fetal findings. You see fetal
and pup mortality and you see fetal and pup
decreased body weights. In some of these studies
we have observed these findings at exposures
equivalent to the therapeutic exposure.
If you look at studies where higher doses
were used and greater exposures were achieved, you
begin to see the developmental delays which involve
changes in reflexes, such as the righting reflex,
the auditory startle response, and you see effects
in swimming and open field effects. You also see
some incomplete skeletal ossification.
If you go at still higher cephalosporins,
25 times, you begin to see these skeletal
malformations that I discussed previously. These
translate to increased supernumerary ribs and wavy
ribs and, in addition, you still see the incomplete
skeletal ossification. I want to emphasize that
all these findings occur in the absence of maternal
In addition to those studies, Merck has
also looked at co-administration of lovastatin in
the presence of the end products of HMG CoA
reductase, specifically, mevalonic acid
co-administration or cholesterol co-administration
with lovastatin. Our interpretation of these data
is that you do see attenuation of the more severe
fetal malformations, but you still see wavy ribs
and incomplete ossification present, and you still
see evidence of maternal toxicity. To us, the
results of these series of studies support that the
fetal toxicity is related to disruption of
cholesterol biosynthesis by lovastatin.
If I could summarize our interpretation of
these studies, it would be that fetal and neonatal
toxicity is seen in the absence of maternal
toxicity; and that the drug-related fetal and
neonatal toxicities include skeletal malformations,
mortality and developmental delays. Moreover, some
of these fetal findings occurred at exposures that
are similar to the clinical exposure, that is, the
proposed 20 mg lovastatin OTC dose. And, these
findings are potentially relevant to clinical risk
assessment. Moreover, our feeling was that the
pregnancy category designation is still valid.
A developmental no-effect level can be
established in various species, as shown on this
slide, for both rat, as you have seen, the rabbit
and the mouse. This is a level of exposure where
there are no fetal or neonatal findings observed,
and that is indicated in this column where the no
observable adverse effect level is indicated. This
exposure level is then expressed in this next
column, indicated by the safety margin column.
This exposure level is, again, expressed as a
multiple of the human exposure following a proposed
20 mg lovastatin OTC dose. The comparisons are
based on body surface area rather than actual
pharmacokinetic or AUC exposure data but they do
indicate that there is establishment of a
developmental no-effect level, which is comparable
across the species but, as you can see, the
exposure multiples are relatively low.
In 2004 Merck submitted to us new
postnatal neurodevelopmental data. This data was
actually requested by the agency to address data
gaps in the neurologic development based on
limitations in postnatal study design between the
species. For example, the major periods of
myelination occur in the rat postnatally,
specifically weeks two through four, but occur
during the second and third trimester in humans.
Our feeling and the advice of our internal
experts was that the postnatal developmental study
designs may not adequately evaluate this particular
event. Moreover, as you have seen briefly, the
prior studies had shown that developmental delays
occurred in prior postnatal studies. So, we
specifically requested a detailed
neurodevelopmental assessment and recommended
direct dosing of rats during the critical period of
neurologic development. We specified that we would
like to see evaluation of exposure, establishment
of a no-effect level, detailed brain histology, and
certainly adequate behavioral and functional
The study that we actually received in
2004 was a direct dosing neonatal rat study. The
dose selection for the higher dose tested in the
actual study was based upon a dose-range finding
study looking at acute dosing. The results of that
study suggested that at a dose of 20 mg/kg/day
there were findings such as a decrease of body
weight gain in these neonatal rats, and some
injection site alopecia and scabbing.
Based upon this, in the definitive study
the high dose was halved so that a 10 mg/kg/dose
was tested. The drug was given subcutaneously from
postnatal day 4 in these neonatal rats up to days
41 or 51, depending upon the type of evaluation
that was performed.
The results of these studies suggest to us
that there was a short-term learning retention
decrease. Specifically, there was an effect in the
passive avoidance test. Moreover, the functional
observational battery also showed an increase in
central nervous system activity in the same group.
We felt a no-effect level for this particular study
could be established at 5 mg/kg/day, which would
achieve a rough exposure of 20 times that of the
proposed clinical dose based on AUC.
I should point out that this 20-fold
sounds like a large exposure multiple relative to
the other postnatal studies that I described, but
you have to keep in mind that the study design for
this particular study is very different. This
study is a neonatal rat study in which the neonates
were directly dosed and exposures were based upon
known exposures in these neonates. In the previous
postnatal studies the mothers were the ones who
were directly dosed and so the exposures are based
upon maternal plasma exposures.
Moreover, the only way that the neonates
could be exposed in the earlier postnatal studies
would be through placental transfer--I should say
that is how the fetuses were exposed. The neonates
would be exposed only through drug that was
excreted in the milk.
So, our assessment of the new
neurodevelopmental data is that there are decreases
in short-term learning retention; increased
activity in the central nervous system, at least in
high dose females. And, these learning and
behavioral findings are consistent with the prior
postnatal evaluations. However, we felt, through
several discussions with the sponsor, that the
neurologic evaluation was somewhat minimal in that
the passive avoidance test, being the only measure
of cognitive function, was somewhat minimal. Our
reasoning for this was since various tasks could be
assisted by different neural systems a second
neurobehavioral test had been recommended,
specifically a swimming maze.
I should also point out that the
histopathology done in the study was focused on
neural tissues only. I believe it was brain,
tibial and sciatic nerves, and only in the high
dose treatment groups compared to controls.
Toxicology endpoints in other tissues were not
performed, and the neural anatomical and
biochemical evaluations according to protocol were
only going to be performed if there were lesions
that were observed in the high dose group, and
since they weren't the evaluations weren't done.
The other part of the assessment is that
the study design of this study is to evaluate acute
and not delayed developmental effects which were of
So, if I could summarize our
interpretation, although I didn't talk about this,
there is clearly an established statin mechanism of
action. The extensive developmental studies
submitted from 1980 to 2004 show consistent
findings with lovastatin exposure. These findings
include fetal mortality; decreased fetal weight;
skeletal malformations; and behavioral and learning
delays. The limited neurodevelopmental neonatal
rat study with the delayed learning effects is
consistent with the prior postnatal studies.
Some of these findings, as I mentioned,
occur in animals at exposures that are similar to
the therapeutic exposure, that is exposure that
could be achieved in humans following a 20 mg
lovastatin OTC dose. Moreover, this was reviewed
by our in-house panel of experts on the CDER
reproductive toxicology subgroup and there was
Post-marketing reports of first trimester
fetal adverse effects although, as I mentioned,
represent very limited data which results in
failure to show cause and effect, certainly don't
allay the potential concern.
If I could conclude, based upon the
extensive animal data, a potential human fetal risk
exists following exposure to lovastatin during
pregnancy in women of childbearing potential. The
contraindication of statins, including lovastatin,
during pregnancy is valid. Thank you.
DR. WOOD: Thank you very much. Merck has
asked to respond to this and, in the interest of
fairness, I think we should let them do so.
Before we get to that, and I may have been
postprandial, help me understand what the data are
in humans. You sort of alluded to that but I
didn't actually hear that data, I don't think.
DR. DAVIS-BRUNO: I didn't present that
DR. WOOD: That is why I didn't hear it!
DR. DAVIS-BRUNO: --because that is not my
expertise, although it is summarized in the
briefing document that has been presented to the
DR. WOOD: I understand that. Can you
summarize that for us?
DR. DAVIS-BRUNO: If I can get an overhead
DR. WOOD: Well, maybe while Merck is
presenting you can be thinking about that because
that is obviously key.
DR. HEMWALL: Thank you, Dr. Wood. As you
can see, this is a complicated issue. In fact, we
agree with the regulatory definition, such as it
is, that when there is no benefit to treat during
pregnancy the drug should remain labeled category
X. But I think we need to put a little perspective
on the data. Recognizing the complicated nature of
all of these different interpretations, we will
have just a few remarks by Dr. George Lankas who
supervised the conduct of most of these studies,
and then I will have some follow-up remarks after
DR. LANKAS: Hello. I am George Lankas
and I am a toxicologist at Merck, and I have been
responsible for conducting many of the studies that
were just alluded to.
As Dr. Davis-Bruno mentioned, there has
been an extensive amount of preclinical
reproductive and developmental toxicity data that
has been generated with lovastatin over the years,
and there is certainly opportunity for reasonable
scientists to disagree in the interpretation of
many of these findings. But given the potential
significance of two certainly key findings that
were just mentioned, the developmental effects on
body weight and also the fetal death, I thought
that those findings warranted closer scrutiny. So,
what I would like to do is just briefly review for
the committee the differences in the approach of
how these data are analyzed and actually show an
example of the actual data and the difference in
interpretation. So, if I could have slide 766,
This is my attempt to summarize for the
committee the differences in methodology with
respect to how these data are looked at based upon
reviewing the FDA briefing document. The FDA
method focuses on actual individual group mean
differences between treatment group data and
concurrent controls, and tends not to utilize
statistical analyses unless the statistical
analysis indicates that there is a significant p
value. The Merck method, the MRI method, relies on
a combination of looking at dose-response
relationships, that is, evidence of a dose-related
trend in the response that is under analysis, as
well as statistical significance and an evaluation
of both concurrent and historical control data.
The committee has to realize that for many of these
data there is tremendous variation in control data
in a given species. So, reliance just upon
concurrent control data can sometimes be
In addition, when there are multiple data
available from different studies on a given
endpoint, we also look at reproducibility of those
findings as further evidence or confirmation of
whether there is a treatment-related effect.
On this slide I would like to summarize
the FDA's analysis of the data as indicated in the
briefing document that was supplied by FDA. This
is characterized by FDA's study number 2. This was
a rat study in which dosages of 2, 20 or 200
mg/kg/day were administered to rats, beginning 15
days prior to mating and then throughout mating and
then throughout the gestation period until
gestation day 20.
These are the doses here. The FDA's
review indicated that these are the exposure
multiples relative to the OTC dose of 20 mg. The
check mark indicates that there were findings that
were delineated by FDA as being drug related. Note
that at the highest dose there is nothing indicated
as being drug related, but at 20 mg, the mid-dose
group, there were findings of fetal death as well
as decreases in fetal body weight.
This slide actually shows the data on
which this interpretation is based. So, these are
the various groups in the study, control through
high dose, and these are the number of dead pups
that were evidenced in this study by control group.
You can look at the total number of pups across the
groups. It is a relatively high number. You will
note that there is really no evidence of any
dose-related effect when you look at the concurrent
control through the high dose of 200 mg/kg/day.
Just to add perspective, this is roughly 25- to
30-fold based on exposure multiples, the proposed
20 mg OTC dose. So, this would be characterized as
a relatively high dose.
So, the findings of fetal death are really
based upon a finding in the mid-dose of 20, which
is really due to the findings from one litter. One
dam lost the entire litter, almost the entire
litter, 8/14 pups. So, in our view, this does not
rise to the level of a drug-related effect and we
would discount this one litter as being evidence of
a treatment-related finding, particularly when
there was nothing in the high-dose group.
Similarly, if we look at the effects on
fetal body weight in these various treatment groups
by time--PND stands for postnatal day, these are
the days after birth on which these measurements
were taken. Please note that the statistical
analysis shows absolutely no evidence of any
statistically significant effect. I believe that
the effect that is being noted as possibly being
evidence of a drug-related effect is on postnatal
day zero or postnatal day seven, a period which
really doesn't indicate any evidence of trend with
respect to dose response.
So, our conclusion is that there was no
evidence of a drug-related effect on mortality or
on postnatal body weight not only in the 20 mg
group but the other treatment groups as well.
This is an attempt to summarize for the
committee what animal findings look like with
respect to other over-the-counter products and also
another lipid-lowering agent that is currently
prescription, fenofibrate. So, if we look at
cimetidine, fenofibrate, epinephrine--this is
actually ephedrine, and ibuprofin relative to
lovastatin and we look at the effect on these
various endpoints and look at the lowest effect
level, that is, the lowest dose at which the
reported effect has been observed, and then compare
that to the animal relative to the human dose
ratio, if this ratio is less than one it indicates
that there is absolutely no evidence of a safety
margin relative to the human recommended dosage.
So, for these various agents you can see that the
safety margins for lovastatin are well in line or
exceed the margins for these other products.
So, it is our conclusion, our firm
conclusion that the findings that are noted with
lovastatin are non-specific findings, not
indicative of a direct fetal toxic or teratogenic
effect and that lovastatin certainly has an
adequate safety margin relative to other
DR. HEMWALL: We do have just a little bit
more here. I want to put this in some perspective.
First of all, my conclusion is that these studies
are really complicated and it is tough to ask the
committee to make some kind of judgment on what
they just saw, but I want to try to put this into a
little bit more context.
Let's go back to the pregnancy categories
that we were looking at and the definitions, and
let's remember--let's have the first slide--
--that our position is that lovastatin is
not a teratogen. There are certainly some findings
in animal studies that put it in a situation where
it has to be judged to either be category C or
category X, and it has been put into category X
because of the fact that the fetal risk that is
seen is enough to outweigh possible benefit, and we
have all established that we agree that there is no
benefit to treating a woman with a lipid-lowering
drug during the period of pregnancy. The very fact
that there are other drugs that have very similar
findings but are listed category C is because they
do have benefit. Drugs used in diabetes; drugs
used in asthma; drugs used in hypersecretory
conditions are all category C with very similar
findings, but that is because they have benefit
when given to a mother and a doctor is asked to
make that decision as to whether or not the risk
outweighs the benefit, and they are called category
C. In fact, a heartburn drug approved by NDAC just
a couple of years ago has a category C label with
animal findings and even sporadic reports of fetal
abnormalities in human exposures. Next slide,
But let's take a look at what the human
exposures actually are. These are numbers from the
IMS database that show the number of women of
childbearing age that have been prescribed
lovastatin. To be exact, it is the number of
prescriptions that have gone to women of
Let's just look at 2004, and you can see
the numbers are increasing. About 19 million
prescriptions were written in 2004 for a statin.
Of these, about 100,000 were women of 21-30 years;
480,000 were prescriptions for women of 31-40
years; and the numbers start to rise dramatically
as you get into the older age group but still
technically of childbearing age. Over two million
prescriptions were written for statins for women of
childbearing age in 2004, and there is a cumulative
number of prescriptions obviously written over the
years. Next slide, please.
In our own database we have, as you have
heard many times and will remember it after today,
the 27 million patient-years of exposure. We do
have 105 reports of pregnancy in our WAES database.
The majority of these are in the first trimester.
There are 67 cases where the actual report is
prospective. That means that we got the report
before the pregnancy went to term so we were able
to follow the pregnancy--or the reporter was able
to follow the pregnancy to term. Then, 38 reports
were retrospective. That is, once an anomaly was
found, often these reports come in and they are
more commonly seen. So, in those 38 reports we do
have 7 congenital abnormalities, and the specific
pattern of defects in those reports is very
diffuse. There is no pattern which would suggest
something is going on that would be representing a
mechanistic cause. Next slide.
So, our conclusions are that the reported
experience with lovastatin exposure during
pregnancy is limited, and that is because of the
labeling and that is appropriate and we would want
to reinforce that message in anything we do with an
OTC product to minimize the potential for women of
childbearing age to actually use the product. And,
there is no evidence that exposure during early
pregnancy is associated with any specific pattern
of congenial abnormalities when they do appear.
Also, just to take a quote directly out of
your background package that the FDA provided to
you, in their Office of Drug Safety Review: A
causal association between in utero statin exposure
and identified birth defects cannot be made based
on the current information. So, we are not talking
about a teratogen. This is not thalidomide; this
is not Accutane where true fetal toxicity is known.
We are talking about a drug that has a signal that
is consistent with a category C drug but, simply,
the history has been that there is no benefit for
treating women during pregnancy so, by definition
of the categories, that puts them in category X.
