FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

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JOINT MEETING

OF THE

NONPRESCRIPTION DRUGS AND GASTROINTESTINAL DRUGS

ADVISORY COMMITTEES

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Friday, October 20, 2000

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The meeting was held at the Holiday Inn Gaithersburg, Two Montgomery
Village Avenue, Gaithersburg, Maryland 20879, at 8:00 a.m., Eric P.
Brass, M.C., Ph.D., Chairman of NDAC, presiding.

PRESENT:

ERIC P. BRASS, M.D., Ph.D., NDAC Chairman

GEORGE A. BLEWITT, M.D., NDAC Industry

Liaison (non-voting)

LOUIS R. CANTILENA, JR., M.D., Ph.D., NDAC

Member

SIDNEY COHEN, M.D., GIDAC Guest (non-voting)

SUSAN COHEN, NDAC Consumer Representative

(non-voting)

RALPH D\'AGOSTINO, Ph.D., NDAC Consultant

(voting)

GEORGE DOUGLAS, Ph.D., GIDAC Guest (non-

voting)

PRESENT (Continued):

JANET ELASHOFF, Ph.D., NDAC Consultant (voting)

NANCY L. GELLER, Ph.D., GIDAC Member

EDWIN E. GILLIAM, Ph.D., NDAC Member

JULIE A. JOHNSON, Pharm.D., NDAC Member

Y.W. FRANCIS LAM, Pharm. D., NDAC Member

JON MIRSALIS, Ph.D., GIDAC Guest (non-voting)

RICHARD A. NEILL, M.D., NDACA Member

MALCOLM ROBINSON, M.D., GIDAC Guest

(non-voting)

GEORGE SACHS, M.D., GIDAC Guest (non-voting)

HARI C. SACHS, M.D., NDAC Member

SAMUEL SHAPIRO, M.B.B.CH., MRCP, NDAC

Consultant (voting)

MARVIN M. SHUSTER, M.D., GIDAC Guest

(non-voting)

WILLIAM M. STEINBERG, M.D., GIDAC Member

DONALD L. UDEN, Pharm.D., NDAC Member

HELGE L. WALDUM, M.D., GIDAC Guest

(non-voting)

SANDRA TITUS, Ph.D., NDAC Executive Secretary

SPONSOR REPRESENTATIVES:

DOUGLAS Ws. BIERER, Ph.D., Procter & Gamble

TOMMY ANDERSON, Ph.D.

DONALD O. CASTELL, M.D., Graduate Hospital

LEWIS KINTER, Ph.D.

DOUGLAS LEVINE, M.D., AstraZeneca, L.P.

SPONSOR REPRESENTATIVES (Continued):

BRIAN REID

BERNARD P. SCHACHTEL, M.D., Yale University

School of Medicine

NORA ZORICH, M.D., Ph.D., Procter & Gamble

FDA REPRESENTATIVES:

MARK AVIGAN, M.D., DGCEDP

LING CHIN, M.D., M.P.H., DOTCDP

JASPI CHOUDARY, B.V.Sc., Ph.D., DGCDP

JOSEPH DeGEORGE, Ph.D., DGCDP

ROBERT DeLAP, M.D.

CHARLES GANLEY, M.D., DOTCDP

LARRY GOLDKIND, M.D., DGCDP

LINDA KATZ, M.D., DOTCDP

KAREN LECHTER, J.D., Ph.D., DDMAC

VICTOR RACZKOWSKI, M.D., ODE III

C-O-N-T-E-N-T-S

[PAGE]{.underline}

Introductions 5

Conflict of Interest Statement 8

Introduction to the Issues, Charles Ganley, M.D. 12

Sponsor\'s Presentation:

Douglas Ws. Bierer, Ph.D. 13

Don Castell, M.D. 21

Nora Zorich, M.D., Ph.D. 28, 71

Bernard Schachtel, M.D. 43

Douglas Levine, M.D. 56

FDA\'s Presentation:

Larry Goldkind, M.D. 99

Ling Chin, M.D., M.P.H. 112

Mark Avigan, M.D. 120

Karen Lechter, J.D., Ph.D. 148

Charge to Committee 180

P-R-O-C-E-E-D-I-N-G-S

(8:03 a.m.)

CHAIRMAN BRASS: Good morning. I\'m Eric Brass. I\'d like to welcome you
all to this joint meeting of the Nonprescription Drug and
Gastrointestinal Advisory Committees to consider the approval of
Prilosec or omeprazole.

We have a number of guests with us today. So I\'d like to begin by just
going around the table allowing everybody to introduce themselves. This
will also be microphone practice. Please be sure to turn on the
microphone when you speak and to turn it off when you\'re done so that
miscellaneous remarks don\'t get broadcast throughout the room.

Perhaps we could being with Dr. Mirsalis.

DR. MIRSALIS: I\'m Jon Mirsalis, Director of Toxicology at SRI
International in Menlo Park, California.

DR. GEORGE SACHS: This way?

I\'m George Sachs, physiology and medicine, UCLA.

DR. ROBINSON: I\'m Dr. Malcolm Robinson at the Oklahoma Foundation for
Digestive Research at the University of Oklahoma Health Sciences Center.

DR. BLEWITT: George Blewitt, industry representative for NDAC.

DR. DOUGLAS: I\'m George Douglas. I\'m head of the Mutagenesis Section,
Department of Health in Canada.

DR. WALDUM: Helge Waldum, professor of gastroenterology, Trondheim,
Norway.

DR. SHAPIRO: Samuel Shapiro, emeritus Director of the Sloan Epidemiology
Unit at Boston University.

DR. SHUSTER: Marvin Shuster, gastroenterologist and professor emeritus
of medicine and psychiatry at Johns Hopkins University School of
Medicine.

DR. COHEN: Sidney Cohen, gastroenterologist, Chairman of Medicine at
Temple University School of Medicine in Philadelphia.

DR. STEINBERG: William Steinberg. I\'m a gastroenterologist in private
practice in Washington, D.C.

MS. COHEN: I\'m Susan Cohen, the consumer representative.

DR. GILLIAM: I\'m Edwin Gilliam a family nurse practitioner from Tucson,
Arizona on the NDAC Committee.

DR. TITUS: I\'m Sandy Titus. I\'m the Administrator for the
Nonprescription Drugs Advisory Committee. I\'m with the FDA.

DR. CANTILENA: Yes. I am Lou Cantilena, head of clinical pharmacology at
the Uniform Services University.

DR. ELASHOFF: Janet Elashoff, biostatistics, UCLA and Cedar Sinai.

DR. GELLER: Nancy Geller. I\'m the Director of Office of Biostatistics
Research at the National Heart, Lung, and Blood Institute in Bethesda.

DR. UDEN: I\'m Don Uden, University of Minnesota, member of NDAC.

DR. JOHNSON: Julie Johnson, University of Florida, member of NDAC.

DR. D\'AGOSTINO: Ralph D\'Agostino, Boston University, biostatistician.

DR. LAM: Francis Lam, University of Texas Health Science Center in San
Antonio, a member of NDAC.

DR. NEILL: Richard Neill, a family physician and faculty member from the
University of Pennsylvania.

DR. KATZ: Linda Katz, Deputy Director from the Division of
Over-the-counter Drug Products at the FDA.

DR. GANLEY: Charlie Ganley, Director of Division of Over-the-counter
Drug Products, FDA.

DR. RACZKOWSKI: I\'m Victor Raczkowski, Deputy Director in the Office of
Drug Evaluation III, at the FDA.

CHAIRMAN BRASS: Thank you.

I\'ll now ask Dr. Titus to review the conflict of interest statement.

DR. TITUS: The following announcement addresses the issue of conflict of
interest with regard to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

Based on the submitted agenda and the information provided by the
participants, the agency has determined that all reported interests in
firms regulated by the Center for Drug Evaluation and Research present
no potential for a conflict of interest at this meeting, with the
following exceptions.

In accordance with 18 USC 208(b), full waivers have been granted to Drs.
Eric Brass, Ralph D\'Agostino, Edward Krenzelok, Hari Sachs, William
Steinberg, and Ms. Susan Cohen.

Copies of these waiver statements may be obtained by submitting a
written request to FDA\'s Freedom of Information Office, located in Room
12A30 of the Parklawn Building.

In addition, we would like to disclose for the record that Dr. Francis
Lam has an interest which does not constitute a financial interest
within the meaning of 18 USC 208(a), but which could create the
appearance of a conflict. The agency has determined notwithstanding this
interest that the interest of the government in his participation
outweighs the concern that the integrity of the agency\'s programs and
operations may be questioned. Therefore, Dr. Lam may participate in
today\'s discussion of Prilosec.

We would also like to note for the record that Dr. George Blewitt is the
non-voting industry representative and is on the Nonprescription Drugs
Advisory Committee to represent industry interests. As such, he has not
been screened for any conflict of interest.

With respect to FDA\'s invited guests, their reported interests which we
believe should be made public to allow the participants to objectively
evaluate their comments.

Dr. Marvin M. Shuster would like to disclose for the record that he has
in the past served as a consultant to Glaxo Wellcome, Janssen, and Tap
Pharmaceutical.

Dr. Shuster would also like to disclose that he is retired from Janssen
Pharmaceutical.