This is also looked at in a computerized,
well recognized teratogenic tracking system, called
the TERIS database. We have provided the actual
printout from the TERIS database to everybody at
the table here. This is something that accumulates
all the animal data and all the human data and puts
it into a computer-based system, and then it is
reviewed and there is consensus by a group of
clinical toxicologists. They group them into three
broad categories, either no risk, minimal risk or
unlikely, a small risk or risk undetermined. Next
In the TERIS database, and you can read it
in the handout you have, lovastatin is listed among
only 6.4 percent of drugs which are actually listed
as unlikely to pose teratogenic risk in human
pregnancy. About 90 percent of the drugs have not
enough information. They have actually viewed that
the lovastatin information is enough to support
that conclusion. They have also noted that the
non-minimal or unlikely category is equivalent to
the FDA use of the pregnancy category A or B. Last
So, just in summary, it is labeled
category X because of the lack of clinical benefit
and the potential risk that we have seen from these
animal studies. We are not disputing that there
are findings, and we can have our dueling experts
going back and forth about which is the level and
which is not the level, but there are findings that
are consistent with category C. There is no
evidence that we have seen in our databases that
exposure during early pregnancy is associated with
increased risk of any specific congenital anomaly,
and the TERIS database supports this, listing it as
unlikely. That is why we believe that the risk to
a mother who has an inadvertent exposure, however
much we try to minimize the frequency of that
event, is very low, especially compared to the
overall benefit to the large population of people
that should be getting this drug, lowering their
cholesterol and lowering their risk of
DR. WOOD: Karen, do you want to say
anything in addition to that?
DR. DAVIS-BRUNO: To address the Chair's
question about what the actual findings were in
those limited human experiences, this table that I
am going to present is also in your briefing
DR. WOOD: That is fine. Just tell us
where it is and then keep going.
DR. DAVIS-BRUNO: It is at Tab 4, around
page 4 or page 3, in the beginning of my review.
DR. WOOD: Okay, keep going.
DR. DAVIS-BRUNO: Well, I am done with my
presentation, unless you want to entertain
DR. WOOD: Let's keep the questions until
the end and let's go straight on to the next
presentation, which is from Capt. Laura Shay.
Label Comprehension Study
CAPT. SHAY: Well, good afternoon.
This is switching gears quite a bit from
the last talk. My name is Capt. Laura Shay. I am
a consumer safety officer for the Division of
Over-the Counter Drug Products.
The purpose of my presentation this
afternoon is to provide a summary of my review of
the pivotal label comprehension study for Mevacor
OTC. First, I will provide a description of
basically what label comprehension studies are;
followed by a description of the Mevacor study
design. Finally, I will provide a summary of the
The purpose of a label comprehension study
is to evaluate whether or not consumers can
comprehend important communication objectives on
the label. It is important that both literate and
low literate populations are evaluated, and that a
diverse population is evaluated that is
representative of the United States population.
Generally, label comprehension studies are
performed prior to the behavioral or actual use
study. This is in order to optimize the label
before placing it into a naturalistic setting. It
is important to note that low comprehension may be
predictive of poor results in the actual use
setting. However, as has been mentioned
previously, high comprehension does not necessarily
guaranty success in the actual use setting.
For the pivotal label comprehension study
the primary objective was to evaluate consumer
comprehension of the label used in the CUSTOM
actual use study.
Secondary objectives included were to
determine how well respondents correctly respond to
questions designed to try to measure
self-selection; to evaluate low literacy
respondents; and to evaluate non-Caucasian
The key communication objectives are
provided in your FDA background package under Tab
6, page 1. But I will provide more detail on them
as I present the results of the study.
It is important to note that in the Code
of Federal Regulations an OTC label must be likely
to be read and understood by the ordinary
individual, including individuals of low
comprehension, under customary conditions of
purchase and use.
So, how do we assess comprehension? There
is no defined numerical value for acceptable
comprehension. Ideally, we would like everyone to
understand everything on the label 100 percent.
However, realistically we understand this concept
is not possible. However, the more clinically
significant a communication objective is, the close
to 100 percent comprehension is desired. For
example, for the consumer's ability to understand
that they need to stop Mevacor OTC if they
experience unexplained muscle pain, we would like
to see high comprehension. For other communication
objectives we might accept a lower score. A good
comparison would be a driver's manual. After
someone reads a driver's manual you can test them
on their comprehension of the manual, and you would
like to see comprehension for understanding the
need to stop a car at a red light. If someone
doesn't comprehend well the need that you need to
park at least 10 ft from a fire hydrant and not 8
ft, this would not be viewed at the same level of
importance as the red light. In the process of
developing and testing a label judgments have to be
made on the areas that need to be fixed and what
areas can be left alone, even if they are not even
close to 100 percent.
Everyone at this point I think is familiar
with the label. This is the principal display
panel that was tested and also used in the CUSTOM
This is the drug facts label.
The study design was as follows:
Recruitment was done when subjects were selected if
they were found to be cholesterol-concerned
respondents. They were shown a concept board and
they were asked if they were interested in lowering
their cholesterol. If they were concerned or would
like to lower their cholesterol, they were asked to
participate in the study. And, they were paid
$20-$25 for participating and essentially to cover
the cost of their time.
The study was conducted in 25 shopping
malls across the country in a very diverse
The total number of study cohorts was 696.
Of those, 203 tested at low literacy. The
definition for testing at low literacy--and they
used the REALM test which also was mentioned. That
stands for the Rapid Estimate of Adult Literacy in
Medicine test. That is if they test less than or
equal to an 8th grade reading level. And, 493 were
considered adequately literate; 207 were
non-Caucasian; and 489 were Caucasian.
The gender breakdown, 44 percent were
male. Of the males, 51 percent were greater than
or equal to age 45, which is the target population
for this product, and 56 percent were female and 35
percent of those were greater than or equal to age
55, the target population for this product.
The questionnaire design was testing one
label. They used structured interviews, and the
respondent was allowed to refer to the label
throughout the study. The questions were primarily
multiple choice, and there were many scenarios used
in order to test key communication objectives and
to test decision-making ability based on
information found on the label.
An example of one of the scenarios is one
for unexplained muscle pain: Diane has been taking
Mevacor OTC for several weeks. She didn't do any
unusual physical activity and isn't feeling sick,
but she has started to feel pain in her leg
On the drug facts label there are two
areas that explain to consumers what they should do
if they develop unexplained muscle pain. Under
warnings it states "stop use and ask your doctor.
If you develop any unexplained muscle pain,
weakness or tenderness stop immediately. This can
be a sign of a rare but serious side effect."
Under directions, it is also stated a
second time. Unexplained muscle pain--:stop using
immediately and talk to your doctor if you develop
unexplained muscle pain, weakness or tenderness.
This can be a sign of a rare but serious side
According to the protocol, the answer
definitions were as follows, a correct answer would
be if a respondent's answer adhered to the label.
An acceptable answer is if a respondent's answer
did not specifically adhere to the label but would
not pose a safety risk.
The answer selection for the unexplained
muscle pain is the following, the choices they had
and the results are going to be listed right now:
They were told to stop using the drug. Must talk
to a doctor. That was considered correct. They
could select continue to use but must talk to a
doctor. This was considered acceptable. Stop
using; does not need to talk to a doctor--also
acceptable. Continue to use and does not need to
talk to a doctor--incorrect. And don't know would
be considered incorrect.
The breakdown of the scenario results
according to correct--and that would be, again,
just strictly adhering to the label, the results
were between 74-81 percent. When acceptable
answers were factored in the results were 98-99
Another scenario is for liver disease.
Barbara has liver disease.
On the drug facts label the issue of liver
disease is under one area in the warning section
and it states liver disease--"do not use if you
have liver disease."
The answer options for this
scenarios--this person should not use at
all--correct. Before using, this person needs to
talk to a doctor--acceptable. This person could
start using right away--incorrect; And, again,
don't know is considered incorrect.
The results of this scenario, for the
correct answers, adhering to the label, the range
was 65-71 percent. When acceptable was factored in
the range was 99-100 percent.
I will now present the study results.
There was little difference between the cohorts of
the low literacy, normal literacy, Caucasian and
non-Caucasian. Therefore, I will present only the
total representative sample, and I will only
present the correct answers, which were those
answers in which respondents strictly adhered to
Ninety-nine percent understood what the
product was used for; 99 percent, dosage and dosing
information; 95 percent, the need to consult with a
healthcare professional prior to use if on a
prescription drug. Ninety-two percent understood
the active ingredient; 87 percent, time frame for
cholesterol testing. Eighty-six percent understood
the need to have diet and exercise before taking
the medication; 82 percent, that evening was the
best time of day for dosing; and 78 percent, the
need to fast before cholesterol testing; and 50
percent, that the cholesterol will go up if Mevacor
OTC is stopped.
The percent of correct answers according
to the label for scenarios that indicate the need
to stop Mevacor OTC with multiple scenarios and the
range of correct answers were 47-90 percent. Of
most clinical significance was the unexplained
muscle pain at 79 percent.
The percent of correct answers according
to the label for self-selection scenarios was a
range of 37-81 percent, with an average of 54
percent. Of most clinical significance, allergy to
lovastatin 72 percent; and in the scenario they
listed a prior history of muscle pain on
cholesterol-lowering medicine and the correct
answer for that according to label for that was 42
The percent of correct answers according
to label listed under the warning section of the
label, "do not use if...," 74 percent for
pregnancy; 77 percent for breast feeding; 69
percent for liver disease.
The percent of correct answers for false
positives--and what these were was the sponsor did
a nice job of integrating scenarios that may not
necessarily be on the label but forced the
responder to have to think in a decision-making
manner, sort of common scenarios such as if you
developed a cold, you were taking Tums for
indigestion, you have poison ivy, you have gas from
food or constipation. The correct answers
according to label, the range was 64-72 percent.
Again if acceptable was factored in the range was
Self-selection was also looked at.
Respondents were asked if they could start Mevacor
OTC today. This was after they had a period of
time to look at the label and it was asked at the
very beginning of the study. This answer was then
compared to the self-reported medical history
questions and demographic data in order to validate
if the response was correct.
Of the 696 total respondents or total
representative sample, 461 reported that they could
not start Mevacor OTC today; 209 reported that they
could start Mevacor OTC today; and 26 respondents
The results, of the 461 that responded
that they could not start today, 100 percent of
them were correct. All 461 had a contraindication
on the label that they discussed in their
self-reported medical history. Out of the 209
respondents who reported they could start Mevacor
OTC today, three, or one percent, self-selected
correctly according to the label criteria. That
brings a total of 67 percent, or 464 out of the 696
total respondents that self-selected correctly
according to the label.
In summary, this was a well-designed study
in that it covered a diverse population and
included non-Caucasian and low literate subjects.
The questions were non-leading and well
constructed. And, the study was able to
distinguish varied levels of comprehension.
The areas of clinical significance that
adhered to the label strictly, for unexplained
muscle pain 70 percent; for breast feeding 77
percent; for pregnancy 74 percent; allergy to
lovastatin 72 percent; liver disease 69 percent;
and explained muscle pain 47 percent.
This point of unexplained muscle pain is
not a clinically significant issue but it does
point to the fact that respondents had a difficult
time understanding the difference between explained
and unexplained muscle pain. Although, again, not
clinically significant in that we would rather see
someone stop and ask a doctor if they are
uncertain, it does point to the complexity of this
label in that it attempts to convey medical
information to the consumer that is more
complicated than what is seen in current OTC
In summary of the self-selection, the
total number who self-selected correctly according
to the label was 67 percent or 464. Of those who
said they could start Mevacor OTC today, one
percent or 3 out of 209.
Now, the issue of correct versus
acceptable, when acceptable answers were factored
in the answers increased most scores to greater
than 90 percent. In some situations factoring in
acceptable responses could actually be considered
correct if these issues or scenarios fell under the
sub bulletin in the label that states do not use;
ask a doctor of pharmacist, or under the sub bullet
do not use unless directed by your doctor.
However, the acceptable answers often contained
"ask the doctor" even when not indicated to do so
on the label. It is important to note that
respondents often had a greater than or equal to 50
percent chance, or a three out of five chance of
selecting either a correct or an acceptable answer.
The sponsor chose to use both correct and
acceptable answers to assess comprehension of this
label. This method potentially creates an
elevation of the scores, resulting in an
overestimate of a consumer's ability to comprehend
the label. Should the acceptable answers that
contain "ask a doctor," even when not directed to
do so on the label, be factored in? Did they truly
assess the ability to comprehend the label or are
they attempting to predict the behavior? Did the
respondents choose an answer that contains "ask the
doctor" rather than the answer "I don't know"
because it was more comfortable? These are
important questions to ponder.
Again, it is important to remember that
the label comprehension study cannot predict
consumer behavior. Even labels with high test
scores for comprehension can do poorly in the
actual use setting. As previously described, this
label was tested in the CUSTOM actual use study. A
review of this study will now be presented by Dr.
DR. WOOD: Just before you leave, on page
two of your briefing document and also on your
slides you get to the total number who answer a
question correctly by adding the numbers who
couldn't start with the numbers who could start
and, it seems to me these are not equal questions.
So, getting the question wrong that you could not
start and, therefore, not starting is a quite
different outcome from getting the question wrong
that you could start and starting. And, only one
percent of the people who could start got the
question right whereas a large number who could not
start got the question right and that is what gives
you this 67 percent answer. So, it seems to me,
that is like asking people if it is all right to
jump out of the plane and the people who did jump
out of the plane, only one percent of them got it
right because they had the parachute on--
--and, you know, the ones who said it
wasn't time to jump out of the plane, all of them
got it right so that was all right, we will just
add the two together. Well, I am not so sure that
is right. So, could you comment on that? I mean,
that seems to me an extraordinary addition to make.
CAPT. SHAY: You want me to comment on
DR. WOOD: Yes, please. I mean, only one
percent of the people who jumped out of the plane
got it right.
CAPT. SHAY: True, but I think it is
important to look at the entire balance and, in all
fairness, when a person goes and selects a product
you also want to make sure that they are not
selecting appropriately if they shouldn't. So, we
always factor that into the whole decision-making
process. But I agree with your scenario in that of
the 209 who did self-select correctly and the one
percent, or three, that got it right--that is of
DR. WOOD: So, I am reading that right?
DR. GANLEY: Alastair, could I just add to
that a little bit?
DR. WOOD: Sure.
DR. GANLEY: I think the analogous
situation is when you look at the actual use study
and you have the purchasers and non-purchasers.
Those non-purchasers, they did have to make a
decision whether to select to use the product and
they chose not to use it for various reasons. And,
many of the answers there were correct answers.
So, you can't really ignore that.
DR. WOOD: No, I am not ignoring it.
DR. GANLEY: That is why we have broken it
up like that and not just given you 67 percent.
DR. WOOD: But I just wanted everybody to
be sure they understood where that 67 percent came
from. Let's move along to the next talk.
CUSTOM - Actual Use Study
DR. SHETTY: Good afternoon.
My name is Daiva Shetty. I am a medical
officer in the Division of Over-the-Counter Drug
My presentation today will briefly cover
some aspects of actual use studies; actual use
issues that are important to address for Mevacor
over-the-counter marketing; and the results of the
actual use study submitted to support the
prescription to over-the-counter switch of Mevacor.
My presentation and the results will focus on the
analyses that strictly adhere to the label
This morning Merck presented multiple
analyses that looked at ways to view the data.
Some of them were prespecified and some of them
were not prespecified. Most of them assess data
from the benefit to the population point of view.
Before presenting data from the CUSTOM
study, I would like to mention a few words about
actual use studies in general. Actual use studies
attempt to simulate over-the-counter use.