Dr. Helge Waldum would like to report that ‑-

DR. SHUSTER: Could I correct that, please? I am professor, the
Janssen-Strauss-Hallbright Professor of Medicine emeritus. So I\'m a
former professor of medicine, which was co-sponsored by Janssen.

DR. TITUS: Thank you.

Dr. Helge Waldum would like to report that his daughter is employed by
AstraZeneca.

Dr. George Sachs would like to report the following interests. He
consults for AstraZeneca, Wyeth Ayerst, Byk Gulden, Eisai-Janssen, and
Takeda Abbott. He also serves as a speaker for Wyeth Ayerst and
Eisai-Janssen.

Dr. Sachs has also reviewed and served as a scientific advisory on
omeprazole, lansoprazole, pantoprazole, and rabeprazone.

Dr. Sidney Cohen reports that he has given individual talks, performed
research studies, and consulting on omeprazole and lansoprazole.

Dr. Jon Mirsalis reports that he has in the past performed work for
SmithKline Beecham, Procter & Gamble, Merck, and Tap Pharmaceutical. Dr.
Mirsalis has also served as an expert on a review panel for lansoprazole
in the early 1990s.

Finally, Dr. Mirsalis reports that he served on an advisory panel for
Tap Pharmaceutical on the toxicity of omeprazole and lansoprazole.

Dr. Malcolm Robinson reports that he has served as a consultant and
speaker for firms that manufacture H2 receptor antagonists. Dr. Robinson
has spoken most recently for Janssen Pharmaceutical.

Lastly, Dr. Robinson has served as an investigator for Johnson &
Johnson, Tap, Wyeth Ayerst, AstraZeneca, Eli Lilly, SmithKline Beecham,
and Procter & Gamble.

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 first whose products they may wish to comment upon.

CHAIRMAN BRASS: Thank you.

Yes, sir.

DR. SHAPIRO: Some time in the past \-- I can\'t remember when \-- I
performed a study of Astra.

CHAIRMAN BRASS: Thank you.

I will also note that anyone who is interested in participating in the
open public hearing this afternoon, please be sure to register at the
information desk in front.

I\'ll now turn the floor over to Dr. Charles Ganley to introduce the
issues for today\'s discussion.

DR. GANLEY: Yeah, I\'m just going to be very brief about this so that we
can get on with the meeting. I know there\'s a lot of information to go
over, and what I want to do is just try to focus the committees on what
the differences are in views between the sponsor and the agency.

The Advisory Committee will review the data to support the use of
Prilosec for the treatment of heartburn in the over-the-counter market.

There are some differences of opinion between the sponsor and FDA review
divisions in the interpretation of the data, the efficacy data,
particularly the data pertaining to the acute relief symptom, the acute
relieve of symptoms and how this product is likely to be used in the OTC
market.

I think you\'ll see these distinctions as we go through the
presentations, and the one concern of the FDA is how the product is
likely to be used, and that individuals with gastroesophageal reflux
disease may be actually using this product in the over-the-counter
market, and we don\'t really take a view on this.

We actually want the opinion of the committees of whether this is an
appropriate treatment, and if it is an appropriate treatment, is the
product appropriately labeled for that?

I think I\'ll leave it at that for now and get started with the
discussion.

CHAIRMAN BRASS: Thank you.

We will now turn the floor over to the sponsors for their presentation,
which I understand will be coordinated by Dr. Bierer.

DR. BIERER: Ladies and gentlemen, the Advisory Committees, and members
of the Food and Drug Administration, good morning. My colleagues and I
are pleased to be here today to present the data that supports the new
drug application for the Rx to OTC switch of omeprazole magnesium.

My name is Doug Bierer, and I have the regulatory responsibility of
Procter & Gamble for this product, which is a collaborative effort
between AstraZeneca and the Procter & Gamble Companies.

The purpose of our presentation today will be to show you that
omeprazole magnesium is an excellent candidate to be switched from Rx to
OTC status.

In our NDA, we studied two indications: the relief of and prevention of
heartburn, acid indigestion, and sour stomach. We also studied two
doses. We studied the lowest Rx dose, 20 milligrams, and half of the
lowest Rx dose, ten milligrams.

When we began our program about four years ago, we based our program on
existing H2 receptor antagonist paradigms and models. We have learned a
lot since then, and we want to share this learning with you during our
presentations today.

Omeprazole has been marketed for over 12 years and is approved for eight
indications at doses ranging from 20 to 80 milligrams. Recently both ten
milligrams and 20 milligrams were switched from Rx to OTC status for the
treatment of heartburn in Sweden.

Omeprazole is currently available in more than 100 countries and today
more than 380 million patient treatments have been used worldwide.

In our program we conduct an extensive clinical program to understand
the safety and efficacy of the product. In addition, we conducted an
extensive consumer research program to broaden our understandings of
consumers\' needs and how they use the products. And our presentation
today will show the results of this.

There has been a steady evolution in the OTC heartburn management. It
started with antacids for the symptomatic relief of heartburn systems.

Next, H2 antagonists added prevention, which is prevention before
provocative meal.

And now we\'re looking at a new entry into the OTC heartburn management,
which is omeprazole proton pump inhibitor.

We believe that omeprazole provides a new level of benefit, 24 hour
protection with the convenience of a single tablet. And this will extend
the existing continuum of heartburn management.

What I\'d now like to turn to is how consumers use \-- what their
heartburn is, how they use medications, and also their interactions with
physicians.

In the consumer research that we conducted, we found that 40 percent of
U.S. adults currently experience heartburn, quite a common ailment, and
of those, 46 percent have heartburn that occurs once a week or more.
That\'s more than 50 million consumers.

And of the consumers that use OTC H2 receptor antagonists, they
generally suffer a frequency of heartburn about 2.4 times per week, and
of those, 58 percent of the H2 users suffer heartburn on two or more
consecutive days during the week.

Thus, many OTC heartburn consumers have frequent heartburn.

People who have heartburn also use OTC medications to manage their
heartburn. In fact, 77 percent of them use OTC medications, and the
medications that they use ar basically antacids, 80 percent, or H2
receptor antagonists, 64 percent.

And the reason this adds up to more than 100 percent is that several
times H2 users will use an antacid product to supplement their
medication regimen. OTC medicines are used for both relief and
prevention of heartburn. In fact, we found that 26 percent of OTC H2
users used it preventatively.

There is a question of whether people who are using H2 products actually
see their physician or speak with them. In the research that we
conducted in more than 2,000 OTC consumer users, we found that 60
percent of them who suffer heartburn consult with a physician or a
pharmacist. In fact, those people who have heartburn greater than once a
week, 79 percent of them seek physician advice.

And when those people do see their physician, more than 60 percent of
them have a recommendation for an OTC medication. This raises a question
of whether the people that in switching a drug from Rx to OTC, whether
that will actually keep people from seeing their physician, and we
studied that in the following ways.

We wanted to understand whether the H2 antagonist from Rx to OTCs
actually resulted in less physician visits. Let\'s look at the data.

The first evidence comes from studies that are two published studies and
one study that we conducted ourselves. The first was from the Fallon
Clinic involving more than 2,000 patients with acid related conditions,
and that study reported there was no change in the number of doctor
visits before and after the switch of H2 receptor antagonists.

Second, the Minneapolis consumer survey conducted by Dr. Shaw showed
there was no change in the mean number of doctor visits before and after
the switch of H2s.

And in the study that we conducted looking at administrative claims of
move than 7,000 patient records, we found that the number actually
increased of doctor visits for heartburn, dyspepsia, and reflux. So the
data supports that with the switch of Rx to OTC, especially of the H2,
that there was no change in the number of physician visits.

We believe that physician visits and seeking professional help is
important, and we want to emphasize this with our labeling and our
consumer education program.

Despite the fact that OTC products are widely available, both the H2
antagonists and the antacids, we found that there are definite unmet
consumer needs, and this involves, first, a lack of all day efficacy and
symptom breakthrough. We found that many people need to take more than
one product a day in order to control their heartburn.

Sixty-three percent of antacids take more than two doses a day, and the
number is 42 percent among the H2 users.

Also, they use multiple therapies to control their heartburn. With
people that are taking daily H2s, also 74 percent take an antacid
product two or more times a week in order to control their heartburn,
and they do this either before, during, or after they have taken their
H2 product, and also consumers do want the convenience of dosing.

In looking at this, we wanted to find out and discover who are the
consumers who will benefit from the OTC use of omeprazole. These are
adult users of OTC products. They\'re also the consumers who use
heartburn medications preventively and also consumers who have heartburn
more than one time a week and use OTC medications. This is the OTC
population that we are seeking for OTC omeprazole.

Even with the unmet consumer needs, we find that many consumers are
still looking for ways to control their heartburn, and we believe that
omeprazole magnesium provides a solution for this by providing 24 hour
duration of effect, complete prevention of symptoms with the convenience
of a single tablet.

In considering the switch of omeprazole to OTC status, we evaluated our
data against six key criteria. There are:

The appropriateness of the omeprazole for the OTC management of
heartburn;

The effectiveness of the doses under consideration;

Whether the ability of consumers to comprehend the label instructions
and to use the product appropriately;

The safety for use in an OTC setting;

The benefits of OTC use outweighing potential risk;

And, finally, the appropriately labeled for a consumer use.