Recruitment is usually done through print and
broadcast media directed toward the general
over-the-counter population targeted for use of the
drug. Study sites are usually located in areas
where consumers would seek to purchase
over-the-counter medications, such as pharmacies
and grocery stores. The studies have very few
exclusion criteria and ideally should not have
recruitment pre-screening and minimum interactions
between the participants and the study personnel.
As much as they try to mimic over-the-counter use,
these studies are not perfect. There are
procedures, such as informed consent, information
gathering and diaries that always involve
interactions between the subjects and the study
personnel, and participants usually are compensated
for their participation in those studies.
The objectives of an actual use study
depend on the specific product and concerns related
to that product, such as self-diagnosis, which
refers to a consumer's ability to diagnose the
condition for which the over-the-counter product is
indicated; self-selection, which refers to a
consumer decision to use the drug or not to use it.
De-selection refers to a consumer's decision to
stop using the drug in cases such as not achieving
a benefit or development of an adverse reaction to
the drug. They also assess compliance, the dosing
and duration of use; off-label use; safety and
sometimes efficacy in over-the-counter use
In the actual use study there are several
important behavioral issues for the nonprescription
Mevacor marketing. First of all, are consumers
able to self-diagnose hypercholesterolemia? Did
they know their own cholesterol values? And, did
they understand serum cholesterol values? Are they
able to identify risk factors for coronary heart
disease? And, do they understand how many of those
risk factors they should have or should not have to
qualify for the treatment? Are consumers able to
self-select appropriately based on the label
eligibility and the contraindications for use?
Are consumers able to self-treat
hypercholesterolemia? Are they able to follow
label directions for dosing and duration of use?
Do they follow directions for when to get follow-up
cholesterol tests or when to see a physician? Do
they understand the treatment goal? And, are they
able to identify risks during therapy and
de-select? For example if they develop muscle pain
or start new medication that may have a drug
interaction with Mevacor, or do not achieve goal
cholesterol levels, would they stop using the
Now I will switch my presentation to the
data of the actual use study submitted to support
this application. The study, as you have already
heard, was called CUSTOM, Consumer Use Study of OTC
I will start from the label used in the
CUSTOM study and tested in the label comprehension
study which is identical to the proposed label for
over-the-counter marketing. According to the
proposed label, there are four conditions that
determine correctness of the self-selection. The
order that consumers have to go through in their
thought process when looking at the label is as
follows: To be eligible for treatment with
Mevacor, the consumer must be a man at least 45
years of age or a woman at least 55 years of age;
must have LDL cholesterol between 130-170 mg/dL;
must have at least one of the following risk
factors for coronary heart disease, smoking, low
HDL cholesterol, family history of coronary heart
disease or high blood pressure, and also must be
free of conditions that may put him or her at
increased risk from using the product.
The study did not evaluate self-selection
as the primary endpoint. Rather, it assessed the
decision to purchase Mevacor. It is obvious that
purchasing the product can be construed as
self-selecting a product. A total of 3316 subjects
participated in the decision to purchase Mevacor
and 1205 decided to buy the product and 2111 did
not. The majority of both those who purchased and
those who did not purchase stated that they needed
more information to make a decision to buy or to
use the product. The most common reason among
purchasers needing more information was to obtain
their cholesterol numbers. Non-purchasers commonly
cited a need for personal health information or to
talk to a physician. The reasons for not
purchasing the product were evaluated. We believe
that the majority of non-purchasers may have made a
correct decision not to use the product.
In the next few slides I will show the
self-selection decision results based on the four
previously mentioned label criteria, age,
cholesterol levels, risk factors and the warnings
listed on the label. It does not include the
physician override concept. Since the raw data
were submitted late into the review process, the
numbers I will present today will differ a little
bit from what you have in your background packages.
There were a total of 1061 subjects in the
study who not only purchased but also used the
product. Two were excluded because of protocol
violations. Of all the users, 797 subjects met the
age criteria. That means that they were men at
least 45 years of age or women at least 55 years of
age. Of those who met the age criteria, 281 had
LDL cholesterol levels between 130-170. Of these,
206 had at least one risk factor for coronary heart
disease. The majority of them were men. Only 69,
out of 430 women were in this group meeting the
first three labeled criteria.
A further three subjects with underlying
liver disease, which is contraindicated in the
contraindications for use, were excluded and 18
subjects with a history of muscle pain or weakness
from using statins, and we are left with 185
Then, there were 22 subjects who had only
one risk factor for coronary heart disease, in
addition to age, and a high HDL level above 60
which did not qualify them for treatment. Finally,
there were 53 users with high triglyceride levels,
over 200. The final numbers of correct
self-selection according to the strict label
eligibility criteria were 110 users, 33 women and
77 men, which is 10 percent of all the user
population. This does not include the physician
It is important to look at the
demographics of the users. Among the 1061 subjects
who purchased and used the drug, there were 430
women. Of the 430 women who used the drug, 37.4
percent were less than 55 years of age, below the
targeted age by the label. The breakdown of women
users by age was as follows: 11 percent were less
than 45 and another 26 percent were between 45-54.
The actual use study suggests that women
of childbearing potential may select to use the
product. Over 20 percent of all women users were
less than 50 years of age. Consequently, because
during the first trimester of pregnancy women may
not realize that they are pregnant, it is important
to understand the risk to the fetus if women of
childbearing potential are going to use the product
in an over-the-counter setting and determine what
mechanisms could decrease that risk.
Now I would like to show the study results
on whether the users knew their LDL cholesterol
value at the time of purchase. The knowledge of
cholesterol value becomes important in an
over-the-counter setting especially if there is not
access to testing.
The rows in this table represent user
self-reported cholesterol values and the columns
show the results of LDL cholesterol at baseline.
Highlighted in yellow are the numbers of subjects
who knew and correctly identified their LDL
cholesterol. Around two-thirds of those who
thought they knew their LDL cholesterol correctly
identified it. It comprises 47.7 of all user
It is important to note that over a third
of all users did not know their LDL cholesterol
value or their values were missing. Given that the
label states that you should know your cholesterol,
why would these subjects purchase Mevacor without
knowing their cholesterol? There could be two
reasons. First, they could get a physician
override, and I don't have data on which of those
318 plus 27 subjects consulted their physician.
Or, they could have purchased a test at the site.
Everybody in the study had an opportunity to buy a
test at the time of purchase. However, out of 318
who did not know their cholesterol, 67 decided to
buy a cholesterol test on site in order to find out
Another important fact that could be
learned from this table is that a significant
number of users had a baseline LDL cholesterol
below the targeted level. That means that they may
not need to be treated. Even though the
correlation between the self-reported and measured
LDL cholesterol values was high in the subgroup, 87
out of 122, knowing that their cholesterol is low,
chose to use Mevacor; 168 out of 265 subjects who
had higher than targeted LDL cholesterol also
incorrectly chose to use Mevacor.
This is the summary of consumer knowledge
of their LDL cholesterol values based on the data
from the previous table, 30 percent of the users
did not know their LDL cholesterol and chose to use
product; 47 percent of all users actually correctly
identified their LDL cholesterol value; 71 percent
of users who correctly identified their cholesterol
is less than 130 chose to use Mevacor; and 75
percent of those who correctly identified their
cholesterol above 170 also chose to use Mevacor.
The sponsor analyzed the self-selection in
more than one way. One of those self-selection
assessments was based on the number of risk factors
for coronary heart disease, ignoring whether the
user cholesterol values were within the labeled
range of 130-170. The results of this study showed
that 42.7 percent of users did not have at least
two risk factors and used the product even though
they did not meet the label criteria.
Now I would like to explain how the
sponsor assessed the correctness of self-selection
and why our results are so different. The original
definition in the study protocol defined correct
self-selection as according to label, or AL, which
represented a decision that is entirely consistent
with the product label. Or, if not according to
label, the consumer achieves LDL cholesterol goal
after six weeks of treatment.
In the middle of the ongoing study the
sponsor redefined the categories and the major
difference that was introduced for assessment of
self-selection is the physician override concept,
which means that if a consumer failed
self-selection for any reason but stated that their
physician approved the use of Mevacor, they were
classified as correct self-selectors.
There is nothing wrong if people consult
their physicians to make a better decision for
self-treatment, however, in this study the contact
with a physician or the information discussed was
not verified and we don't know why the majority of
users in the study failed the label criteria and
were approved by their physicians despite the risks
or no benefits for the treatment.
The sponsor also introduced two additional
categories for assessment of correctness of
self-selection. The first one was called "closely
adhered to the label" and included users who did
not meet one or more of the criteria for age, risk
factor profile, and had LDL and HDL values outside
the targeted range for treatment. But because they
knew their lipid profile; did not have elevated
triglycerides; did not substitute Mevacor for their
prescription lipid-lowering medication; and did not
have diabetes, heart disease or stroke, they all
were assessed as correct self-selectors.
In addition, the sponsor reevaluated
subjects who failed the previously mentioned
definition, "closely adhered to label" benefit
criteria, and looked at the subject's 10-year risk
profile for myocardial infarction or coronary
death. This approach allowed them to reclassify
the users who failed self-selection according to
the label if they did not know their lipid profile,
if they had elevated triglycerides, substituted
Mevacor for their prescription lipid-lowering
medication, or had diabetes, heart disease or
stroke but were eligible for study therapy by ATP
III guidelines based on the calculated more than 10
percent 10-year risk for myocardial infarction of
These are the sponsor's results of the
correct self-selection, 484 self-selected correctly
according to the label or medically acceptable for
self-management definition; 68 of those
self-selected on their own without a physician's
input. An additional 202 subjects who closely
adhered to the label were added to the correct
self-selection group. Finally, the sponsor states
that although 357 did not adhere to the label
benefit criteria, 258 of this cohort were eligible
for statin therapy by ATP III guidelines, thus
raising the correct self-selection rate to 89
percent or 944 subjects.
These analyses are not based on subject
self-selection decision but, rather, on the
retrospective analysis of their baseline
characteristics. When consumers are picking up the
package from the shelf they should be able to make
the right decision by reading the label.
There are several relative
contraindications for the use of Mevacor listed on
the proposed label. Of the 1061 users, 55.5
percent had at least one or more contraindication
specified on the label. In addition, 2.2 percent
subjects' data was not known due to missing
information. This brings the number to 42.3
percent of users who did not have any relative
contraindications for using Mevacor. The majority
of those users with relative contraindications were
classified by the sponsor as correct self-selectors
because they stated that they spoke to their
physician. Even if we assume that some
participants in fact discussed their particular
risk condition with their personal physician, a
significant proportion of users with those
contraindications remain who did not get physician
A listing of these non-clearance users is
shown on this slide and 37.5 percent of those who
substituted prescription lipid-lowering medication
with OTC Mevacor did not consult the use of Mevacor
with their physician; 64.5 percent of those with
high LDL or high triglyceride levels used Mevacor
without physician clearance; 37.5 percent of those
taking potentially interacting drugs; 41 percent of
diabetes; 41.5 percent of subjects with coronary
heart disease; 51.6 percent with a history of
stroke; and 61.6 percent of subjects with a history
of previous muscle pain while taking statins also
used Mevacor without consulting with their
Another consumer behavior aspect that was
assessed in the study is the self-management or
compliance with treatment and de-selection. Over
the next two slides I will show you how users in
the CUSTOM study behaved after the initiation of
Thirty-seven percent, or 393 subjects did
not get any follow-up cholesterol test after they
started using Mevacor, and the majority of them,
277, continued therapy; 63 percent, or 666, had at
least one follow-up cholesterol test.
Of those who had at least one follow-up
cholesterol test, 7 discontinued the treatment and
659 continued on therapy. Of those who continued
on therapy, 375 were at goal for LDL cholesterol
goal on their follow-up test; 160 subjects were not
compliant with their label treatment because they
were not at goal, and their cholesterol was above
130 or their follow-up cholesterol values were
missing and they continued on therapy. The rest
complied with the label treatment criteria
according to the sponsor because they either
continued with physician override or discontinued
because they were not at goal.
By the end of the six-month study a lipid
test was not optional but required by the protocol.
There were 548 subjects among the 878 tested with
LDL cholesterol below 130 mg/dL. However of those,
160 subjects had LDL cholesterol less than 130 at
baseline and for 39 subjects baseline LDL
cholesterol values were unknown. So, we don't know
what benefit, if any, these 199 subjects received
from the therapy. There were 349 with LDL
cholesterol values above 130 at baseline who
achieved goal by the end of six months of the
Since there were some questions about the
compliance and how consumers in the study complied
with the treatment, I want to mention that the
median number of tablets that the users purchases
in the study was 122, which is approximately a
four-month supply for the treatment.
Despite many self-selection errors, there
were no safety signals reported during the study
and 17 percent of all users reported at least one
drug-related adverse experience and only one of
those was assessed as a serious event. That was an
allergic reaction to lovastatin. No other serious
drug-related adverse events were observed during
In summary, based on the information I
have presented, the actual use study showed that
the majority of the participants, those who
purchased and those who did not purchase Mevacor,
needed more information to make a decision.
Although approximately one-half of the users
correctly identified their LDL cholesterol,
approximately one-third of all users did not know
their LDL cholesterol values and chose to use
There were some self-selection errors and
37 percent of women users were less than 55 years
of age; 26 percent of users met the age and
baseline LDL cholesterol range; 19 percent of users
met the age, LDL cholesterol and the risk factor
for coronary heart disease criteria. Based on our
assessment 10 percent of all users self-selected
correctly by the strict label eligibility criteria
without a physician override. It is not clear
whether the complicated paradigm of treatment of
high cholesterol, or the label used in the study,
or both led to such poor self-selection results.
Forty-two percent of the users did not
meet the label eligibility criteria for the number
of risk factors for coronary heart disease. More
than half of the users had at least one relative
contraindication for the treatment with Mevacor.
There was relatively good compliance with
follow-up cholesterol tests, 63 percent; 35.6
percent of users achieved the target LDL
cholesterol goal of less than 130 at follow-up
testing. Data was not presented, as the sponsor
already mentioned--those who used Mevacor had
lowered their cholesterol approximately 21 percent
and 25 percent lowering in those who had fasting
cholesterol values. Even though testing at the end
of six months showed that over half of all users
had LDL cholesterol less than 130, one-third of
them started at a level below 130 or their baseline
values were missing.
There were no serious safety signals
observed during the study, but if Mevacor becomes
available over-the-counter, based on the study
results, it is likely to be used by women of
childbearing potential, consumers with
contraindicated conditions, consumers with no risk
or low risk for coronary heart disease, and
consumers at high risk for coronary heart disease
who can potentially be under-treated. This ends my
presentation. Thank you for your attention.
DR. WOOD: Thank you very much. Let's
take a break.
DR. WOOD: Dr. Koenig will now talk about
simvastatin use in the United Kingdom.
Nonprescription Simvastatin in the United Kingdom
DR. KOENIG: Good afternoon.
I am Michael Koenig, an interdisciplinary
scientist in the Division of Over-the-Counter Drug
Over the next 15 minutes or so I am going
to be providing some additional information about
what you have heard referred to earlier today as
OTC simvastatin in the United Kingdom. This is
currently the only statin available without a
prescription anywhere in the world. Simvastatin in
10 mg tablets has been marketed in the United
Kingdom as Zocor Heart-Pro since July of last year,
just a little under six months.
The information that I will be presenting
comes from the Internet and has been vetted by
colleagues at the British Medicines and Healthcare
Products Regulatory Agency.
My presentation can be divided into three
parts. First, I will describe how medicines are
classified in the United Kingdom. Second, I will
outline the process by which medicines can be
reclassified or switched between classes, which is
the process that we are going through here today.
This is part of that same type of process. Third,
I will bring up some of the issues that were
considered in the United Kingdom in considering
specifically the switch of simvastatin from
prescription to nonprescription status.
As in the United States, medicines in the
United Kingdom can be broadly classified into two
categories, prescription and nonprescription.
Prescription medicines are also known as
prescription only medicines, or POM medicines, and
they are in this class because of safety concerns.
The British feel that the medicines in the
prescription only medicine class present a direct
or indirect danger to human health if they are not
used under a doctor's supervision. Additionally,
these medicines may contain a substance or
substances requiring further investigation or they
require injection. All new medicines, and by that
I really mean all new chemical entity-containing
medicines, are initially placed in this class,
prescription only medicines.
Unlike in the United States, the
nonprescription classification of medicines can be
further broken down into two different subclasses.
The first of these that I am going to talk about
are those in the pharmacy, or P class of medicines.
These are available in pharmacies and only in
pharmacies, and they are administered under the
supervision of a pharmacist or the pharmacy staff
who have been trained to work with this medicine.
In the United States we would refer to this type of
medicine as behind-the-counter if we had such a
class but we currently do not. There is no legal
behind-the-counter classification. Simvastatin
falls in the pharmacy class of nonprescription
More like our OTC drugs are those listed
on the general sales list. These are available on
pharmacy shelves, open pharmacy shelves. They do
not require the assistance of pharmacy staff. They
are also found in supermarkets, and they include
medications such as analgesics and cough-cold
medications. As I indicated, the comparable class
in the United States is what we refer to as OTC or
At this point I would like to point out
what you may have seen in the literature, and you
have already heard referred to this morning. You
have heard simvastatin referred to as OTC
simvastatin. All nonprescription drugs, that is
both classes, pharmacy and GSL, are considered and
are sometimes referred to as OTC medications. So,
there is that distinction that I wanted to bring
Let me now talk about the reclassification
process itself, or the switch from one
classification to another. I am going to focus
specifically on the reclassification from
prescription only to pharmacy type of medicine
because that is the one that is involved with
simvastatiin. It is also possible to reclassify
medicines from pharmacy to GSL but medicines in the
United Kingdom do not jump directly from
prescription only to what we would consider OTC to
The first thing that goes into the
application, as you would expect perhaps because it
is included in any NDA, new drug application for a
switch in this country, is the safety profile for
the drug. This includes reports of adverse
reactions; the results of post-marketing
surveillance studies; published literature
supporting the reclassification; and safety reviews
that may be available. Additionally, the
application includes patient information which is
the proposed labeling for the product. In the case
of a medicine being considered for switch to the
pharmacy class, the applicant must show how the
pharmacists and their staff are going to be
trained. Finally, the application includes a
detailed evaluation by a clinical expert and, of
course, since the application comes from the
sponsor the clinical expert is provided by the
The process itself can really be broken
down into five steps: First, the application
containing the information I have just talked about
is submitted to the Medicines and Healthcare
Products Regulatory Agency, or MHRA, a body that is
directly comparable to our FDA. The MHRA takes
this application in for review.
In the case of simvastatin and most other
switches from prescription only to pharmacy, the
MHRA likes to include the Committee on Safety of
Medicines, or CSM. This is analogous to you, to
the advisory committee members. These are experts
from around the United Kingdom who come together to
advise the MHRA on what they think, or contribute
their thoughts on the advisability of making the
Upon completion of the review, a
consultation letter is prepared which contains the
findings and tentative conclusions of the MHRA in
conjunction with the CSM, the Committee on Safety
of Medicines. This is then sent out to the
different health agencies for comment and for their
response. Whether the MHRA is leaning toward a
switch or against a switch, the information goes
out for public comment, and that is probably not
terribly different from what we will be having
tomorrow morning when we have the open hearing--the
same type of public input. This meeting is public
The responses are received back at the
MHRA. In this case the respondents were given 60
days to respond. They are then reviewed to
determine whether or not any new issues have come
up that the MHRA feels must be addressed. Then, in
the final step, the MHRA takes some sort of action,
either approving the switch or not approving it.
In the event that it is not approved there is the
right of appeal.
In the specific case of Zocor Heart-Pro,
this medicine was reclassified as a nonprescription
pharmacy type medicine in July, as I said, of 2004.
I would just like to briefly go over some of the
labeling. You have heard extensive talks about the
labeling both from the sponsor and from my
colleagues in the FDA. But let's look at the
labeling briefly for Zocor Heart-Pro, and I will be
going into some more detail on this a little later
in my talk.
This labeling is available in your Merck
background package right at the very end. For this
particular label the display panel is on page 343
of the Merck background package. You can see that,
just as labeling in this country, the labeling
indicates the proprietary name, Zocor Heart-Pro, as
well as the active ingredient.
What I wanted you to see is the primary
indication. In the United Kingdom Zocor is
marketed to reduce the risk of a heart attack. On
the back of the package there is the same sort of
information that you might find in this country,
although not in drug facts format. I want to point
out that Zocor Heart-Pro is for people who have a
moderate risk of coronary heart disease. So, I
believe that is the same indication that Merck is
But in the United Kingdom patients are
advised or would-be purchasers are advised that the
pharmacist can advise them further and help them to
identify their risk level. Merck has already said
that will be the case with Mevacor. Here it is
actually a requirement. That is a specific
designated nonprescription class.
Additional labeling that consumers are
exposed to includes the questionnaire which must be
filled out in the pharmacy itself and is assessed
by the pharmacist or his staff or her staff to
determine whether the patient qualifies to receive
Then, if they are able to obtain the
medicine, once they get home and open their package
detailed patient information is provided in this
patient information leaflet, and I will be
referring to this in somewhat more detail just a
little bit later on.
I would now like to get to the real meat
of what I hope to present to you today, and I would
like you to consider some of the issues that were
considered in the United Kingdom when they were
thinking about switching simvastatin to a pharmacy
The public consultation letter, as I said,
contained all of the issues considered by the MHRA.
I have just picked six of these for a little deeper
presentation to you, a little bit deeper
discussion. The MHRA considered the potential for
myopathy and rhabdomyolysis. They also looked at
the potential for liver toxicity in consumers who
would be taking this product. They were concerned
about possibly use by pregnant women--if this
sounds familiar, it should. They were concerned
about whether or not consumers could adequately
self-diagnose that they were at moderate risk of a
heart attack, again with the assistance of a
pharmacist. They addressed the issue of whether
consumers even needed to know their LDL cholesterol
numbers or not. And, for this medication which is,
again, a pharmacy medicine, the MHRA considered the
adequacy of training materials provided to the
With regard to the potential for myopathy
or rhabdomyolysis, the MHRA felt that this was a
sufficiently rare condition that they were not
particularly concerned about it, especially since
they considered the warnings on the labeling to be
So, now if I take you back to that patient
information leaflet which is included in the
package, there are four things I would like to
point out here that all deal with myopathy and
rhabdomyolysis on the labeling. First, consumers
are advised not to take these tablets if they have
had muscle problems in the past after taking a
Secondly, consumers are advised to stop
taking the tablets immediately and check with their
doctor if they develop generalized muscle pain,
tenderness or weakness unless it is an explained
pain. That is, unless it is clearly the result of
flu, unaccustomed exercise, recent strain or
Thirdly, consumers are advised that they
should not be taking certain medications
concurrently, those being cyclosporin or other
prescription cholesterol-lowering medicines, as
these may cause problems if they are taking Zocor
at the same time.
Finally, and this is not on the labeling
in this country, the British pointed out that
consumers should not drink huge quantities of
grapefruit juice, more than a liter a day; 250 ml
Now, regarding the potential for liver
toxicity, the MHRA concluded that this was an
extremely rare condition and that routine testing
of liver function was not required. Again, they
felt that the warnings included in the labeling
Again looking at the patient information
leaflet, we see the following three items: First,
consumers are told not to take these tablets if
they know they have liver disease or they have been
told they have had abnormal liver function blood
tests in the past. Secondly, do not take these
tablets if you drink excessive amounts of alcohol.
Third, stop taking these tablets and see your
doctor if you develop the symptoms of
hepatotoxicity--it doesn't say hepatotoxicity but
What about the possible use by pregnant
women? This has come up today I think. It was not
a concern to the folks at the MHRA. They pointed
out that the labeling clearly specifies, right at
the very outset, that it is only to be used by
women by 55 and over. Furthermore, again they felt
that the warnings in the labeling were adequate.
Again, if I could refer to the patient
information leaflet, there is this directive: do
not take these tablets if you could become
pregnant, are pregnant, are planning to become
pregnant or are breast feeding.
What about the consumer's ability to
self-diagnose that they are at moderate risk of a
heart attack? The MHRA concluded that with
pharmacists' assistance patients should readily be
able to identify whether or not they are at
moderate risk based on age and the risk factors.
This is included in the questionnaire which the
pharmacist goes over with the would-be purchaser,
as well as in the patient information leaflet.
On the questionnaire, right at the top,
patients are asked if they are of a certain age. I
would just like to point out because this came out
earlier today too, females ages 55-70, and if you
are female, have you reached menopause? Yes/no?
They are also asked about four risk
factors, and these are similar but not identical to
the four risk factors on Mevacor. Smoking is the
same. Family history of early heart disease I
think is very similar to what is on the Mevacor
label. But not on the Mevacor label, and of
concern to the British regulatory agency, was
whether the consumers were overweight and whether
or not they were of a family origin from South
The same information is on the patient
information leaflet. You are likely to be at
moderate risk based on age criteria as well as
those same risk factors. So, there is plenty of
exposure to determine if they are at risk for
coronary heart disease. This, by the way, as in
the United States, is the leading killer of adults
in the United Kingdom, coronary heart disease.
What about do consumers need to know their
LDL cholesterol levels? The MHRA pointed out that
reducing the level of LDL cholesterol or bad
cholesterol reduces the risk of a heart attack, and
you have heard that described already today.
Therefore, the MHRA felt that there was no specific
requirement to know initial LDL cholesterol levels
or to monitor these levels after starting.
Consumers that are found to be at a higher
risk--and this is based on the answers they give to
that questionnaire--would be identified by the
pharmacy staff and would be given opportunities to
determine their LDL cholesterol levels. These
people could then be referred to a doctor for
Finally, what about the MHRA's feeling on
the adequacy of pharmacy staff training? It
doesn't really apply in this case but to complete
the major issues. The MHRA felt that this had been
prepared in consultation with national pharmacy
bodies and was adequate; would be distributed to
pharmacists and medicine counter assistants
throughout the United Kingdom; and the education
specifically included understanding of
pathophysiology of coronary heart disease and major
risk factors; contraindications, precautions, and
possible adverse effects of taking Zocor, as well
as alternative interventions including, for
example, lifestyle changes--diet and exercise.
The consultation letter went out in
November of 2003 and was sent to over 250 different
health service agencies. Of those, they received
100 responses. Most of these came from national
health service trust organizations, but they also
got significant input from pharmacy bodies, royal
medication colleges, medication bodies and
academia. Additionally, there was input from
industry and from patients.
Well, what did people think? Of those 100
responses, 9 percent said unequivocally yes, we
feel this should be switched to pharmacy status; 24
percent said yes, they felt it should be switched
but they had issues they felt warranted further
consideration; 21 percent said neither yes nor no
but stated that they had issues that they felt
should be addressed; 11 percent responded with no
comment; and 35 percent said no, it should not,
either statins in general nor Zocor in particular
should be switched to pharmacy status.
I will just briefly and quickly go through
the major concerns raised in response to that
consultation letter. At least 50 of the
respondents indicated that they felt the dose of
Zocor 10 mg was too low to be effective, and
pointed out that there were no clinical trials at
this dose so it was not clear how the MHRA had
reached a conclusion that it was efficacious.
At least 27 felt that, although the MHRA
did not feel this way, there was a need for
cholesterol testing, arguing that since this is an
asymptomatic disease, a chronic asymptomatic
disease, how could people know if it was effective
if they had no way of seeing anything or measuring
At least 21 felt that there was a need for
liver function testing, something that you will
remember the MHRA did not feel is necessary. The
argument was that preclinical only medicines
require liver function testing so it was not clear
to these respondents why it shouldn't be required
for pharmacy class medicines.
At least 21 respondents raised the issue
of the potential for ignoring lifestyle changes.
In other words, people might forego changes in
their diet or exercise regimens in favor of taking
Another 21 brought up the issue of the
cost of OTC statins. That is not an issue that we
worry about in the FDA but it was an issue that
came up over there. Zocor costs about 12-15 pounds
per package. That is a 28-day supply, taken once a
day, usually in the evening. That equates to about
$24-30 and that is about $360 a year. So, there
were concerns that there would be a disparity
between the ability of those who could afford it to
buy it and those who really couldn't afford to buy
At least 16 raised the issue of the burden
on the pharmacist and the pharmacy staff and the
training that would be required. We felt that
either the training wasn't completely adequate or
they felt that training and the time spent
counseling potential purchasers would be too great
a burden on the pharmacist.
Another 16 were concerned about record
keeping and patient management. The feeling here
was that since the pharmacy had one set of records
and the doctors had another set of records there
might be a disconnect between the two and the left
hand doesn't know what the right hand is doing. So
that was an issue.
Ten felt that interactions with other
medications warranted further consideration, and 10
felt that the side effects, for example the
rhabdomyolysis and the liver toxicity, merited
further consideration as well.
In summary, as I said, this was
reclassified as a pharmacy medication in July of
last year because the medicine does not produce, in
the view of the MHRA, a direct or indirect danger
to consumer health without medical supervision, but
only if it is given with the advice of a pharmacist
and supported by a comprehensive pharmacy training
package. Again, this type of behind-the-counter
classification does not currently exist in this
country. There is no legal basis for it at
present. Thank you.
Questions from the Committee
DR. WOOD: Thanks to all the presenters
for sticking to time. I guess now is the period
for the committee to ask questions and we will
entertain questions. DR. WOOLF: A couple of
questions. The system in Great Britain has been in
place for six months. Do we have any idea, in this
short period of time, how well it has worked?
DR. WOOD: The question was it has been in
place for six months in the U.K., how well has it
DR. HEMWALL: Yes, as you noted, it has
only been on the market for six months in the U.K.
We don't have a good handle on how well it is
working yet. I do have Dr. Steve Mann, who
actually was the person who took the application
through the MHRA, here and he can answer a lot of
your questions about this. Maybe you have a
comment now, Steve?
DR. MANN: Thank you. Firstly, I want to
thank Dr. Koenig for what I thought was a fair
characterization of the process in the U.K. As Ed
said, it is a little early to judge exactly how
well this is working, although we are committed to
monitoring how the system works.
We did pilot the questionnaire that is
used in pharmacies before or actually during the
process of the application and showed that it works
well, with pharmacists being able to use it
adequately, and actually, a fair proportion of
people being able to fill in the questionnaire
without any pharmacy help.
Perhaps the only comment I would make on
the process is that the Committee on Safety of
Medicines was heavily involved in approving this.
It is not just the MHRA. The Committee on Safety
of Medicines, as Dr. Koenig pointed out, is an
independent body of advisers to the government.
The only comment I would take slight issue
with is we do encourage people to test their
cholesterol. It is just simply not mandatory for
them to know their cholesterol level going in. The
view of our experts and of the Committee on Safety
of Medicines was that if people have a risk level
that justifies treatment, whatever their starting
LDL cholesterol level, there is evidence that they
will benefit, and that it is important to know that
their cholesterol is reducing, and that they don't
have a high level on treatment. That really is the
place of cholesterol testing is the current view in
the U.K. I hope that was helpful.