During our presentation today, we will show you that we have met each of
these criteria.

With this, I\'d like to introduce the flow of our presentation today.
First, Dr. Don Castell will talk about heartburn management and where
omeprazole fits into the OTC use of that.

Next, Dr. Nora Zorich will review our extensive clinical data showing
that the strength of omeprazole is in treating and preventing heartburn.

Next, Dr. Bernard Schachtel will review the consumer use studies and
also our label comprehension studies.

Next, Dr. Douglas Levine will review our vast amount of safety data with
omeprazole, showing that omeprazole is safe for OTC use.

And finally, Dr. Nora Zorich will show us how with appropriately
labeling omeprazole is an excellent candidate to be marketed as an OTC
product.

We are confident that the data we will now present demonstrates that
omeprazole is both safe and effective for the use in an OTC setting, and
now I\'d like to introduce Dr. Don Castell.

DR. CASTELL: Good morning, everyone. Can you hear this in the back? Oh,
now you can hear it in the back.

It\'s nice to be here with you. My name is Con Castell, and as you
heard, I\'m the Chairman of Medicine at the Graduate Hospital. More
importantly, I\'m a gastroenterologist, and I hesitate to tell you this,
but I have been one for over 30 years.

And during that time, I have focused my interest primarily on the
esophagus, both clinical and research interests. People call me an
esophagologist, and perhaps I should define that term for those of you
that are not familiar with it. That\'s best defined as an individual who
makes a living out of heartburn, whereas most folks have heartburn from
making a living. And even though that\'s amusing, that\'s exactly what
we have done.

We esophagologists have studied these patients with heartburn as a
symptom of gastroesophageal reflux, and again, let me define that term
for you, if I might.

We esophagologists tend to use the term \"gastroesophageal reflux
disease,\" or GERD, as many of you know. It\'s become very popular. The
definition that most of us subscribe to is that this is basically the
symptoms that are produced by the reflux of gastric contents, primarily
acetic gastric contents, into the esophagus with or without the presence
of esophageal mucosal damage or esophagitis.

And one of the points that I will try to leave you with today is that
this symptom of heartburn pervades the entire spectrum of GERD.

Now, thinking about the potential for an over-the-counter switch for a
very effective drug like omeprazole, a number of questions, I think,
need to be dealt with. I\'ve listed them here for you.

When is heartburn not GERD?

What is the prevalence of this condition? We\'ve heard a little bit of
that already.

Which patients are candidates for the potential OTC switch of a PPI?

Is long-term PPI use safe?

And perhaps the most important question: would an OTC proton pump
inhibitor use mask an important disease?

Let me try to deal with these. Here you see a perspective on the
so-called GERD iceberg. Now, I have to tell you that 15 years ago we
published this in a very obscure publication, but for some reason it has
a life of its own and it keeps recurring.

But the concept that was developed at the time was to try to give a
perspective on how reflux disease presents in the population. Underneath
the water line, which would be somewhere here perhaps, are a large group
of patients that treat themselves over the counter. You\'ve heard some
about that. You\'re going to hear more about that today.

And they treat themselves with life style in various over-the-counter
medications. Somewhere up here, we could draw a line, and now the
physicians begin to interact, and usually the primary care physicians
using therapies, such as proton pump inhibitors and prescription H2
blockers.

We gastroenterologists and esophagologists are more likely to see the
patients up here at the tip of the iceberg. The difference in where
people are on this iceberg basically relates to the chronicity or
persistence of their symptoms, and that symptoms is heartburn.

You heard these data already. So I will very quickly go through this.
This is from a study we performed again almost 24 years ago in 1,000
individuals where we simply asked do they have heartburn and how often.
What precipitates it, et cetera?

And as the slide shows, about 11 percent of the U.S. adults have
heartburn every day, about 13 percent on a weekly basis, and about 18
percent on a monthly basis for a total of about 42 percent. This is a
common condition.

More importantly perhaps is what do we find when we endoscope a patient
with heartburn? This then being the endoscopic spectrum of GERD,
heartburn being the symptom that brings the patient to the physician.

Approximately half of the time we do not find any evidence of injury,
that is, there\'s no esophagitis. Some people would call that innocent
GERD, but GERD nonetheless.

Forty percent of patients will find some evidence of esophageal erosive
disease, and roughly ten percent of individuals will find evidence of
Barrett\'s esophagus. Now, that\'s a metaplastic change in the lining.
That\'s, I would argue, the important condition that people are worrying
about masking when they consider over-the-counter treatment.

And then this little slice here says that about one half a percent of
patients with Barrett\'s per year are likely to develop adenocarcinoma
of the esophagus, or cancer of the esophagus.

I think that this observation is a very important one that summarizes
what\'s been known for some time. It, however, happens to be a very
recent one, published just two months ago by these investigators out of
Duke University, and they\'ve compared roughly 100 individuals with
Barrett\'s esophagus. That\'s the yellow bars, and patients with
otherwise uncomplicated GERD, with or without esophagitis. That\'s the
blue-green bars here.

And they looked at the severity of reflux symptoms, that is, heartburn,
and what they found was that they could not predict whether the patient
was a Barrett\'s patient or an uncomplicated GERD patient based on the
presentation. The severe symptoms were just as likely in both groups.

And, in fact, mild heartburn was more likely in patients with Barrett\'s
esophagus than in patients of uncomplicated GERD. Now, we\'ve known this
a long time, but when you have the metaplasia to the lining of the
esophagus, you lose the sensitivity to the ongoing acid exposure.

So one could argue that if we\'re worried about masking Barrett\'s with
a more potent acid suppressing drug, that we are potentially already
doing that with the over-the-counter products that are already out there
because many of these people have mild symptoms and will respond to an
H2 receptor antagonist.

What about heartburn and GERD then? I would argue with you that
heartburn is the typical symptom of GERD. The symptoms have been shown
to correlate poorly with the level of tissue damage, particularly the
Barrett\'s, as I discussed.

GERD usually recurs after effective treatment. That is, we see it as a
chronic condition.

Now, let\'s talk about the risk for just a minute. And, again, I try to
bring to you the most recent comment that I could find in the
literature, again, in the year 2000 by John Dent and colleagues, a very
well respected international esophagologist, if you will.

And Dent said in this particular publication the substantial data that
now exists from long term treatment of humans with proton pump
inhibitors has not thus far revealed any definitive risks.

Then he went on to say as a little barb to our surgical colleagues the
risk of death from anti-reflux surgery, although small, would seem to
far exceed any possible risk associated with long-term proton pump
inhibitor use.

Perhaps more important, the studies out of Amsterdam by Ellie
Klinkenberg and her colleagues, published in
[Gastroenterology]{.underline}, again, in this year 230 patients with
continuous prescription treatment with omeprazole for 11 years and doses
ranging from 20 up to 120 milligrams a day.

Yearly endoscopy looking for histologic changes in the gastric fundus.
After 1,500 patient-years of follow-up, no serious adverse side effects
have been seen. This is the longest continuous observation of any series
of patients worldwide.

Conclusions then, coming back to the questions that I posed at the
beginning. What is the relationship for heartburn and GERD? Heartburn is
the symptom throughout the spectrum of GERD. I don\'t believe you can
separate the two, and any kind of separation I think is artificial.

What is the prevalence? Roughly 42 percent of the population has
heartburn some of the time.

Who then do I think might be candidates for over-the-counter omeprazole?
I think those patients that can use it for the prevention of predictable
heartburn, and perhaps it\'s time to let the consumer be involved in the
management of their heartburn.

And then finally, what about safety? I think the safety of long-term
omeprazole is well established. What about masking of an important
disease, particularly Barrett\'s? I think that it\'s unlike, if properly
labeled, and in fact, I would argue that, again, if properly labeled, it
may actually bring more heartburn patients to doctors rather than less.

Thank you very much for your attention.

DR. ZORICH: Good morning. My name is Nora Zorich. I\'m a Medical
Director of Procter & Gamble Pharmaceutics.

I\'m going to take you through a brief review of the efficacy data in
support of the treatment and prevention of heartburn using omeprazole.

There are really just two topics I\'ll talk about. Very briefly we\'ll
cover some basic pharmacokinetic and pharmacodynamic parameters relative
to the application of omeprazole for over-the-counter use, and then
I\'ll turn to the efficacy trials.

Here\'s the pharmacokinetic data shown by the drug plasma concentrations
in people taking 20 milligrams omeprazole magnesium. This is with the
MUPS, the multi-unit pellet system, which is the dose form that\'s
intended for market use in OTC.

What I\'d like you to see here is that the time to maximum plasma level
is about an hour and a half, ranging from one to two and a half hours.

Relative to the pharmacodynamic behavior, this slide shows the dose
dependent inhibition of pentagastrin stimulated adzes secretion after
single doses of both 20 and 40 milligrams omeprazole. In this model you
see the greatest magnitude of effect within about one or two hours after
the dosing.

Now, omeprazole binds to the proton pump and inactivates it. This slide
demonstrates the duration of action over time. What you see is the
length of effect reflects the appearance of new proton pumps over the
subsequent few days. I think you can see that after 24 hours about 50
percent of the baseline acid output is restored. The acid inhibition
effect then is essentially gone over the subsequent several days.