DR. WOOLF: The second question is for the
FDA. On page 2 at Tab 4 of our briefing document
it states that there were 195 cases of women who
were pregnant who received a statin. We only have
the data on the 25 who had lovastatin. Do we have
the information for the remaining 170 who took a
different statin and what was the outcome in those
DR. DAVIS-BRUNO: That particular data was
obtained from an Office of Drug Safety consult that
we requested. I don't know of Jocelyn Swann is
here but she is the one who actually did the
consult and could specifically address that
question. I don't have slides on the other
DR. WOOD: Well, while you are up there,
if my recollection is right, Merck said there were
seven fetal abnormalities in your database, and on
page 2 and 3 of your Tab 4, are these overlapping
or are these additive, or what is the story there?
DR. DAVIS-BRUNO: If you are referring to
the pharmacology/toxicology briefing document, that
table with clinical findings--
DR. WOOD: I am referring to Tab 4.
DR. DAVIS-BRUNO: Right. Those particular
human findings are relevant only to lovastatin.
DR. WOOD: No, no, I understand. These
are the numbers from the AERS database.
DR. DAVIS-BRUNO: Correct.
DR. WOOD: And in the Merck database there
are seven, they said. I was surprised, first of
all, that the seven didn't seen to be reported to
the AERS database and the question was did these
seven that they have include these five, or are
there really 12, or what are the numbers? I
thought they had an obligation to report all the
numbers, so how come there are less?
DR. LEVINE: I am Jack Levine, with Merck.
The five that are there are included in our
seven--those six are included in our seven.
DR. WOOD: Okay, and what is the seventh?
DR. LEVINE: There was one aborted fetus
that the FDA refers to, and we have two where there
is actually a question of whether they are the same
DR. WOOD: All right. So, the total
universe is seven including 1/2.
DR. LEVINE: Correct.
DR. WOOD: Thanks. Dr. Parker?
DR. PARKER: It seems that there was some
valuable information obtained from the label
comprehension study, as well as the use study,
about the bottom line of people who would use this
drug, their ability to understand what they need to
know. I am wondering if the insights gained from
the label comprehension study, however you slice
the pie, were used to modify the label for the use
study. In other words, what is the exact timing of
the label comprehension study and the use study,
and whether or not the results from the label
comprehension were used to make the label better in
the use study?
DR. HEMWALL: As you saw in one of the
slides that Jerry Hansen showed, we did research
for about three years, and the total amount of
research going even further back that that was with
about 30,000 consumers, studying every possible
element of the label in focus groups and in pilot
label comprehension studies. So, once we had the
label that we were confident was well understood,
we did the studies, the CUSTOM study and the label
comprehension study simultaneously, knowing
full-well that the next study would be one with
input from this committee and from the FDA, having
reviewed and commented upon the results of not only
the label comprehension study but the CUSTOM study,
to help further refine that.
DR. WOOD: Mary?
DR. TINETTI: I have a few questions
related, first of all, to label comprehension, and
this would be both for the FDA and Merck. First of
all, I was sort of interested that it had an 8th
grade comprehension level. I wonder if anybody
knows what the median comprehension level for the
older population is. I guess the last I heard, it
was closer to 5th grade. I am curious. In this
population there is only 35 percent for women, for
example, who are over 55 and probably few of those
are over 70. My concern is that there is a large
number of those people who are going to have many
of either the contraindications or most likely the
indications for discussing it with their
physicians. So, I wonder if there was any
sub-study looking specifically at that population,
and whether the people we are most concerned about
understand the label, and could they, indeed, do
I am also concerned about the size of the
print for the older population. Finally, I was
sort of curious. It sounded as if people
understood that if you stopped the medicine your
cholesterol would go back up. But do they really
understand the question that we are interested in,
that once you start this medicine you are only
going to get better if you take it forever and
taking it in fits and starts is not going to be
particularly helpful. I wonder if there were any
questions related to that and, if not, what do we
think the repercussions of not having that
CAPT. SHAY: There were no questions in
the label comprehension study that addressed that
but, I agree, that would have been an important
element to come out in the study.
DR. WOOD: Let's go on to Dr. Follman.
DR. FOLLMAN: I wanted to talk a little
more about pregnancy. In the sponsor's analysis
that they showed on the screen a little while ago,
my recollection was that they talked about 67
reports of statin use during pregnancy and that
nothing happened as a result of this, no toxicities
or problems, or anything. But in their briefing
document they talk about these 67 and note that in
34 of these pregnancies that were reported during
statin use outcome data was available, and in this
table they note that three of these 34 with known
outcome data ended in elective abortion; one in a
spontaneous abortion and one in fetal death.
So, I wanted to, I guess, set the record
straight in terms of what they said earlier that,
in fact, there were some untoward events during
I also have a couple of comments about the
analysis of the mice data. One was that the
sponsor's analysis sort of disparaged what the FDA
did and noted that one of the litters had, I think,
8/8 fetal abnormalities. So, all of the
abnormalities were in one litter and that seemed to
be sort of over-counting. I don't know exactly
what statistical analysis the FDA did but there are
certainly analyses that I trust the FDA did which
take into account the fact that outcomes in a
litter are likely to be similar. So, just the fact
that you used litters in your analysis doesn't
necessarily mean that it is incorrect.
Another point I wanted to make was that in
the weight loss analysis they had a table which
showed various outcomes in the control group and
then weights at different times for the three
different doses of statin, and they said these were
all non-significant. But if you look at them, in
each instance, except for one of the 12 I believe,
the weight was less in the lovastatin-fed mice than
it was in the control group. So, to me, if you
would combine that it would suggest something more
consistent with what the FDA said, which was that
there was concern about weight loss with
Finally, there was some comment about
disparaging the use of concurrent controls and that
historical controls would be better. I have never
heard that argument before; it is kind of
mystifying to me.
DR. WOOD: Does the sponsor want to
respond to that as these were in their
presentation? No? All right.
DR. DAVIS-BRUNO: Can I just clarify? I
just want to make sure that it is clear that the
FDA looks at both concurrent controls and also
historical control data when we do our analysis.
DR. WOOD: Okay. Dr. Watts?
DR. WATTS: I would like to hear from
Merck. You have one of your products now approved
at the pharmacy level for use in the U.K. and you
are asking us to approve or recommend approval of a
different drug in the same class for use in the
U.S. I wonder why you picked simvastatin to use in
the U.K. and lovastatin to use in the U.S.
DR. HEMWALL: There is a fairly simple
answer. Lovastatin was never approved for
prescription marketing in the U.K. so simvastatin
was our only option for switching in the U.K.
DR. WATTS: But why not simvastatin here?
DR. HEMWALL: Well, as you have heard
today, we have done an awful lot of work on
lovastatin, including additional investigative
animal work, and this has been our project I think
since about 1997. It would have been difficult to
switch in midstream to simvastatin. Secondly, in
keeping with the data-driven determinations that
are made by this committee and the FDA, lovastatin
is directly tied to a study, AFCAPS, which showed
risk reduction in the primary prevention target
population that we are considering for OTC.
Simvastatin has many excellent long-term studies
but they are in different risk level populations
although the HPS study was certainly a basis for
approval in the U.K. without needing to know one's
DR. WOOD: While we are talking about the
comparison between the two, you obviously went with
an approval in the U.K. without an LDL measurement,
and you are going here with an LDL measurement. Do
you want to comment on why you made that
DR. HEMWALL: I think I will ask Dr. Mann
to comment on the thinking that was considered in
the U.K. In the U.S., of course, we are trying to
be as consistent as possible with the NCEP
DR. MANN: Yes, if I could comment, in the
U.K. we faced a very different situation I think to
what prevails in the U.S., in that there has not,
in the U.K., been an extensive cholesterol
awareness campaign over many years, and I think it
is fair to say that the level of consumer knowledge
about cholesterol risk factors for coronary heart
disease and the connection between the two is not
very high in the United Kingdom. We were faced
really with a quite different setting I think from
what prevails here.
Our expert panel and the Committee on
Safety of Medicines concurred with this view and
felt that the current state of knowledge about
cholesterol dictated that intervention should be
based on someone's absolute risk of coronary heart
disease and, if that risk justified intervention,
then the person would benefit from reduction of
cholesterol whatever the starting level of LDL-C.
I think you saw earlier today that Dr. Pasternak
presented those data, suggesting really that the
benefit is there throughout the line of what the
starting cholesterol LDL-C is.
It is also the case in the United Kingdom,
and I think it is probably true to a similar degree
in the United States, that with these age and
gender categories there are very few people who
have what is characterized as a desirable LDL-C
level and, on that basis, it was felt that not
having to know the LDL-C at the start of treatment
would discourage fewer people in the United Kingdom
from taking part because really the knowledge of
those numbers didn't exist. But knowing what their
LDL-C was on treatment is something that would be
encouraged both to motivate and to continue but
also to pick up those who are inadequately treated.
DR. WOOD: Dr. Fincham?
DR. FINCHAM: I would like to preface my
question with just perhaps a comparison between
pharmacy in the U.K. as opposed to pharmacy in the
U.S. If you look at the sheer numbers of
pharmacies in the United States, there are probably
four times as many pharmacies in the U.S. as there
are in the U.K. But, yet, because of the
population difference, if you look at it as a
pharmacy per unit of population, residents of U.K.
have probably twice the opportunity to see a
pharmacist perhaps as we do in the U.S. Plus, the
types of pharmacies that you see in the U.K. are
vastly different from what you see in the United
States, and there is some penetration of chains
much more recently into the U.K., and certainly it
is dominant in the United States. So, the size of
the pharmacies is perhaps different. Thank you for
allowing me to say that.
The question is it appears, when looking
at the training materials either for consumers or
for consumers and pharmacists, that the process in
the U.K. seems to be driven through a pharmacy by a
pharmacist or a trained technician to aid the
consumer, whereas, in the United States what has
been proposed, or at least what I have seen in the
documentation, indicates that it is much more of a
consumer-driven process within a pharmacy and, by
the way, you can ask a pharmacist in the United
States should you need to. And, I would just like
to have an answer to the question why is there a
difference in how this is being marketed to
consumers through pharmacies in the different
MR. HANSEN: Maybe I will have Steve
comment on access to pharmacists in the U.K. versus
the U.S. My understanding, after being over there
several times, is that it is pretty similar to the
U.S. in that two major chains do have about 50
percent of the market share--but I will let Steve
confirm that--and the rest are independents, which
is similar to what you see in the United States--
DR. FINCHAM: However, one of those
pharmacies traditionally has been a major player,
and it is Boots, and Boots has always had smaller
pharmacies as the norm as opposed to the opposite.
DR. HANSEN: Yes, it is not true anymore.
They look more like a CVS or a Walgreens than they
do the old Boots that you remember. In fact, they
even have a dentist's office in a lot of them. So,
they have expanded over the past few years. I was
actually surprised. So, we can debate whether they
look the same or not the same.
But I think the key question is why the
difference; why aren't we putting it behind the
counter here and putting it behind the counter in
the U.K.? And, the key difference, as Dr. Koenig
from FDA said, is that there is no third class,
legislative third class in the United States.
DR. FINCHAM: That is a great answer but I
don't think it answers my question. The question
is that driving the product for consumer use
appears to be vastly different between the two
models. My point is that in the U.K. you are
driving it through consumers to go through the
pharmacist in a pharmacy, whereas here, at least in
what has been proposed and what is on the boards,
etc., it appears that this is driven by the
consumer in the pharmacy who may or may not have a
consultation with the pharmacist.
MR. HANSEN: Yes, I think the difference
is the hallmark of our program, that the consumer
can do it on their own here, in the United States,
because you have to consider worst case, that they
are not going to talk to the doctor; they are not
going to talk to the pharmacist and, therefore, we
developed a system for them to do it on their own.
That is number one.
Secondly, understanding the type of
consumer who is interested in using this, we know
that most of them see their doctor on a regular
basis. Most of them consult with a pharmacist.
So, we want to make sure we facilitate that and we
want to make sure that they do have that option in
a pharmacy so that it is there. It is not
mandatory. It is not behind the counter because
there is no legislation for that, however, we do
want to make it easy for consumers to avail
themselves of that as well.
DR. WOOD: Also, I would not oversell what
actually happens in a U.K. pharmacy when they are
behind the counter.
MR. HANSEN: I was going to stay away from
DR. WOOD: Right, you may be reluctant to
say that what happens is the consumer goes up to
the girls who stands behind the counter and says
they would like that, and the sales person waves it
at the pharmacist who says okay, and then it gets
issued. Is that fair?
DR. MANN: I think it is probably fair for
acute symptomatic treatments. They take it much
more seriously with the newer medicines that are
becoming available, and I think simvastatin is
probably the first of a new class and is very much
recognized as having to have a different approach.
One thing I would add to what Jerry said
is that access to healthcare professionals in the
U.K. drives to a large extent how people get their
medical care, and primary care doctors are under a
huge amount of pressure in the U.K. just by virtue
of the numbers. So, people are used to accessing
care in pharmacies. However, the model that is
applied in pharmacies in the U.K., particularly for
simvastatin, is relatively simple and certainly our
experience with piloting the questionnaire is that
many consumers can do that without pharmacy
assistance although the pharmacist is always there
at the point of sale.
DR. FINCHAM: But there are really some
sophisticated materials that are provided in the
U.K., a pharmacist training guide, medicine counter
assistance training guide, Zocor Heart-Pro consumer
questionnaire pad, concise guide to when to
recommend, BMI height/weight chart, customer
DR. KOENIG: If I could just add
something, I pointed out, I thought, during my talk
that the reason this is a pharmacy medicine is that
you can't go directly from prescription to GSL, or
what we would call OTC, in the United Kingdom. You
go sequentially and usually you stay in each class
at least five years so that a sufficient safety
record can be built up. So, simvastatin doesn't
have the option of being sold as we would do it in
this country; it has to be sold as a pharmacy
medication under those regulations.
MR. HANSEN: The only point I was going to
make is that exactly the same materials, at least
as they apply to the United States, would be
available here. In fact, a lot of the materials
used in the U.K. were actually adopted from the
U.S. because we have been working on the program
longer here than they have in the U.K.
DR. WOOD: Neal?
DR. BENOWITZ: I wanted to just follow-up
on some of the differences between the U.K. and the
U.S. trials. First, I just wanted to be sure that
we had data on primary prevention, that lowering
cholesterol below--or treating someone with
cholesterol below 130 is still a benefit because we
saw that a lot of people who are going to be taking
this drug will have cholesterols that don't meet
the entry criteria. I would like to know is it in
fact of shown benefit in primary prevention.
A second thing I am curious about is why
the U.K. criteria did not include hypertension
which is one of the major cardiovascular risk
factors. Was there some concern about why
hypertension should not be one of the indications
for use in the U.K.?
DR. WOOD: Tony?
DR. GOTTO: Tony Gotto. The log linear
plot of LDL was relative risk reduction showing an
intercept of 1 and LDL of approximately 40 mg/dL
where risk was not increased. There is nothing
magic about 130. The sponsor has very carefully
tried to make these recommendations consistent with
the NCEP guidelines to avoid causing further
confusion in the case of the person who is trying
to follow the directions or the physician. So,
they are very consistent with the guidelines but
there is nothing magic about 130.
In fact, the recommendations of the
National Cholesterol Education Program, ATP III
guidelines were that the optimal LDL level for all
patients is less than 100. I realize that in the
CUSTOM study there were people with LDLs less than
130, a third or so, who followed the program, but
it is very unlikely that you would do harm and, in
fact, some people with levels in that range will
get down to the optimal level. Only 23 percent of
the adult population in the U.S., based on the
current NHANES data, have an LDL under 100. So, it
is very unlikely that you will get down to very low
As has been said before, there has been
much less cholesterol education in the U.K. and a
great deal of impetus for the Zocor OTC there, I
believe, came from the Heart Protection Study where
the investigators very strongly believed that you
treat risk levels, not cholesterol levels. As they
said in the presentation when HPS was presented at
the American Heart Association, if a patient is in
a high risk category we give 40 mg of Zocor
regardless of what their LDL level is because it is
too high for them. The OTC program in the U.K. and
in the United States is aimed at a moderate risk
category. So, based on the prevailing conditions,
lack of cholesterol measurements and education in
the U.K., they have gone a different route but here
we have been very closely tied to the numbers,
spending huge amounts of time and funds trying to
educate the public and physicians about the
guidelines. So, there certainly is benefit in
trying to have the guidelines as closely as
possible in sync with what is being recommended to
avoid confusing the public and the doctors.
DR. WOOD: Tony, before you sit down, what
you are saying has great importance for
interpreting the labeling studies because the HPS
study and other studies really suggest that most
people in the groups that are under study here will
benefit. So, the studies of label comprehension
and so on, my sense is, don't allow people to be
treated who wouldn't derive some benefit based on
most of the studies. Is that correct? Do you want
to develop that a bit because that is relevant to
understanding these studies and whether they
DR. GROTTO: Well, I think there is no
question that the patients are people who would
fall into this category with LDL between 130 and
170 with the age criteria and additional risk
factors. These were the patients that we studied
in AFCAPS/TexCAPS. Only 17 percent of those
patients would have qualified for statin treatment
by the guidelines at that time. We saw no
diminution in treatment. We were aiming at trying
to get LDLs down as low as 110 and the mean was 115
in the group on lovastatin. But we saw no
breakdown or no diminution in benefit going down to
the lower levels. The relative risk or the
absolute risk is related to the LDL level so you
have to treat more patients, obviously, at the
lower risk range in order to see benefit. But it
was a very robust result and indication for primary
prevention was given based on a single study. So,
I think going by the data that are available from
clinical trials, patients below 130 would benefit.
DR. WOOD: My point was also that if you
have patients who haven't had an LDL measured and
who fit the other criteria for risk, the proportion
of patients who won't benefit in that group is
relatively small. Isn't that right?
DR. GROTTO: That is absolutely correct.
DR. WOOD: So, that is relevant to
interpreting the apparent disparity in the labeling
DR. GROTTO: Yes. I completely agree.
That is a good point. Thank you.
DR. WOOD: Frank?
DR. DAVIDOFF: Yes, I have a question
about the issue of cost in the U.K. because, as we
have heard a number of times, cost is not
considered by the FDA in its decisions here. But
the British system of financing medical care is
obviously very different since the NHS pays for
virtually all healthcare in the U.K. including
I notice that there were editorials both
in the British Medical Journal and in the Lancet
apropos the decision to go to over-the-counter
statins, which took up the issue of cost as a very
major one. The BMJ more specifically pointed out
that if all those patients who were at moderate
risk were actually treated with statins, and most
of them currently are not, it would actually
consume 10 percent of the total NHS budget.
The arguments can go either way because it
was also pointed out by Lancet that going
over-the-counter would mean that those people who
could afford to pay what it cost to buy the
over-the-counter drug would do so and those who
couldn't would not, and that this would actually
increase the disparities in health care.
So, my question is whether in the
regulatory process, approval process, in the U.K.
cost is actually formally considered because it
clearly, from the NHS point of view, could make a
huge difference in making the decision to go
DR. MANN: It is not explicitly a
criterion for whether something goes
over-the-counter or not. However, it clearly has a
considerable impact on how people behave. The
joint British societies that issue our guidelines
on treatments of coronary heart disease have always
recognized that levels of risk, more moderate
levels of risk--that there is very good evidence
that treating them is beneficial. That has been in
the guidelines since 1998. But the thresholds for
treatment under the NHS are governed entirely by
socioeconomic factors. The new joint British
guidelines which are shortly to be issued and have
already appeared in some abbreviated formats do
suggest treating at lower levels of risk, going
down to 15 percent, or broadly the equivalent to 15
percent 10-year coronary risk. So, there is a
shift gradually downwards within the National
Health Service as resources allow--I think those
are the weasel words to be used.
I think the recognition here is that the
OTC approach is entirely complementary to what is
available on the National Health Service, and that
people should have the option to take that should
they wish to. Obviously, people then have choices
whether to spend their money on healthy lifestyles
or reducing their cholesterol.
DR. WOOD: Dr. Neill?
DR. NEILL: Earlier this morning Dr.
Ganley discussed what constituted the OTC and we
reviewed a little bit of that today in terms of the
fact that this is a consideration that includes a
condition that meets few or none of the classic OTC
conditions. In a prior NDAC meeting, in discussion
of non-sedating antihistamines, it was interesting
to listen to a company have to answer why a
medicine should not be made OTC since it was safe
and effective, and I believe it is still the case
that it is incumbent upon the FDA to make something
available in the OTC setting if it is for an OTC
condition and if it is safe and effective for use
in the OTC setting. In other words, a company
cannot simply decide to make it prescription if all
of those things are met because they would like to.
Rather, the FDA may compel them. And, it is my
understanding that that in part informed the
discussions between health plans in California and
the manufacturers of some of the non-sedating
So, with that background in mind and given
that we are talking about a new OTC condition that
you already have approved in the U.K. a different
product from your company, I am anxious to hear, if
you are willing to reveal, how you would respond to
a health plan provocation to encourage you to take
other safe and effective statins OTC at some dose,
number one and, number two, perhaps for FDA, to
what extent is it in the public interest to make
these over-the-counter statins available across
product lines and across companies if, in fact, we
reach a decision--and I don't know what will happen
tomorrow--that this is an OTC type condition and we
are okay with that, and that this is a safe and
I am confident that we could sit here for
months discussing the individual dose for
Zocor--list all the statins--and we could discuss
how or whether they were safe and effective. But
that is a dichotomy that I think requires some
explaining. In other words, if the default is that
these must be OTC, why aren't they?
DR. WOOD: At the risk of sounding
cynical, it usually happens when the patent
DR. HEMWALL: I am not sure if that is a
question that has a straightforward answer. It
sets forth a number of hypothetical situations. I
think that we have been trying to develop the data
to convince the Food and Drug Administration and
your committee that a product like this should be
OTC for about seven or eight years.
DR. NEILL: We should approve Zocor as
well, and you should be compelled because the issue
here for me, in my mind, is that this is an issue
of compulsion. It is the FDA's duty to make these
medications OTC. That is the default. The only
reason to have them Rx is if they are not safe and
DR. WOOD: Hang on, hang on. We are here
to discuss Mevacor and that is probably more than
we can cope with before five o'clock. So, although
these are all very reasonable and interesting
points to discuss in the bar on Friday night, I
think we need to focus on Mevacor right now and
just stick to that. I don't mean to cut you off
but I think I have bitten off as much as I can chew
with that right now. Your point is noted. Leslie?
DR. CLAPP: I have a brief observation to
share with Merck about the packaging, and that is,
as my eyes mature I have increasing difficulty
seeing small print. But additionally, the script
that is in red on the label that is supposed to be
more important is very fuzzy and blurry. The only
one I can see in terms of red is "test at two
weeks." So, if you can consider emboldening the
red script, perhaps it will be easier for aging
eyes to see. That is just an observation.
But now I have more of a question for the
FDA. I would like to have some clarity about
pregnancy category labeling. As was stated
previously, Mevacor is pregnancy category X and the
components that seemed to go into that
determination is the clinical benefit of a
medication, as well as the human and animal fetal
risk. I don't know if there is any weighting that
has been done in terms of a perspective from the
FDA as to category X for Mevacor, but I heard some
comparisons from Merck as to those medications that
were category C. I am wondering if the perspective
we might be encouraged to feel is that Mevacor
could be a category C because of the lack of
risk--I think that is what Merck is touting as a
fact, that there is very little or negligible risk.
Whereas, the final statement on Dr. Davis-Bruno's
presentation certainly does mention that, based on
extensive animal data, potential human risk does
exist following exposure to lovastatin during
pregnancy. So, I am not sure if there is a
weighting that the FDA has to risk for the
medication from the human and animal fetal
component versus the benefit to the mother or the
woman of childbearing age taking the medication.
The other question I do have is are there
any other OTC medicines that are category X?
DR. MEYER: I will take the first part of
that question. I guess, to make it clear, under
the wording of the regulations as they stand for
the pregnancy categories, if one is to advise that
the drug not be used in pregnancy because the risks
outweigh the benefits, then it is a category X and
you can get to that calculus because of large risks
in the face of benefits, or you can get to that
with a smaller risk in the face of no perceived
I think that you have heard from the
sponsor, and I am not sure we would very loudly
disagree with it, that that is more the case with
lovastatin, that we are in a situation where the
animal data suggests there are in fact some risks.
The human data don't really answer it at this
point. So, the temporary or short-term treatment
of the mother during her pregnancy does not
outweigh the potential that we feel the animal data
suggests might exist for the fetus. The decision
about the category obviously was made some time ago
and data continue to accrue both with the
post-marketing experience and otherwise.
I would urge the committee not to focus a
whole lot on whether it is category X or not. I
would ask you to consider the data that we have
presented and that the sponsor presented and look
at whether you think that represents a significant
risk and, if so, does the labeling that the sponsor
has undertaken help minimize that risk? That is
really the question because when you get to the OTC
setting pregnancy categories have no relevance.
DR. CLAPP: Yet I do just wonder whether
or not there are any over-the-counter medicines
that have been switched, that were category X as
prescription medications that are over-the-counter
DR. ROSEBRAUGH: We have considered
category X drugs. We have drugs that are OTC that
do have teratogenic effects. The poster child is
probably nicotine replacement.
DR. WOOD: Dr. Parker?
DR. PARKER: I just wondered if you could
comment on the Zocor warning about alcohol use and
the fact that that is not there for Mevacor. Did I
DR. HEMWALL: That is simply a matter that
that was something that was requested by the U.K.
It seemed like sound judgment to warn against
alcohol use, and certainly we would consider that
for the U.S. as well, but it is not because there
is any evidence that people with alcoholic liver
disease are at any greater risk. But, again, it is
meant to be more of a safety net and to keep the
risk to a minimum.
DR. PARKER: I guess that was a part of
the discussion that went on at the time.
DR. HEMWALL: In the U.K.?
DR. PARKER: Yes.
DR. MANN: In the U.K. we submitted this
to the expert opinion about the need for liver
monitoring and concluded that it was not necessary
and probably unhelpful. However, we started with a
Zocor label that said that people with preexisting
liver disease should not receive the drug, and we
really didn't feel we had evidence to say that we
shouldn't do that. Therefore, we have excluded
people with known liver disease and I think that is
just a precautionary principle. On that same
basis, people who have used alcohol and therefore,
potentially at least, have the risk of liver
disease were also excluded, again, on a
precautionary principle, not on the basis of any
great data that those people are at special risk.
DR. PARKER: Could I just ask do we have
from CUSTOM alcohol use? Was that a variable that
DR. HEMWALL: No, we do not.
DR. WOOD: Does the Tylenol label have an
exclusion for liver disease?
DR. GANLEY: I would have to check on it
but I am not sure that it does right now. I don't
believe it does.
DR. WOOD: It would be worth knowing
because it is relevant to this.
DR. GANLEY: It has an alcohol warning.
DR. WOOD: I actually was asking for prior
liver disease. Jack?
DR. FINCHAM: I know we are not supposed
to talk about cost but it is hard not to think
about it in the context of at least the tradition
in the United States. When a drug is switched
insurance coverage ceases whether it is managed
care or whether it is Medicaid or soon to be
Medicare. In the U.K. previously, at least
according to pharmacy informatics organization, the
consumer paid in effect a third co-pay for a
month's supply of simvastatin, an equivalent of $10
for a $30 prescription. Now they pay between $19
and $30 and the government doesn't pay anything.
There can be no question that these drugs are
important to take. I just wonder what the result
will be, and this may be a rhetorical question but
I just wonder what the result will be when this
burden is forced more and more on consumers, not as
an opportunity to help themselves but, yet again,
another decision that they have to make relative to
how they spend limited resources.
DR. WOOD: Do you have that question to
address to somebody?
DR. FINCHAM: I don't have the answer to
it. If somebody else in the room does, I would
sure like to hear it. I think it is a concern that
is not addressed in any of our materials, nor
should it be.
DR. WOOD: Dr. Snodgrass?
DR. SNODGRASS: Just a couple of brief
comments around the birth defects, the fetal
adverse effects issue. One has to do with sharing
medications. If Susie buys it and shares it with
Sally and Sally turns out to be pregnant is an
issue. The comparison I will make is not,
obviously, a very good one at some levels but it is
a real one. Many years ago, before the current
procedure for Accutane in a physician's office to
fill out the long forms, Ed Lammer, in California,
had shown by epidemiologic data that there were at
least 1000 malformed infants in the United
States--this is well over 10, 15 years ago--with a
drug that had been marketed with a black box
warning about teratogenicity, realizing that it is
a very well characterized potent teratogen. So,
that occurred under prescription circumstances with
a black box warning.
The other comment is about the folate
receptor in in vitro studies. When you lower
lipids around that receptor it doesn't work as
well. It doesn't take up folate; it doesn't
respond as well, and we know the relationship
between folate and neural tube defects.
DR. WOOD: We have gone round and round on
this pregnancy issue so maybe we should try to
reach some sort of closure on that. If I can
summarize where we are, nobody disagrees that it
shouldn't be taken by pregnant women. So, the
question really evolves into--were this to be
approved and we are not there--have we got
sufficient confidence in the methodology to prevent
it being taken by pregnant women? That seems to me
the issue rather than debating the biology, which I
suspect we have neither heard enough about to
really deal with adequately today, nor do we have
sufficient time to do that. Is that fair? I mean,
are people comfortable with that? If people have
further comments, let's deal with that issue and
then put it away. Neal, is your comment on this
DR. BENOWITZ: Yes. Let me say that I
don't think you can make it quite that simple
because if we are talking about Accutane, then we
want to be very, very, very sure that no pregnant
woman takes it. If we are talking about a low
theoretical risk, then you might be more willing to
have a little bit of an error. So, I do think
there is a quantitative issue here.
DR. WOOD: Do you want to address what you
think the quantity looks like? I mean, are you
suggesting you think this is Accutane?
DR. BENOWITZ: No.
DR. WOOD: Okay, good. So, help us
understand that. I mean, where do you think this
fits in the quantitative level?
DR. BENOWITZ: I certainly can't answer
that. To me, it looks like it is low in terms of
evidence in human exposure levels but I wouldn't
want to have a woman take it if she is pregnant if
I could help it.
DR. WOOD: Right, I think we would all
agree nobody wants this to be taken by pregnant
women, but that would be true of most drugs that
don't have a benefit in pregnant women. So, the
issue then is can we avoid it and how do we avoid
it being taken by pregnant women? You are raising
a new issue--well, tell me what the new issue is.
DR. BENOWITZ: No, it is not a new issue.
It is how large is the risk. If a pregnant woman
absolutely takes it and the risk is really
substantial, then you want to make sure absolutely
and do everything possible to make sure no pregnant
woman ever takes the drug. If it is a theoretical
risk or very obscure risk, then if there are some
exposures it is not going to be of as much
consequence for the population so we may be a
little bit more willing to say let's have a little
bit of leeway. Now, I don't have the parameters
for that in terms of numbers for risk. It seems to
me that the risk in humans has not been
demonstrated at something equivalent to a 20 mg
dose. That is not to say it couldn't happen in
some case. But I think it is important in terms of
how strong the barriers have to be to prevent any
woman who could possibly get pregnant from getting
DR. WOOD: Does the company want to
respond to that issue? Oh, I am sorry, we will let
Dr. Makris talk first.
DR. MAKRIS: Thank you, just a few
thoughts. It seems that there is pretty much
agreement I think between FDA and the sponsor that
what has been seen so far in human incidence data
really doesn't indicate that there is a real
concern for birth defects when there has been
accidental or unintentional exposure. So, there is
agreement on that.