In this model, 20 milligrams was not different from placebo after three
days from the initial dose.

The omeprazole program has two components, as Dr. Bierer mentioned. I\'m
going to talk about the efficacy program, and after my talk, Dr.
Schachtel will tell you about the use trials. So that\'s where the
overall program then has over 11,600 people in the clinical studies.

Let\'s look in greater detail now at the efficacy program. This is kind
of a road map for my talk, and what you\'ll see is over about 9,300
consumers were enrolled in both studies looking at prevention and
treatment, and you can see altogether there are six studies in the
clinical efficacy program.

The prevention program is what I\'ll talk about first. And there are two
studies which looked at the model that had been previously used in the
H2 receptor antagonist switches, and that\'s one hour before a meal the
product is taken.

Then there are two unique studies that have never been done before, and
these were specifically designed to investigate the duration of action
of omeprazole. These studies assessed 24 hour heartburn prevention with
people taking omeprazole in the morning for 14 days.

And then the treatment studies I\'ll talk about next, and you can see
there are two of those studies which are 14 days in length.

Now, before I go into individual studies, I want to talk about some
common features across the entire program of six studies. How were these
consumers identified? This is a very important question.

The majority of the people who participated in these trials were, in
fact, recruited through a national, which is coast to coast, advertising
campaign, which included television, radio, and mail flyers. The
respondents self-identified to the simple question do you have
heartburn, and there was no further specification or any understanding
of the attributes of their heartburn at that time.

Now, once the consumers were identified as potential participants, then
they could enter into a screening phase in which subjects had to have
more appropriate criteria with respect to their heartburn history.

Now, we enrolled people with mild to moderate uncomplicated heartburn
and excluded people who we thought would be better served under the care
of a treating physician. In order to understand that, let\'s look
specifically at some of the key inclusion/exclusion criteria.

The participants had to have uncomplicated heartburn, and as such, one
of the inclusion criteria is that they had controllable heartburn, and
what we mean by that is that they had said that in the past, they were
able to manage their heartburn using over-the-counter products.

Specifically we excluded people who said that they only could manage
their heartburn if they took an over-the-counter product every day. We
also specifically excluded anyone who had been evaluated for the
complications of acid reflux disease. So these are people who had a
diagnosis of GERD, erosive esophagitis or any other complication of acid
reflux.

Now, as is standard for heartburn studies, we enrolled people who had
heartburn at levels enough that we could measure it. So we recruited
people who said by history, by recall that they had had heartburn at
least twice a week in the month prior to their participation.

Once people went through this screening phase, they entered the
qualifying phase, and in that one week run-in period, we documented
that, indeed, they did have heartburn at least twice, and we also wanted
to make sure that they were correctly filling out the forms.

Once they moved through these two phases, they could be enrolled in the
actual clinical studies.

Now, I\'m going to in the interest of time just summarize for you the
demographics across the entire six studies. I think what you\'ll notice
here is that if you were to look at across the U.S. census, that these
people, in fact, are very representative of the U.S. population in
general, and not surprising for people enrolled in heartburn studies,
their weight is a little high, about 190 pounds. There\'s a decent
amount of use of tobacco, alcohol, and just about everybody consumes
caffeine.

Now, again, back to our road map. Let\'s first talk about these 24 hour
prevention trials, and as I said, there were two identical trials. These
trials represent the first of their kind to demonstrate all day
heartburn prevention with a single dose. People received either placebo,
ten or 20 milligrams, which is a common dosing throughout all six
studies. Since these people were not housed in the study setting and
were not given any of the means, the heartburn they were having was
heartburn caused by their usual lifestyle and their usual meals.

Gelucil, an antacid, was provided if they felt they needed additional
relief, and the use of this was monitored.

These trials looked at the prevention of heartburn for a full 24 hours,
including the assessment of nighttime heartburn, and that\'s why we
elected to dose in the morning.

The first slide I\'m going to show you is 24 hour prevention after the
very first dose. Because it\'s a single dose, plotting on the Y axis are
the percent of subjects heartburn free. As I said, there\'s two
identical studies, 171 and 183, and what you\'ll see across both doses,
ten and 20 milligrams omeprazole, there are significant differences
compared to placebo. This was the primary endpoint of this trial.

Next, we\'ll look at the results over the entire 14-day period. Now,
because it\'s 14 days, I\'m looking at the percent of days heartburn
free. When all episodes are considered over the entire study period,
omeprazole at both ten and 20 milligrams provided a higher percentage of
days with complete prevention of heartburn versus placebo. You could see
very small P values.

Now, 20 is numerically superior to ten in these trials, in both of the
trials, but I think it\'s important to note that ten was also
statistically significantly superior to placebo, and in Study 171 very
comparable to 20.

Now, at the end of the 14 days all subjects were switched to daily doses
of placebo. This follow-on phase was an important element of the study,
as we wanted to know what would happen once the drug was discontinued.

The vertical axis here I\'m plotting the percent of subjects with no
heartburn and day zero would be the last day that they took active study
drug. Then they were all provided placebo, but the study remained double
blind.

The lines represent the daily incidence of heartburn within the
medication groups, and you can see that the heartburn symptoms begin to
recur one day after omeprazole was discontinued. These results are
consistent with the pharmacodynamic data that we just reviewed, showing
that the inhibition of gastric acid secretion by omeprazole is maximal
for the first 24 hours, and then the effect diminishing over the next
two to three days.

Back to the road map, we\'ll now look at the one hour meal induced
trials. As I said, this was the model employed by the over-the-counter
H2 receptor antagonist in their switch programs, and these are very
comparable to those studies, except that we modified the primary
endpoint and enhanced it by employing a very stringent criteria for
efficacy, which I\'ll discuss.

Now, in contrast to the previous studies, these are single dose, the
same dose as ten and 20 milligram omeprazole, and the subjects are dosed
one hour before the provocative meal, and rescue medication use was also
monitored.

As I mentioned, we employed a very stringent criteria of efficacy which
was the complete relief of heartburn for a full four-hour period after
the meal. Here are the results.

These are two identical studies, 005 and 006, and I\'m plotting now the
percent of subjects heartburn free. In study 006 on the right, you see
that there are statistically significant differences from placebo for
both ten and 20 milligrams. In study 005 on the left, the percentage of
subjects who experienced relief was similar to study 006, and they are
numerically better than placebo, but the placebo rate here was higher.
So these differences do not amount to statistically significant changes.

There are additional support of efficacy endpoints that we employed
throughout our program. Each participant in this case was asked for an
overall assessment of their satisfaction at the end of a four-hour
period with the dosing, and we also, as I mentioned, monitored the use
of back-up medication, which we think is an important parameter because
it\'s the one way that the participant can actively describe their
dissatisfaction with their dosing.

And I\'m showing you here these secondary endpoints. Again, the findings
in 006 were statistically significant, and in 005 only at the 20
milligram dose.

In summary, for the prevention program both ten and 20 milligrams
omeprazole was effective in preventing heartburn. If approved, this will
be the first over-the-counter heartburn medication that provides all day
prevention, provided taken at least one hour before a provocative meal.
We think as such, it represents an important benefit to consumers who
have predictable heartburn.

Now we\'ll turn to the treatment trials employing over 3,700
participants. Again, the same two doses of ten and 20 milligrams
omeprazole were used. Now, in contrast to the 14-day prevention trials
in which the people were instructed to take one tablet every morning, in
these trials the subjects were instructed to take the medication when
they had heartburn or, more specifically, when they would normally take
their over-the-counter heartburn remedies.

Therefore, the study participants controlled their own dosing and, as
such, the dosing was intermittent.

They were instructed, however, not to take more than one tablet within a
24-hour period, and back-up medication was provided.

Now, our primary endpoint to assess efficacy was a very stringent
criteria of sustained complete relief, and let me explain that to you.
That means that the participant had to say that within one hour of
dosing, they had no heartburn. It was completely gone, and that they had
to remain at that level of complete relief for the next two full hours.

This is the first time this endpoint has ever been used in the
assessment of a heartburn medication.

Now, just to reiterate, dosing was intermittent in these trials in
response to heartburn symptoms. So how often were these people having
heartburn?

And what I\'m showing you here is the frequency of days with heartburn
in the placebo patients, those people not receiving any benefit of
therapy. We\'re looking at the frequency of days, and we found that the
median number of days with heartburn was six, on average then about
three times each week.

Twenty-five percent of these people had heartburn on more than \-- equal
to or greater than ten days. Now, if you look at days of consecutive
dosing, 83 percent of these consumers had heartburn on two consecutive
days, and when you start looking at longer strings of consecutive days,
only about a third of them had four consecutive days of heartburn.

Now, I don\'t have a slide, but in relevance particular to the severity
of their heartburn, before the very first episode of heartburn about 30
percent of these people were having mild symptoms, almost 60 percent
moderate, and about ten percent severe.

We\'ll look at the primary endpoint of sustained complete relief at the
first treated episode. So this is a single day. We\'re looking at the
percent of subjects, and as you can see, the percent of subjects on
treatment who describe complete relief within one hour of dosing was not
different from placebo in either study.

There are additional prospectively planned endpoints, and we can look at
these. There\'s a slightly lower bar of sustained adequate relief, and
that was measured. People had to report that there was relief of their
symptoms and it was sustained, but it did not have to be complete
relief.