It seems that there are some disagreements
in terms of how to characterize the animal data,
developmental data and having sat on a number of
peer review committees, I know that if you put
three toxicologist in a room you get seven
--about how to interpret the data.
Usually you have to go back to the individual
animal data and look at it a whole lot more
carefully to be able to weed things out, and I
don't know that that is really an issue here or
something that we need to be addressing.
But there is something that I do see in
the data that was presented that, you know, raised
some concerns with me. It had to do with some of
the functional assessments that were done. I
believe it was the seg. 3 study that characterized
a number of functional deficits in the pups and a
number of different parameters. And, there was a
follow-up study done that was a neurodevelopmental
study that dosed from postnatal day 4 through
somewhere around 41 or 50 of age, and did a number
of additional tests. The evaluation of that study
by FDA indicted that there were still some concerns
or that they felt that the endpoints that were
assessed in that study weren't enough to truly
characterize what they were getting at.
But even that being said, I think that the
original functional assessments that were done that
raised the concern were not addressed in quite the
same way in that second study because it was
looking at different stages of development. It is
possible that the functional deficits seen in the
first study may have come from in utero exposure;
may have come from postnatal exposures, and you
can't determine that from these types of studies.
The follow-up study that was done was
essentially trying to mimic human exposures in late
gestation and early postnatal and maybe even
through almost adolescence. But the early in utero
exposures were not captured in that study and that
seems to be what some of the concerns are here,
what happens when a woman who just finds out she is
pregnant is taking the drug and those early
gestational exposures are the ones of concern. So,
they haven't, I think, been characterized fully.
So, there are some uncertainties I think in terms
of whether or not there might be developmental
exposures that could result in some kind of
functional outcome in the fetus or child.
So, I am not sure that there is any way to
address that with the data that have actually been
collected, and there is nothing that I see in any
of the human or epidemiological data that would
suggest that maybe that is an outcome, but I think
we need to at least recognize that lack of
DR. LANKAS: I would just like to make a
brief comment relative to your comment, and that is
that the neonatal toxicity study where the animals
were treated beginning on postnatal day 4 was done
expressly to, hopefully, try to ally some of the
concerns that FDA had raised that a statin-like
drug could affect myelination as a function of its
effect on lipid metabolism. As Dr. Davis-Bruno
pointed out, rats are quite different
developmentally than humans with respect to the
time of myelination. So, the specific study was
done to address the issue of when myelination
occurs the exposure to lovastatin was initiated,
and in the rat it is during early postnatal
development and in humans it is basically during
the latter part of pregnancy, during the second and
third trimester. So, that was the reason for that
Again, there are differences in
interpretation but I think Dr. Davis-Bruno's
characterization, a conservative one, indicated
that there was a clear no-effect level at the
middle dose group of 5 mg/kg which, in terms of an
exposure, would far exceed any exposure that a
human fetus would receive because we were dosing
the pup directly as opposed to any in utero
exposure or lactational exposure.
DR. MAKRIS: Yes, I understand that and
the study was not designed specifically to follow
up the effects that had been seen in the previous
study. It did have a completely different intent
and was designed to assess that.
DR. WOOD: I think Neal Benowitz's
question still needs to be addressed. Are you
going to do that?
DR. HEMWALL: Yes, if I can remember back
to the beginning of the discussion, you are
concerned about some of the behavior in CUSTOM.
There were 12 women who were pregnant or breast
feeding that came to the study site and evaluated
whether or not to use Mevacor OTC. All 12 of those
women elected not to use it, and there were no
pregnant women that took the product.
DR. BENOWITZ: What I was talking about
really was the number of women of childbearing age
who took it and, obviously, could have become
pregnant without knowing it.
DR. HEMWALL: Yes, that is correct. I
think what we want to be able to do is be stronger
in the labeling about the potential for
childbearing. Again, we don't believe that there
is a significant risk at all, but we do want to
minimize as much as possible the use of the product
by women who are of childbearing age, and labeling
that has been used for other products that have the
same problem, such as nicotine replacement which is
obviously used by women of childbearing
potential--we would extend that to Mevacor and work
with the agency or with committee recommendations
on the best language.
DR. WOOD: I thought, Neal, you also had
the question about getting some quantitative
measure of the risk in humans.
DR. BENOWITZ: Well, I was trying to.
DR. WOOD: Right. Well, let's see if they
can respond to that.
DR. HEMWALL: We don't have a quantitative
measure of the risk in humans. We have examined in
an abstract the number of prospective and
retrospective pregnancies, both in the lovastatin
and simvastatin database, and there is no clear
signal that rises above the level of background.
However, you can't rule out a certain multiple of
background just because of the pure statistics.
DR. GANLEY: Alastair, could I just
DR. WOOD: Yes?
DR. GANLEY: We have obviously been
thinking about a lot of this internally, and I will
give you my perspective and others can chime in.
But I don't think I am as concerned about pregnant
women using this product. Remember, this has to be
a highly motivated population who would want to use
this and understand that they are going to get some
benefit from this. If a woman knows she is
pregnant, I think most women are very careful--I
may be wrong in that assumption--and I think the
evidence from the CUSTOM study where 12 women
actually showed up and chose not to use it, which
was the correct thing to do--well, that makes a lot
Now, if these neurodevelopmental issues
are second and third trimester issues and a woman
may know she is pregnant by her second or third
trimester, well, I don't think she is going to
necessarily choose to take this drug. So, I don't
have this much concern about that.
I think the issue that I have is this
childbearing potential and what really is the risk
in that first trimester. I think, going back to
the CUSTOM study, what is difficult for us, or for
me at least personally, to understand is that
clearly someone knows their age, and if it is said
that this is for a woman greater than 55, well, why
did women less than 55 take it, other than being
overridden by a doctor?
Merck had some survey data at the end of
the study and I don't know if there is something
within that that could help us understand, well,
what was it that women did not understand there
that caused them to take it. Did they have their
tubes tied or was there something else in there
that gave them a comfort level? Because, clearly,
if 100 percent of the women in this CUSTOM study
were greater than 55, we probably would not be
having this discussion right now.
So, I think that is how we sort of have to
think about this, what went wrong there? Or, if a
lot of it was physician override, the prescription
labeling for Mevacor says if women of childbearing
age are going to be put on this, they should be
instructed about not getting pregnant, or they
should have some other type of birth control, or
something to that effect. But women still got
pregnant while on Mevacor.
So, that system failed in itself. The
system is not perfect whether it is prescription or
OTC so we are not going to get perfection. But I
think we need to understand a little bit why, you
know, there was such a high percentage less than 55
that chose to take it. Until we can understand
that I am not sure--you know, that may help us get
closer to the perfection part of it here. So, I
don't know. I know they had a survey, a certain
percentage of people were surveyed at the end of
the study to better understand their behavior. But
I think it would help us sort of consolidate this
issue and we could, you know, possibly address that
by some other mechanism and understand the risk in
the first trimester.
DR. WOOD: Well, it seems to me there are
two issues on the table. One is the one you just
articulated, how do we avoid them getting it and
how do we understand why they took it. If they all
had a hysterectomy, for instance, you know, that
would be different.
The second one that I am surprised nobody
from the agency or the company responded to
directly is, you know, if there are seven cases in
the database of adverse outcomes in pregnancy, just
by the seat of the pants, to me that seems
extraordinarily low. I am surprised, therefore,
that no one has offered us that kind of assurance
because it would seem to me that, given the number
of abnormalities in pregnancy that occur by chance,
that seems a pretty small number. So, it would be
interesting to know what the data are for--you
know, pick a drug. I am surprised that Merck and
no one else has told us because that is clearly the
issue that Neal was getting at. You know, he says
is this Accutane? It is clearly not Accutane and
we need to be clear on that. David?
DR. ORLOFF: Actually, I do think Merck
did answer the question in their own presentation
in this regard by concluding that, while they
believe there is a theoretical risk to exposure
with regard to fetal exposure in the first
trimester specifically related to potential
teratogenicity, they think, based on everything
that they know, that the risk appears quite low.
Again to reiterate what Dr. Meyer said and
what Dr. Davis-Bruno said, there are some animal
findings that suggest a theoretical risk. Although
there is nothing in the spontaneous reports of
exposures during the first trimester, there is
nothing that obviously stands out as a pattern, as
a clear pathological presentation that seems to
describe a syndrome of lovastatin fetal exposure,
nor do those reports completely allay any concerns.
So, nobody here can give the answer. You
have given an answer that says, flying by the seat
of your pants, you think it is relatively low.
Merck has not been so--you know, they don't fly by
the seat of their pants and they think it is
relatively low. I think the FDA has to conclude
that, on balance, it seems like it must be a
relatively low risk. But nobody actually can tell
you exactly what that is.
DR. WOOD: So, the FDA calls "the seat of
their pants" "on balance."
DR. TINETTI: My question has to do with
the long-term use of this medication. As we heard
today, this is really a new direction for
over-the-counter towards long-term use for primary
prevention. I think it is a very exciting
opportunity, but still playing by the old rules,
particularly with the actual use studies which I
think are still predicated on short-term use for
symptomatic conditions, my question to the FDA is,
is there any interest in having actual use studies
that will now more actually match the long-term use
of long-term medications if we are going to start
putting them over-the-counter?
My question to Merck is, regardless of
whether you will be required, is there going to be
some long-term monitoring if this does go
over-the-counter to make sure that as people's
cholesterols do go up after six months, do they
continue to monitor their medication if they now
take on new conditions such as diabetes that they
get more aggressive care and are not in a situation
MR. HANSEN: Can you bring up slide 1824?
As you have seen, both us as well as other
sponsors of OTC statins have done a lot of use
studies, and we really feel like most of the
questions, at least in that environment, have been
answered. So, we are very committed, if this
product is approved, to do post-marketing
surveillance and we have given a lot of thought to
this. The key issues we would be looking at are,
first of all, do consumers use it safely once it is
more available in the broad market and, secondly,
is their use consistent with the label.
So, here are the methods we have used with
other OTC medicines, and they would be extended
further in the case of Mevacor. The methods would
be that, first of all, we do surveys, toll-free
number, hotline, websites and third-party data
collection, and we would do this both among
consumers and healthcare professionals because both
of those would be important on how this product is
being used in the marketplace. Then, obviously, we
would want projectable samples to the population.
We think it is important to do a
pre-launch study because we want to understand
baseline measurements of awareness and attitudes so
we can see if this product, in effect, is having
the greater population benefit that we are
proposing. So, before the product hit the market
we would want to look at the number of untreated
people at risk and Rx users and understand their
attitudes, awareness and insight prior to being put
on the market.
As far as a post-launch study, we would
look at OTC users in addition to these untreated at
risk and Rx users, again, to see what kind of
dynamics there are with the OTC. We would use
predefined measurement frequency. What we
frequently do with OTCs is at six-month intervals
is data pulls to look at large populations to see
where we can modify the program. So, it actually
leads to actions which, first of all, if something
happened that we didn't anticipate or something
that we didn't see in the use trial, and if we do
see that, whether it is safety or behavior, to take
corrective actions in the marketplace.
DR. WOOD: Dr. Orloff points out that
Charlie Ganley's question didn't get answered and I
am just going to reiterate it, if I can, and let
you think about that while we are going through the
other questions. The question was, what are the
characteristics of the women who took the drug
while they were under 55, and tell us about the
characteristics of these women.
MR. TIPPING: Bob Tipping, from Merck,
again. Dr. Ganley, I believe your question was
about the younger women and how many women under
certain ages were actually using drug in CUSTOM. I
guess to answer that, first of all, I would remind
the committee that the age cutoff on the label for
women was driven by the risk factor approach, not
so much a concern about pregnancy.
But some of the information about the
women in CUSTOM from the user population--there
were 430 among the users in CUSTOM and 81 percent
of this group met the age criteria or did have the
interaction with a doctor. I think most
importantly, only 24 of those women were under 45
and didn't speak with a doctor. So, if we are
talking about a concern within an age group where
pregnancies do occur and then are happening within
the context of an interaction with their physician,
there are low numbers within CUSTOM that that is
Then, one final point, while there were 37
percent of women in CUSTOM less than 55, less than
that age cutoff, if you look at the non-purchaser
population, 57 percent of that group were. So, we
can argue whether 37 percent among the users is too
high, but the label messages do seem to be working
in that, you know, there is a 20 percentage point
drop in the actual women who were using the product
as opposed to evaluating it in that age category.
DR. GANLEY: Do you have any data that
tells you why a physician would tell someone less
than 45 it was okay and did they provide them
information about potential risk if they become
pregnant? Because that is what the prescription
label says a physician should do.
MR. TIPPING: In no part of our program
did we confirm what actually took place in a
physician's office. We are assuming that that
discussion did take place.
DR. GANLEY: In your first survey you
could have asked the woman what did the physician
talk to you about.
MR. TIPPING: Right. We did not do that.
DR. LEWIS: Let me address that because I
see these women every day in my practice. There
are very few premenopausal women for whom I would
recommend lipid-lowering therapy but there are a
few because of the very high risk group that would
take special attention and really don't fit in this
CUSTOM category. But if you look at the CUSTOM age
breakdown, there are a lot of women that are in
this 45-55 group who may be postmenopausal and
maybe they have two risk factors so that the
doctor's evaluation could look at them and say,
yes, you are right, you fit NCEP criteria; one risk
factor plus age 55, you don't fit that but you do
fit by other criteria and, yes, give it a try.
There are large numbers of women in that 45-55
year-old age group that are spreading their 10-year
risk very quickly.
One of the things we looked at was the
comparison of the age spread from the CUSTOM women
to the age spread from the women in the CARE study
and the curves are almost identical, with about a
5-10-year break, pretty much predicting that this
is a group of women that is at risk and the risk is
maybe 5-10 years later than the men, who have not
been getting aggressive risk factor management.
DR. WOOD: Dr. Schambelan?
DR. SCHAMBELAN: Well, I think that this
was alluded to, the reason for the age selection
here is that, as you say, it is efficacy driven,
not avoidance of pregnancy. Nowhere on the label
does it mention anything about being concerned
about becoming pregnant. It says if you are
pregnant or breast feeding you shouldn't be taking
the drug. But there is no reason someone would
think about the risk of becoming pregnant from just
reading this label. So, I am wondering if this
couldn't be alleviated to some extent by adding
that and by having these people take it into
consideration because there are lots of people who
are going to use this who aren't going to talk to
their doctor, and that seems like a pretty simple
fix to at least get that to the consciousness
DR. WOOD: Dr. Carpenter?
DR. CARPENTER: Yes, if I can divert from
the pregnancy issue, otherwise I can come back to
DR. WOOD: Go ahead.
DR. CARPENTER: My question is to Dr.
Shetty. I was really struck with somewhat of the
discordance between the survey of comprehension
versus the behavior information that was somewhat
discordant on a number of different categories. My
concern in particular has to do with the
concomitant medication risk, particularly
antifungals, certain antibiotics, and in the
over-the-counter setting and potential lack of
communication with a physician there is greater
potential for such drugs to be concomitantly
administered. Although the comprehension survey
indicated that people understood that
contraindication of certain co-administered drugs,
what was the behavior or the actual outcome in
CUSTOM as to the use of other contraindicated
DR. SHETTY: There were a total of 32
subjects that were taking interacting medications,
and 12 of them did not consult with a physician. I
think 10 of those 12 continued taking medication.
Maybe sponsor can confirm that. There was not a
large proportion of people that were taking
DR. WOOD: Dr. Parker?