Here we see at least a suggestion of numerical benefit, but only at 20
milligrams in study 095 did this reach statistical significance.

There were three additional single dose trials which we looked at this
endpoint at a two-hour period, and these did not reach statistical
significance.

These findings bring up a very important point. Is omeprazole
efficacious if used to treat heartburn?

While we didn\'t see any statistically significant benefits in any of
those trials when we looked at one and two hours, we did have the
ability to look at a three-hour endpoint because at the end of the
three-hour period, we asked the question to consumers about their
overall assessment, and here\'s the question we asked them. Overall, how
would you rate the medication?

This slide shows the subjects\' overall assessment of the drug, which
was defined at those dosing experiences that were scored as good, very
good, or excellent at the end of the three-hour period from dosing,a nd
we can see efficacy in Study 095 for both does. The P values are shown,
and evidence of efficacy in 092, but these did not reach statistical
significance.

Back-up medicine was also assessed, and it was very similar to the
results from overall assessment.

Now we\'re looking across the entire 14-day period, and as I mentioned,
the median days of heartburn was six over 14 days. So here are the
results for sustained complete relief of all treated episodes in both
studies.

The Y axis gives the number of percent of episodes where there was
sustained complete relief, and as you can see, significantly more people
at 20 milligrams obtained sustained complete relief in both studies when
assessed across the entire trial, and the response with ten milligrams
was slightly less, with the P values as shown.

Now we\'ll look at the remaining efficacy variables across the entire
14-day period. The people reporting sustained adequate relief at both
ten and 20 milligrams omeprazole was statistically significant, as you
can see the P values listed.

Now, sustained adequate relief is a conventional endpoint in the
assessment of over-the-counter drugs, and as such, it is the basis for
the approval of the treatment of frequent heartburn.

Again, the overall assessment by consumers of their degree of
satisfaction with the drug was a very consistent finding in these
studies, and the use of back-up medication was also consistent with this
expectation from consumers of their degree of treatment efficacy.

In summary, this clinical program consisted of well controlled trials
which covered both aspects of the proposed label, prevention and
treatment of heartburn. In support of the prevention indication, both
multiple dose and single dose studies demonstrated prevention of
symptoms when taken in the morning or up to one hour before a
provocative meal.

Omeprazole was shown to be effective in the treatment of heartburn in
subjects who experienced heartburn more than once a week. We tested both
ten and 20 milligrams omeprazole in our studies, and while 20 was often
numerically superior to ten, ten was also effective in that it was
statistically different from placebo, and very often it was quite
comparable to 20.

Thank you for your attention.

And now I\'d like to ask Dr. Schachtel to address us and talk about the
use trials.

DR. SCHACHTEL: That you very much.

The sponsor has asked me to come here today to present the consumer use
program which was conducted over the past three and a half years, and
I\'ll go through each of these studies with you.

I have one right here. Thanks anyway. Just because I wander. That\'s the
reason.

I will address each of the objectives and try to show you how their
program as it was developing a label over the past three to four years
satisfactorily addressed each of the \-- of their research.

The four objectives, of course, were do consumers understand the
proposed label as it was being developed.

CHAIRMAN BRASS: We\'re losing the mic.

MR. SCHACHTEL: They were supposed to set this up. I\'m sorry. I\'ll hold
it then. That\'s better. Switch is on.

I think that Dr. Brass is right. I will stand right over here,
technology being as it is.

Do consumers understand the label? And if a sufficiently comprehensible
label can be developed, how do consumers use the product with that label
under actual conditions of use? Do they comply with it, and do they use
the product safely and effectively?

Could we go on? Thank you.

The entire program is summarized here. There are approximately 2,800
consumers in the different studies. The initial label comprehension
study followed by four different consumer use studies, two of which were
on the 20 milligram dose in adults; an adolescent study on 20
milligrams; and a ten milligram study in adults.

I conducted these two, the 03 and 022. So I\'ll tend to go into greater
detail on them.

Next slide.

The label comprehension study, which was on the initial label, and there
have now been two or three, in fact, developed since then, but the
initial label comprehension study consisted of 504 consumers from ten
geographically distributed shopping centers and with four specific
cohorts in mind, namely, those who did have heartburn and those who do
not.

A low literacy sample, if you will, using the then conventional REALM
test, selecting those who were eighth grade or below in reading level
with heartburn and without heartburn, and finally a cohort was also
identified who took certain contraindicated medications or had
contraindicated diseases as were then on the label.

The results, I think, are in your dossier that\'s been provided, but
they\'re summarized here for each of the different communication
objectives, and there was sufficient understanding of each of the
communication objectives so that the sponsor felt that they could then
further develop the label with the agency and put it into consumers\'
hands, if you will, which they did.

Next slide.

The consumer use studies consisted of four, as I\'ve mentioned to you.
The most important feature of these, as you may recall when we designed
these studies beginning 13 years ago, the purpose was to have no white
coat involvement at all, and intentionally when we\'re at shopping
centers and there are consumers there, there are no physicians present,
no nurses, no pharmacists. These are lay interviewers, and the consumers
identify themselves in this instance, in the two studies that I
conducted. Do you get stomach problems, a purposely general term similar
to the stomach remedy that one sees in drug stores or in super markets?

And if they say yes, they are given a market ready product with the
label that\'s being tested on it and asked: is this an appropriate
product for you or not?

There are no instructions to the consumers about reading it, how to read
it, and certainly no questions are answered.

May I go to the next slide?

Just to give you a sense of what consumer do, and I must say that in the
many actual use studies that we\'ve conducted, this is not an atypical
segregation of consumers, about 25 to 30 percent generally self-exclude,
if you will, and they do this because they may think that the product is
appropriate, but they just don\'t want to enter a clinical trial, not
atypical from the controlled clinical trials that we all conduct.

Interestingly, in this study as in others, people will tell you, \"But I
don\'t get heartburn and, therefore don\'t participate,\" and others
will tell you they get the condition, but it\'s really not that bad, and
they don\'t want to participate.

Fortunately, of course, some people are happy with their current
medication and don\'t want to try anything else, and those who consider
trying new medications do tell us in this study, and we\'ve seen it
repeatedly over the past 13 or so years that I\'ve been doing these
studies; there are those people who will say, \"Yes, but I do want to
call my doctor,\" and they do.

There are some who identify themselves from the label as having \-- as
taking contraindicated medications or having conditions that are
contraindicated, and almost universally, and I\'ve never seen this to
fail, all pregnant women who read labels very carefully do
self-identify, and in these studies also chose not to participate.

Then they are given a supply of the market ready product, again, with no
instructions about how to use the product and told to return in four
weeks, and during that interval, they\'re asked to document their daily
use, if they use the product or not, why they use it, if they take any
other heartburn remedies, what effect the medication has on them, both
beneficial and adverse.

To give you a sense of the demography or conventional demographic
characteristics of the sample, these are taken from \-- excuse me. These
top three conventional demographic handles are taken from all of the
studies, giving you a sense that, in fact, predominantly there were more
women in these studies; that Caucasians were highly represented,
approximately 86 percent, and I believe in your dossiers you can see the
distribution for other racial/ethnic groups.

We had a wide age range, mainly because of that adolescent augmented
study, average age being 44, slightly higher if you exclude the
adolescents, which is not on the label as I understand it that\'s being
applied for, and we had a purposely generous subpopulation of older
persons.

If you look at the two studies we conducted where we also garnered
additional demographic information, namely, education level and
occupation, 42 percent of our samples in both studies, but they were
quite similar actually separately had either graduated from high school,
but no higher and 63 percent were not at the professional, technical, or
managerial/administrative level, a little lower, if you will, on the
totem pole.

Next slide.

In terms of the clinical characteristics of these consumers, here we\'re
looking only at, again, our two studies. When we ask them for how long
have you had heartburn of any kind, a high percentage of these persons
who tended to skew in age to the right, a little older, said that \-- 75
percent said that they had had heartburn, in fact, for more than five
years, and that they got it frequently. Sixty-two percent of them said
they got heartburn during the day two or more times a week, and about
half said they got heartburn at night about two times a week.

What did they do for it? Not dissimilar from other surveys and the ones
that were shown earlier today, about 18 percent of them are taking or
have prescriptions for heartburn therapies, PPIs, or H2 RAs, and again,
as has been seen in other surveys, about 80 percent here, 78 percent are
also taking, with or without the Rx drugs, are taking OTC medications
for their heartburn.

What were the results? In terms as the first objective of these studies
is, what are the consumption patterns?

We looked at it in two ways. I think you have in your dossiers looking
at it in terms of exclusive use. When I received that report from the
sponsors, I could see immediately that fewer than half, 45 or so percent
of these consumers used the product only for relief or only for
prevention.

Therefore, I recommended that a convention that the agency used on
several studies that I\'ve done, namely, that we look at in terms of
predominant use, namely, predominant use meaning if more than half of
the time that you use the product you use it for relief. That\'s how we
categorize these consumers. If you use it more than half of the time for
prevention one hour before a meal or more than half the time for
prevention for 24 hours, that\'s how you\'re categorized.

And there were about 16 percent for whom there was no way to categorize
them. I might point out interestingly that if you were a preventer, more
than 85 percent of the time you used it for prevention. It wasn\'t a
squeaker, if you will, 51 percent.

And similarly, for relief it was about 83 percent of the time you used
it for relief, but not exclusively, and that\'s why I recommended, and
we\'re showing it here, but the exclusive use, I think, is also
available if you want to look at it that way.

The next slide.

Now, the three separate indications or, rather, directions for use were
also examined, and I\'ll show them to you separately. They are, namely,
obviously not taking more than one tablet per dose.

Here, of course, there are two ways to look at it, as there are many
ways to look at everything. One can look at it only on a consumer basis,
and there are about 2,200 consumers, and one can also do, which is what
I recommend, because it tells you each time the person took a dose, did
they do it correctly or not, and of those, there were about 24,000
dosing occasions, if you will, over the four week actual use study.

Looking at it that way for each of the four studies, one can see that
well above 80 percent, 90-plus percent, in fact, of the times that
consumers used this Prilosec I, as it was called, they did take only one
tablet per dose.

Next.

The second direction for use being how many doses did they take per day,
and obviously no more than one dose per day.

On a dosing basis, there were 24,000 dosing days, i.e., days when they
took at least one table. Well, above 80 percent, in this case 96-plus
percent or so, of the times that they took Prilosec I they took only one
dose per day.

I might add it might be of interest to you that we inquired in the O22
study, and I think this is in your booklets, of the four percent in that
study who took two doses a day why they did that, and about half of
them, about half of those persons had some relationship with a physician
that led them to take two tablets.

And if you were to go back, if I could, to the previous slide, that 91
percent here, we know that those nine percent, about half of them also
had some relationship with a physician that had led them to take more
than one tablet per dose.

Now, let\'s go ahead, too. Finally, and importantly for this drug, this
is what fascinated me, is did they comply with the dosing instruction to
take for ten or fewer days, and again, we\'re looking at about 2,200
consumers. Across the board it ranged from 78 to 92 percent compliance
with this direction for use.

When we did our initial study 003, I decided to call the first 50
consumers that we could reach who had gone beyond ten days to talk with
them, an old adage obviously for a physician, and we could see that, in
fact, approximately 70 percent of those persons who used the product for
more than ten days had either been taking Prilosec on prescription, had
it recommended that way by their doctor, or even during the study
consulted with their physician, who recommended that.

So, therefore, with those hypotheses, we incorporated that thinking
prospectively into the subsequent study so that all subjects were asked
the same questions at the exit interview to determine their dosing
behavior, and if you go on, you can see that the 78 percent in that 022
study complied with the dosing instruction.

There were several other mechanisms, if you will, opportunities for how
they interrelated with physicians, some during the study. These three
people told us that their physician told them to take Prilosec that way.

These folks specifically had been given a prescription for PPI or H2Rs,
mostly Prilosec, by the way, during the last year and were familiar with
the product obviously so that if one were to just add up any of these,
you come close to 89 to generously 94 percent, but around 89 percent of
the time they were complying with the instruction to take this way
unless so directed by a physician.

Next slide.

The second objective of our studies is to show what happens to consumers
when they take this product under uncontrolled conditions, and in terms
of safety, we saw that there were common side effects. These are the
most common that were reported, and as I think you can see in the
briefing document, when these side effects are recorded in double blind
randomized, placebo controlled trials, they\'re no different from
placebo.

I can also tell you that there were no serious drug related adverse
events either.

Finally, and this was actually a recommendation of the agency, what is
the effectiveness of this product when given as people will use it?

And so I created two different ways of addressing effectiveness. For
each dose patients were asked at the end of the day, did the medication
work for your heartburn. This is exactly what clinicians do in their
offices when they give a patient a new drug. They say, \"Well, did it
work for you or not?\" the next time they see them, and it was a simple
yes or no determination, very clinical.

Granted, no placebo involved. Just the way people would use it.

A very high percent through all studies both on the first dose and for
all doses responded favorably. I might point out that this was true for
prevention, when people used it on those occasions for prevention, and
also for relief.

And interestingly, there was a discrimination by the consumers of
prevention versus relief, indicating a certain sensitivity to how the
drug performs. It performed 93-plus percent of the time positively for
prevention and about 80 percent of the time for relief, a
differentiation.

So these people are not just saying everything works and everything is
fine.

The corollary to this which is clinically meaningful, I think, is that
people also had the opportunity to record if they needed to take
anything else for their heartburn, and when one looks at that corollary,
the use of other medications, it was three to six percent of the time
only, indicating that the drug they were taking was working and they
didn\'t have to take anything else.

Next slide.

Finally, we used the conventional rating scale that\'s used in clinical
trials, which you\'ve seen in the controlled clinical trials, and if one
looks at the top two very good and excellent ratings for the two studies
it was employed in, one can see that approximately 70 percent of the
patients said it was very good or excellent, and if one includes those
who said it was good, it\'s about 90 percent.

In summary, we saw that the label as it was being developed was well
enough understood to be put into actual use circumstances, and that when
that product was used, it was used according to label, and safely and
effectively.

Thank you very much.

Dr. Levine is next.

DR. LEVINE: Good morning. My name is Doug Levine. I\'m Chief Medical
Officer of GI at AstraZeneca, and I\'m pleased to prevent an overview of
safety of omeprazole for OTC use.

I will show you data in support of the minimal risk of omeprazole for
OTC use, including the safety of prescription use at mainly 20 and 40
milligram doses and the safety in the OTC trials at ten and 20 milligram
doses.

Based on this safety review, we proposed that OTC risk potential will be
well managed by dose selection, duration of treatment, and labeling
instructions on seeking care.

I will speak to four main areas in this assessment: acid suppression,
pharmacokinetics, general OTC safety considerations, and the documented
adverse event profile of the product.

This figure shows the dose response of omeprazole on gastric acidity.
The top line represents before treatment and the dips seen here and here
at one and 7:00 p.m. represent food buffering effects from meals.

The second line down represents the ten milligram dose, and you can see
during the daytime hours, there\'s acid suppression, but then at night
there\'s return of gastric acid secretion to more physiologic levels.

The bottom two lines are the 20 and 30 milligram doses of omeprazole
which demonstrate more sustained acid suppression throughout the 24 hour
period. We should keep these data in mind as we consider potential
effects of acid suppression by omeprazole.

What are the potential effects of acid suppression on absorption?
Achlorhydria is rare even with prescription doses. Acute effects on
nutrient absorption can be demonstrated in the research setting, but
depletion of nutrients is not found in prospective studies.

Absorption of anti-fungal agents can be affected, and this should be
indicated in the label, but the potential for all of these effects is
decreased with a ten milligram dose.

Is there rebound acid hypersecretion when omeprazole use is stopped? In
most circumstances with the 20 milligram prescription dose, acid
secretion normalizes within several days after stopping, but following
more intensive treatment courses, such as 40 milligrams daily for eight
weeks, there can be acid hyper secretion.

This phenomenon has been inconsistently observed in shorter term
studies, but when it has been demonstrated, the effect is reversible.

Regarding potential symptom effects, the OTC trials showed that symptoms
were no worse than placebo during follow-up after cessation of
omeprazole, and again, the potential for this effect is limited with
short-term use of a ten milligram dose.

Based on animal studies, another potential effect of acid suppression is
neoplastic potential. In these studies, rats treated daily with high
doses during their entire lifetime showed a dose related increase in
gastric ECL cell carcinoid tumors. These carcinoid tumors in rats were
shown to have been caused by disruption of gastric acid homeostasis, and
a weight of evidence of analysis of other data do not support a
genotoxic pathogenesis.

The further neoplastic progression of ECL cells to carcinoid tumors as a
result of acid suppression has been demonstrated to occur only in rats
and not in humans.

Previously, the prescription of a omeprazole product had a boxed warning
based on the findings of cardinoid tumors in rats, but this boxed
warning was removed from the prescription label in 1995 based on
long-term data in humans.

Thus, the findings in rat carcinogenicity studies have not been
demonstrated to be relevant in humans.

In patients, omeprazole 20 milligrams can cause increases in gastrin
that stabilize at two weeks, but return to normal within one to two
weeks after stopping. Rarely with doses of 20 or 40 milligrams gastrins
go to above four times the upper limit of normal only rarely, in
contrast to the eight to 15 times observed in the rats.

ECL cell hyperplasia, which is benign proliferation, can be seen, but
the development of ECL cell carcinoids has not been observed in trials
of omeprazole in patients lasting from one to more than 12 years.

In addition, review of clinical trial and post marketing data, there\'s
no evidence that chronic use leads to the development of GI, epithelial
neoplasia or malignancy.

To summarize the potential effects of acid suppression with omeprazole
OTC use, nutrient depletion is not expected. There is a potential for
malabsorption of antifungal drugs. Rebound acid hypersecretion is not
likely, and GI neoplasia or malignancy is not attributable to
omeprazole.

The next area is pharmacokinetics, and the potential for metabolic drug
interactions. This is based on competition between drugs for common
sites of metabolism.

Omeprazole is metabolized by the cytochrome P-450 or CYP, C-Y-P system,
in the liver and almost exclusively by 2C19 and 3A4. However, the
affinity of omeprazole for 2C19 is the strongest so that only drugs that
share this metabolic pathway have the potential for interaction.