DR. PARKER: I had a question about study
personnel, a term that I see on the label seven
times. I could say that the word pregnancy is only
on there twice but this isn't about pregnancy. I
wonder, it is always "doctor or study
personnel"--you know, consult, talk to. I also
took a look at the little brochure, you know, that
helps me get a coupon and, you know, I guess
getting into the study that allows the
post-marketing surveillance. I want to direct this
to the FDA, to ask you to help me understand for
other drugs that have gone to the over-the-counter
status, has the study personnel status been a part
of labels, and what does that really mean, and
could this also be viewed as direct access to
buyers of products, and what are the implications
DR. HEMWALL: I think you need some
clarification. The materials that you have in your
background packages and all the materials,
including the box and the internal materials, were
actually the materials used in the CUSTOM study.
So, in every position where you would see normally
"talk to your doctor" it says "talk to study
personnel or pharmacist."
DR. PARKER: So, these wouldn't be the
ones that would go forward? This was just for the
DR HEMWALL: Right, and that is to be
distinguished from actually going to their doctor
but in areas about study personnel and adverse
MR. TIPPING: Could I come back and just
add some additional information on the potentially
DR. WOOD: Sure.
MR. TIPPING: Just very briefly, we agree
with Dr. Shetty's number. There were 12
individuals at the beginning of the trial who were
on a potentially interacting medication and used
Mevacor without a doctor's interaction. Two of
those, however, indicated that they had stopped
their interacting medication. Then I would add to
that that during the course of the study there were
only two individuals who were prescribed a
potentially interacting medication. In both of
these situations the drug was clarithromycin and we
didn't get into the actual behavior. We
conservatively listed them amongst our 21 but, in
fact, the reported behavior from these two
individuals was that one discontinued his Mevacor
at the time of the clarithromycin and the other one
interrupted his Mevacor dose during his course of
clarithromycin therapy. So, small numbers of
individuals but I think they were exhibiting
exactly the behavior that we would hope the label
DR. WOOD: Dr. Taylor?
DR. TAYLOR: I guess I was concerned a bit
about Dr. Shetty's analyses and how they differed
in many respects, not only in terms of the number
of pregnant women, the number of individuals who
had--for example, 55 percent of users had greater
than one relative contraindication according to the
label and, yet, even with all those problems--I
will call them problems--there were no serious
signals that were seen, and perhaps this is related
to the relatively small sample that you studied.
Nonetheless, in actual practice we violate those
categories anyway. So, the argument that the
CUSTOM is not sufficiently sensitive may be true
but, on the other hand, as a practitioner I see a
lot of women who are in their 40s, with some
counseling of course, and I think some of that can
be taken as labeling.
So, I just sort of want to put a little
balance in there. That is neither a pro nor a con,
but in a real functional sense, a lot of
things--mistakes, if you want to call them
that--that occurred in CUSTOM occur every day and,
despite that, the safety record is fairly good.
DR. WOOD: Dr. Watts?
DR. WATTS: I don't want to revisit the
pregnancy issue but I do want to visit the next
step. I realize that drugs, whether prescription
or OTC, are potentially available to children in
the household. Prescription drugs typically would
come with a child-proof lid. I wonder what
precautions you are taking to prevent accidental
ingestion of Mevacor OTC by children, and if you
can give me some idea of how much drug might pose a
problem for, say, an average one year-old or 18
month-old child who might get hold of it?
DR. HEMWALL: Well, first and foremost,
the package will be in child-resistant packaging
and, obviously, that is something that is done with
prescription drugs as well. We can go to some
slides that we can show you but it is almost
impossible to overdose acutely on lovastatin.
Very, very large doses have been tolerated. It is
actually written up in some detail in your
background package. We have the data from poison
control centers. So, even though we are expecting
full child-resistant packaging and that is our
plan, if some child were to inadvertently be able
to break open a lot of blisters or bottles and get
into it, it would be very hard to overdose.
DR. WOOD: Dr. Schade?
DR. SCHADE: There is a portion of this
package that is very confusing to me. I understand
that the company is targeting the intermediate risk
group, but it seems to me they are actively
excluding a high risk group. This is what is
confusing to me, it says, "do not use unless
directed by your doctor if you have...," and then
they list six things. Included in those six things
are, one, ever had a heart disease (heart attack or
angina, and then diabetes.
Now, let me put this in the context of the
real world. I come from New Mexico where a very
high percentage of our population has no insurance
and the only doctor they ever see is in the
emergency room where they come in once a year with
their pneumonia or something else even if they are
at high risk. Of course, we also have a very high
incidence of diabetes. So, I see them reading this
and they are not going to see a doctor. Even if
they have a doctor, it often takes four months to
get in to see one.
I don't understand why we are actively
excluding the high risk group when the high risk
group, in fact, would probably benefit more from 20
mg of lovastatin than from nothing at all and that
is really the alternative here. In other words, in
the real world where we have many uninsured people
who can't afford to see a doctor, who don't see
doctors, this drug might be of great benefit. And,
I don't understand whey the packaging here seems to
directly try to ward off the high risk population.
Now, Dr. Gotto made a comment with which I
agree, that in the best of worlds all these
patients would be put on 40 mg of simvastatin and
be followed with their LDLs. Well, the fact is
that it doesn't happen in my state and I would like
to see this changed to encourage people at high
risk, who are unable to see a physician, that this
drug might help them, and a statement to the effect
that they ought to see a healthcare professional
because the dosage may be insufficient, or some
other reason, but not to actually ward them off
from taking a drug that may be really beneficial to
DR. HEMWALL: Yes, we agree with you that
people at even high risk could benefit from taking
this if they were taking nothing else, but we still
want I think to stay within the realm where we are
treating the people that could most benefit by this
than trying to get the people that could benefit
from more comprehensive physician care, treating
their diabetes and their post-MI more aggressively
with full physician involvement. So, this would be
a gap I think in reaching the balance between
trying to attract the right people and then
directing the people that are at higher risk to see
their physician. But we take your point.
DR. WOOD: Yes, I agree with Dr. Schade.
It seems to me that there is a huge problem in
listing as a contraindication the patient who needs
it most, which doesn't make a lot of sense in any
sense, and it also trivializes the
contraindications. So, it does seem to me that it
is important that patients understand that
something is a contraindication, not really a very
strong indication which is co-mingled right now.
So the strongest indications are also
contraindications in your label, which is crazy.
MR. HANSEN: I just want to clarify, it is
not a true contraindication--
DR. WOOD: I understand.
MR. HANSEN: --what we say is "do not use
unless directed by your doctor." Then within the
materials a phrase that has been very helpful and
that is that "OTC medicine may not be enough for
you. You may need prescription therapy." So,
there is that balance we are trying to make by not
inducing high risk people.
DR. WOOD: Neal?
DR. BENOWITZ: A question for the FDA,
somewhere I saw mentioned that the marketing
material or promotion material is regulated by FTC,
not FDA, once it is approved. Is that right?
DR. GANLEY: The advertising is FTC.
DR. BENOWITZ: So, will you be checking
out their materials as well to make sure that it is
DR. GANLEY: We can ask a company for
their advertising material and they don't have to
send it to us.
Let me put it this way, and we ask all the
time. I have been in OTC quite a few years and I
can't remember the last time someone sent me some.
It is interesting, you know, usually who we get it
from is a competitor.
But I think the other thing is that we do
have a relationship with FTC, and FTC has a huge
market they have to oversee and they are making
judgments as to what they are going to put their
resources to if they have to take an action because
someone is marketing outside the labeled
DR. BENOWITZ: I am sure this will come up
tomorrow and I don't know if we will have a chance
to talk to the sponsor, but I have a concern about
appropriate communication of benefits to people to
decide where they are going to spend their money
and efforts, and I think it is workable but I think
with a lot of drugs there are concerns, as everyone
knows, about over-promotion and this could be
DR. GANLEY: That is what I was trying to
point out in my initial discussion because the
label is focusing on a certain population, as we
discussed at length. Depending on how a drug is
marketed or advertised, clearly could pull in a
population that was not originally intended. Now,
that is taken in the context of, you know, a
company is such a good marketer that they are able
to convince someone to buy a drug that treats no
symptoms for them for the rest of their life. So,
you know, you have to put it in that context too,
that someone will really have to want to take this
drug. But I think it is important for someone to
understand, you know, what is the benefit up front;
how long I have to take it; what is the downside to
this; and whatever population you are pulling
in--you know, if they don't understand the label
and they are just going to buy the product because
they are very health conscious and they want to
control their cholesterol, well, I am not sure that
is the best thing but that is the way, you know,
people make decisions sometimes.
DR. BENOWITZ: I certainly agree with you.
I think the dietary supplement industry is an
example where you can market to a lot of people
taking medications to allegedly improve their
health for many years at a billion dollars of
expense. I just think that at some point in time
someone should make sure that the benefits to the
individual are really made clear to them so they
will know what they are getting, and how long they
have to take the medicine, and what it is going to
cost them. I just want to be reassured that FDA
will be doing that at some level.
DR. GANLEY: Again, if it is an
advertising issue we don't have much control. If
it is a labeling issue or something to that effect
that will adequately convey that message, then we
do have control. I think that is why it is
important to understand did someone adequately
understand the benefit. You raised it earlier in
terms of the absolute benefit to them--you know,
may be a better way of trying to convey it to
someone so they really understand that. I think
that is very important.
DR. WOOD: But although the FDA may be
unwilling to step into that, this advisory
committee could provide very strong recommendations
that the FDA should take control of advertising
over-the-counter drugs. I am serious--not that I
am ever reactionary, right? I mean, we could make
that as a recommendation tomorrow, Neal, if you
thought that was important and, you know, we would
see probably fewer young ladies skipping through
fields of daisies, and so on. Yes, Dr. Woolf?
DR. WOOLF: I have to get back to the
question of post-marketing surveillance. The EDMAC
committee has probably asked about this at every
committee meeting where we have been asked to
approve a drug, about how effective it is, and it
is certainly an issue that has been in the news the
last month or so.
How can we be assured that, in fact, there
is appropriate post-marketing surveillance that is
carried on despite the promises in this room this
afternoon? What teeth are there that six months
after the drug has been approved for
over-the-counter use, assuming that it is, that in
fact data is being collected, being distributed and
being looked at based upon that surveillance?
DR WOOD: The short answer is there
aren't; there is no assurance.
DR. GANLEY: I am not sure what the
question is. If something happens and someone
takes the time to fill out a MedWatch report,
whether it is prescription or OTC, we look at those
things, as would many companies--look at them
DR. WOOLF: I understand that--
DR. WOOD: He is talking about Phase IV
DR. WOOLF: Merck has promised a
post-marketing surveillance survey to do something
far more elaborate and proactive than that, and the
EMDAC committee has heard this before, that a
company will do that but my understanding is the
FDA has a hard time trying to enforce that.
DR. WOOD: He is talking about a Phase IV
DR. BRINKER: Excuse me, I didn't mean to
interrupt you. I am Alan Brinker from the Office
of Drug Safety. Let me just say that if you have a
specific concern that you want to raise for the
post-marketing environment, then that is engendered
to Merck to provide a protocol and we will look at
that. So, you know, we have almost ten years worth
of experience in looking at this drug alone, plus
all the statins. So, we have a pretty good handle
on that. But if you have a concern, then we will
follow it up in the post-marketing environment.
DR. ORLOFF: But to respond to your
question about how much leverage does FDA have with
regard to enforcement of these sorts of commitments
on the part of the sponsor, in the absence of a
contingent approval, for which there is a
regulatory instrument that would not apply here as
far as I understand, that is to say an
over-the-counter switch, we do not have a legal
That said, as you yourself have pointed
out just for the endocrine and metabolic drug area,
across the different drug areas or the
pharmaceutical classes that are regulated in the
United States, there are multiple such commitments
that are essentially described at the time of
approval as a matter of public record and there are
clear incentives in that alone for the companies to
adhere to or to maintain those commitments.
At some level, it is a gentlemen's
agreement, if you will, but from one instance to
the next there is no necessary reason for you or
for the public to believe that a commitment is not
going to hold. So, our job here, and your job, is
to think about what sorts of information you think
FDA should be concerned about garnering in the
post-marketing period, to propose that, and we can
take it forward from there.
DR. WOOD: Well, David, a third of the
Phase IV studies that are mandated are not started,
or weren't started in the last survey. So, I mean,
that is not entirely true. Anyway, let's move on.
DR. ORLOFF: But, Alastair, I want to make
it clear. I mean, I don't know any other way to
state it but on a case by case basis. I don't
think we can go into this process with an
assumption that no one's word is worth anything or
that putting this out in the public domain has no
weight. There is experience in the Food and Drug
Administration with the pharmaceutical industry of
success in adherence to Phase IV commitments.
There is apparently a record that may be overall
less than satisfactory, but that doesn't mean that
we can't talk about what is necessary now. DR.
WOOD: All right. We have one more question.
DR. HEMWALL: I just want to add that
Merck Research Lab has a perfect performance record
in adhering to Phase IV commitments that we make at
the time of approval, and we would expect to uphold
DR. WOOD: Frank?
DR. DAVIDOFF: Just to get back briefly to
the issue of pregnancy, it seems to me there are at
least two reasons for some reservations about the
existing data. One is that, as I understand, the
reported number of adverse pregnancy outcomes is
really very small. It is 7, or 30 or 40, depending
on which universe you are looking at. But given
the millions of doses and years that is quite
But at the same time, as I understand
this, this is all voluntary reporting and voluntary
reporting is well-known to be grossly
under-reporting and it is not good sampling. So,
it is quite possible that the numbers are larger
than that and we really can't make a judgment about
that. But to assume that these are all the cases
that have happened is not probably appropriate.
The other comment is on the issue of the
apparent lack of a pattern of fetal abnormalities
and the outcomes of the adverse pregnancy outcomes
as somehow being reassuring and that there were no
common biological mechanism at work. On the other
hand, we are learning rapidly that the statins are
not simple agents when it comes to biological
actions. In last week's New England Journal there
was a very striking article about the apparently
cholesterol-independent actions of statins,
probably relating somehow to the inflammatory
response. So, I think that it is hard to interpret
this lack of pattern as meaning that this is
somehow not related to the presumed single action
of the statins because I think the actions are not
single; I think they are quite complex.
I think that that also gets to the issue
of assuming that the teratology or the damage to
fetuses is going to be related to myelination
because it assumed--somehow the simplistic
assumption is made that all they do is to interfere
with cholesterol metabolism. I don't think that is
fair. It seems to me that there might very well be
other developmental abnormalities that have nothing
to do with cholesterol metabolism. So, at least in
my own mind, I have maintained a little bit of
reservation from these data that I have been
hearing are being interpreted otherwise.
DR. ORLOFF: Alastair, I would like to
clarify. Understand, I am not a toxicologist and,
as I said, in terms of absolute risk,
unfortunately, all we are left with is hazarding a
guess. When I said there was no pattern apparent
that would suggest a lovastatin fetal syndrome,
yes, there are clearly multiple final mechanistic
effects of statins. But I think it is safe, for
purposes of at least beginning to conceptualize
this, to understand that there is absolutely no
evidence that statins work in any other way except
as HMG CoA reductase inhibitors. I mean, that is a
hard one to deny. Yes, HMG CoA reductase
inhibition itself engenders multiple cellular,
biochemical and systemic effects but these are HMG
CoA reductase inhibitors first and last.
Now, it may turn out that some of them do
have pleiotropic effects beyond HMG CoA reductase
inhibition per se but that has never been
established. They are designed as such, and I
think we have to start at least by considering that
that is their mechanism of action.
DR. WOOD: I completely agree with you but
I would just caution that what Frank I think is
saying is that beta blockers act exclusively by
beta blockade but practolol had an effect that was
independent of beta blockade. I think that is the
point he is trying to make.
But on that note, and the FDA having
conceded "seat of the pants" analysis, we are going
to stop for tonight and reconvene at eight o'clock
in the morning.
[Whereupon, at 5:15 p.m., the proceedings
were adjourned, to reconvene on Friday, January 14,
2005 at 8:00 a.m.]
- - -