Drug interaction studies were conducted with drugs metabolized by CYP
3A4 and these other CYP enzymes, but no potential for interaction was
demonstrated. In the 2C19 studies listed here, there was a 25 percent
inhibition of diazepam metabolism with a 20 milligram dose of
omeprazole, but this level of competitive inhibition is not likely to be
clinically significant.

The other drugs, phenytoin, R-Warfarin, and tolbutamide, are primarily
metabolized by other enzymes which are not significantly affected by
omeprazole.

A special population with potential for effects are so-called slow
metabolizers. These are people who genetically lack CYP 2C19 metabolic
function, and this occurs in 15 to 20 percent of the Asian population.

Slow metabolizers depend on the secondary metabolic pathway of
omeprazole, the CYP 3A4 pathway, which is somewhat slower than 2C19, and
this leads to a longer plasma half-life. The area under the
concentration time curve is approximately fivefold higher in slow
metabolizers, but there is no drug accumulation.

This effect is well tolerated, and it should be noted that the approved
prescriptive dose for omeprazole in Japan is the same as it is in the
United States.

Other special populations with potential for effects are individuals
with liver or kidney impairment. Studies in the hepatically impaired
show a longer plasma half-life, plasma concentrations which are
approximately sevenfold higher, but again, there is no drug
accumulation.

Studies in the renally impaired show that eliminate of metabolites of
omeprazole is less than that in healthy subjects. So to summarized, we
anticipate minimal risks with OTC use of omeprazole based on the
pharmacokinetic profile. We don\'t expect clinically significant effects
for metabolic drug interactions at CYP 2C19 or in these subpopulations.

With prescription use, dose adjustments are not necessary for these, but
because dose selection is a contributor to plasma drug levels, a
decreased potential for effects is expected with a ten milligram dose.

I\'ll now move on to the third area involving important general OTC
safety considerations, including use by children and elders, use during
pregnancy, and misuse potential, including overdose abuse and chronic
use.

Regarding use by children, no safety issues have emerged during clinical
trials or in post marketing, although data are limited, and for that
reason the proposed label now indicates the uses for adults age 18 or
older.

In elders there may be reduced hepatic and renal function, but review of
clinical trials and post marketing data, there\'s no evidence of
differences in the adverse event profile in individuals over 65.

Regarding use during pregnancy, no prospective clinical trials have been
carried out, but there are post marketing reports and other
epidemiologic studies evaluating exposures to omeprazole, and these have
been submitted to the agency in a supplemental NDA.

These data demonstrate no increased risk of adverse pregnancy outcome.

Regarding overdose, ingestions of up to 900 milligrams of omeprazole
have been reported to us with no serious outcomes. There were two
deaths, but these were associated with multiple drug ingestions.

With overdose of omeprazole alone, a variety of transient symptoms have
been reported, including nervous system and vasomotor effects. Data from
the American Association of Poison Control Centers indicate that most
reports related to omeprazole involve children under six years of age.
The available data on clinical effects are consistent with the
information we\'ve received from post marketing surveillance, and the
OTC label should instruct to seek medical care or recall poison control
in the event of overdose.

With regard to abuse potential, there is no evidence for omeprazole
abuse, for its potentiation of other drugs of abuse, or for its
potentiation of effects of ethanol. Omeprazole does not affect pathways
for the metabolism of ethanol, including CYP 2E1 or gastric alcohol
dehydrogenase.

Another area of potential misuse is inappropriate chronic use despite
label warnings. Chronic use is not likely in consumers with alarm
symptoms because omeprazole alone is not likely to improve these
symptoms, but chronic use is possible in consumers who respond
symptomatically, but who don\'t choose to seek medical advice despite
label warnings.

Such consumers can be grouped into three categories. The first are those
who might have a nonneoplastic upper GI condition, including reflux or
dyspepsia, with or without erosions or ulcers.

The second group are those who might have upper GI malignancies.

And the third are those who might have upper GI conditions with risk of
malignancy.

Coming back to the second group, which are the individuals who already
have an esophageal or gastric cancer, the dominant symptoms when such
tumors are sufficiently large are different from heartburn and include
difficulty swallowing, nausea, vomiting, early satiety and weight loss.
Often individuals with such cancers seek medical care for the first time
for such symptoms when their advanced cancer is already manifest.

However, the diagnosis of cancer is unusual in the absence of alarm
systems, but the presence of the alarm symptoms should prompt a visit by
the consumer to a doctor.

The third potential group of chronic users would be consumers who have
conditions that may increase the risk of malignancy, such as Barrett\'s
esophagus. This condition is commonly identified in patients seeking
medical care for gastroesophageal reflux disease, but progression to
cancer is rare.

Unfortunately from a public health perspective it\'s difficult to
predict who may have Barrett\'s esophagus and then to effectively manage
the overall cancer risk.

So to summarize, we anticipate minimal risks with OTC use of omeprazole.
There are no apparent safety issues in children and elders. Overdose
produces nonfatal and transient effects. There is no abuse potential or
potentiation of drugs of abuse.

Regarding chronic users who do not seek medical advice despite label
instructions, potential deleterious outcomes that I\'ve discussed are
possible, but are likely to be unusual.

It\'s known that among medically diagnosed, symptomatic GERD patients
omeprazole ten milligrams is less effective than the approved 20
milligram dose, which may diminish misuse potential in a subset of
consumers.

The last area I\'ll discuss is the adverse event profile of omeprazole,
and our database includes information from our worldwide clinical
trials, the OTC clinical program, and post marketing spontaneously
reported adverse events for which the surveillance period was ten years,
covering over 380 million prescriptions. Each prescription is defined as
approximately one month of treatment.

This figure depicts the most common events reported during control
trials in medically diagnosed reflux disease. The most frequent events
were headache, diarrhea, respiratory infection, flatulence, abdominal
pain, and nausea. The frequency with omeprazole is not different from
ranitidine or placebo comparators.

The profile of reported adverse events in the OTC trials is similar to
these as seen on the next slide. This figure shows the most common
events reported during the controlled OTC trials. The frequency of
reported events was not different among the ten and 20 milligram doses
of omeprazole and the placebo comparator.

In the entire OTC clinical program, there was one serious adverse event
attributable to omeprazole in a 35 year old woman with multiple
allergies who developed symptoms suggesting serum sickness and
angioedema. She did recover following cessation of omeprazole and
treatment with antihistamines and steroids, but had a similar
hypersensitivity reaction two weeks later after being treated with
Sisapride (phonetic).

This tape shows total worldwide serious adverse event reports during the
ten-year marketing history of omeprazole. Reading across are the
two-year periods during the ten years, the numbers of total
prescriptions, and then the total number of reported serious adverse
events. Both prescriptions and reported events have increased during the
ten year marketing history. In the bottom row is the calculated ratio of
serious adverse events that have been reported to the numbers of
prescriptions, and this ratio declined from almost 20 to 11.5 per
million, which is a pattern that\'s commonly observed following the
entry of a product into the market.

But what about the magnitude of these numbers? In order to get some
insight on this, we looked at the reporting rates for other drugs used
in the same population as shown on the next slide. Here are the
calculated ratios of reported serious adverse events per million
prescriptions in the first five years of marketing of omeprazole
compared to those reported with some H2 receptor antagonists.

This ratio for omeprazole is not meaningfully different and certainly
not higher than the rates reported for these products, which are used in
the same patient population.

One can hypothesize that this reporting rate may be characteristic of
the population being treated and not causally related to particular
treatments.

Here are the ten most frequently reported serious adverse events with
the incidence per million prescriptions in the first five and second
five years of marketing of omeprazole. These include events alluded to
in the agency briefing document, such as platelet and blood cell
deficits and hepatic dysfunction, but all of these are infrequent events
and, again, supporting the hypothesis that this pattern may be
indicative of the patient population being treated rather than the
treatment per se is that the labeling for the H2 receptor antagonist
reports similar kinds of events at frequencies described as few or rare
and certainly events that are reported for omeprazole at these rates
must be considered to be rare.

In conclusion, we anticipate minimal risk to consumers with OTC
omeprazole. Its adverse event profile is similar to those of ranitidine
or placebo based on our clinical trials with the prescription product
and in the OTC setting.

Omeprazole has an excellent post marketing safety profile. The clinical
adverse event profile is independent of dose range from ten to 40
milligrams. Any concern about risk potential for events related to asset
suppression, pharmacokinetics and general consumer use would be lessened
with a ten milligram dose.

Serious adverse events strictly attributable to omeprazole are reported
rarely. Increased risks with long term use have not been documented, and
a wide margin of safety is expected with use of omeprazole in the OTC
population so that based on the safety assessment, we believe that risk
potential for OTC omeprazole is best managed with these proposals: a
dose of ten milligrams, which is less than the 20 to 40 milligram doses
for prescription use; a treatment duration of up to ten days, which is
less than the prescription recommendations of at least four weeks; and
label instructions for seeking medical care.

Thank you.

Let me reintroduce Dr. Zorich who will provide a summary and close to
our presentation.

DR. ZORICH: Thanks.

And I realize we\'re running a little over. So I appreciate your
indulgence. I\'ll try to move along without rushing.

To conclude our portion of today\'s meeting, I\'d like to take you
through our proposed labeling and summarize our thinking in how
omeprazole will contribute to the current OTC management of heartburn.

As with probably many NDAs since the time that we originally submitted
the NDA and the original labeling, we\'ve had some time to think. We\'ve
also had time to listen to the agency\'s questions and consult with
experts in this area, including people who could give us more insight
into the behavior of consumers in their treatment of over-the-counter
heartburn.

And what we\'d like to present to you now is our evolution of thinking
and how the appropriate labeling of this product should be managed in
the OTC environment.

There are three areas in the label which I\'d like to discuss. To be
fair to the agency, I want to be clear that these are modifications from
the original label that we submitted.

The three areas are what\'s the appropriate dose, what are the uses or
indications, and what should be the appropriate consumer warnings.
Relative to the dose, as you hear from Dr. Levine, both ten and 20
milligrams omeprazole were efficacious in the treatment and prevention
of heartburn. We believe ten milligrams is the right dose because it
provided benefit to consumers, and it\'s consistent with the precedent
of H2 RA OTC products and switching at one-half the prescription dose.

As you heard from Dr. Bierer, there\'s now good evidence that the
switching H2 RAs did not change consumer behavior. People still went to
their physicians for care, and in fact, as you heard from Dr. Castell,
there\'s good reason to believe that an increased awareness of heartburn
and appropriate labeling would help bring the right consumer to the
treating physician.

Now, the agency has asked that we provide clarity on who will be the
consumer who will benefit from this product and how can they choose the
right product that\'s right for them. Now, originally we had requested
an indication for the relief of heartburn. We\'re now proposing an
indication for the treatment of heartburn because we think it better
reflects the efficacy of the drug, and it will help consumers select the
right OTC medication for their heartburn. So our proposal is treatment
of frequent heartburn.

The data shows that consumers who choose to use omeprazole for the
treatment of frequent heartburn have a meaningful benefit in the overall
management of their heartburn.

We\'ve also simplified the prevention indication from enumerating
several causes of heartburn. We had listed lifestyle, stress, and
exercise, and we\'ve returned to only listing food and beverage, and the
reason for that is that while almost everybody will describe a
combination of factors that leads to their heartburn, still the common
denominator is always food and beverage.

In addition, we\'ve added the words to take only the days you expect
heartburn to occur. We want to be clear to consumers that they
shouldn\'t take this medication when they don\'t need it, and we want to
also emphasize that it\'s not intended for continuous use.

Now, consistent with the most recent guidelines from the American
College of Gastroenterology, with input from the AGA and ASGE, we
propose to strengthen our warning to provide consumers with clear
directions on when to seek a physician\'s care and when to stop using
the product or, in fact, not to use the product. So we\'re suggesting
that we add additional alarm symptoms instructing the consumer not to
use the product if they\'re having unexpected weight loss, trouble
swallowing, chronic cough or wheezing.

In addition, it\'s important that consumers see their physicians if
their symptoms continue or worsen, and importantly, if their symptoms
are persistent and they find that they have to take the drug on a
continuous basis in order to be free of symptoms. All of these are
signals that the consumer would be better served under the care of a
physician.

As you heard from Dr. Castell, this type of labeling could mitigate the
masking of more serious conditions. We, in fact, believe that all
over-the-counter heartburn medications should provide these types of
warning statements so that consumers can benefit from this information.

Ten milligrams of omeprazole represents a safe and logical addition in
the OTC setting. In the spectrum of care that Dr. Castell shared with
you, we\'ve seen that lifestyle changes which are appropriate for
everyone is really the basis for the first line treatment of heartburn,
and acids provide temporary relief of people symptoms and with the
advent of H2 receptor antagonists people for the first time could
prevent heartburn when taken at least an hour before a provocative meal.

What omeprazole allows consumers to do is those consumers with
predictable heartburn can manage their symptoms with greater dosing
flexibility and longer duration of benefit.

Finally, very briefly I will tell you that we are committed to a
consumer support program. We think that consumer education is very
important. We have developed a consumer education booklet that
reinforces the label messages. This booklet explains importantly what is
heartburn, what lifestyle modifications can be important, and clearly,
importantly, when to seek a physician for care.

We have written this booklet at the sixth grade level, and we intend to
have it available in Spanish, and for those people at the lower
educational levels, we\'ll have a video of the booklet, and for those
people who have Internet access, we are developing a comprehensive Web
site.

Of course, all of our products do have an 800 number for consumer
comment and any complaints.

In summary, if we go back to Dr. Bierer\'s outline at the beginning of
our discussion, Dr. Castell did show that OTC omeprazole can be
appropriate for the management of heartburn in the consumer\'s hands. We
reviewed the data demonstrating that it\'s efficacious.

Dr. Schachtel demonstrated that consumers understand the product
labeling and can use the product safely and effectively.

With the additions to the label as I have just outlined, we\'re
confident the product can be appropriately labeled and consumers and
health care professionals can be educated to insure safe and
appropriate, effective use.

Dr. Levine showed that there is a wide margin of safety for
over-the-counter use. When you consider the number of people who have
taken omeprazole, the long duration of chronic use even at very high
doses, there\'s an impressive safety platform from which we can conclude
that the risks are truly minimal in the over-the-counter setting.

In conclusion, ten milligram omeprazole can be a meaningful benefit to
consumers and can be safely used in the over-the-counter environment.

Thank you for your attention.

CHAIRMAN BRASS: Thank you.

I\'d like to begin the discussion with a couple of questions myself on
the theme of differentiating efficacy and prevention versus efficacy in
treatment or pain relief, and perhaps I could begin with slide EP27. If
we could have that slide please.

This was a trial related to relief, and you suggested this secondary
endpoint as evidence that consumers were deriving benefit in relieving
their heartburn symptoms, but I\'m curious of whether this is really a
surrogate for prevention as you\'re assessing their experience over the
entire 14-day period and whether they get sustained relief. Is that
really a surrogate for prevention of episodes during that 14-day period
or is it really a reflection of when they get an episode, are they
getting relief from it?

DR. ZORICH: I think \-- is this live? Thank you.

It\'s an interesting question and one that we\'ve never really had the
opportunity to address, and so you have a drug like omeprazole with its
biologic behavior, these pharmacodynamic properties, and to answer that
question, I think to be honest it\'s both, and the reason I say that is
that we \-- in the 14-day prevention trials when we looked at that off
study period, you can clearly see some benefit in more people being
heartburn free over those three days even after off drug, but in these
intermittent dosing trials, well, you have every combination of dosing
you can imagine with one day, two days, three days, and then people
taking period breaks, a couple of days off, and then taking the drug
again. And there are as many variations in dosing as there were people
on the trial.

So we\'ve modeled the data, and we asked ourselves what is the
discernable benefit to the consumer in heartburn relief, and so we just
actually did a very careful study of the data that we had and said if
you had been taking the drug, then what was your chance of being
heartburn free the next day, and we looked at people who were taking the
drug for one day, two days in a row, and then three days, and then
asking that question, and then what was the chance of them being
heartburn free two days later or three days later.

And what we found is that, indeed, there is a carryover which is a
discernable benefit in heartburn relief of a day. So I think that what
you can say is that there is probably a combination of both further
treatment and some element of prevention, and our data would say that it
clearly lasts about a day, that you\'re still getting a benefit a day
later, and beyond that you are no long appreciating the prevention
benefit, but you may get further benefit from treatment.

CHAIRMAN BRASS: Do these results stratify by number of episodes at
baseline or any other indicator of severity or frequency of use?

DR. ZORICH: These, what I\'m showing right here do not, but we have
looked, and we importantly asked ourselves the question how about these
people taking it all the time versus the people taking it \-- and we
used the median, which was six days, and asked if you\'re above the
median or below. Is all of the benefit coming from the high end users?

And what we found, in fact, was very comparable benefit in both of those
categories. So I would say and that\'s why we feel confident that, in
fact, it is some combination.

CHAIRMAN BRASS: Your new suggestion for proposed use includes for the
prevention use only on days heartburn is expected, and that would seem
to mirror the studies such as 092 and 095; is that correct? Is that the
\--

DR. ZORICH: Except for prevention. This would be even before any
symptoms began, but 092 and 095, it was in response to symptoms. So in
092 and 095, they already had problems.

CHAIRMAN BRASS: Okay. How about 005 and 006?

DR. ZORICH: Yes, meal induced.

CHAIRMAN BRASS: Okay. Good. I\'m sorry. I picked up the wrong sheet.

And for the primary endpoint, only one of those two trials was positive.

DR. ZORICH: Yes.

CHAIRMAN BRASS: Is that correct?

DR. ZORICH: Yes.

CHAIRMAN BRASS: So what\'s your level of confidence that at the ten
milligram dose the available data support the efficacy of that
recommendation?

DR. ZORICH: Clearly, I think that as we\'ve seen from 092 and 095 one
hour. I think you\'re sitting right at the edge of where this drug will
begin working, and in fact, in retrospect, I guess, you know, you\'re
probably all wondering why did you do that, one hour, but I think what
we learned was unlike some of the other products, really you\'re just at
the edge of efficacy.

And so we think that prevention during the day, as long as it\'s one
hour or more from the inciting episode, will be effective, but clearly
moving closer to the inciting episode will not be effective.

CHAIRMAN BRASS: What would be your expectation a consumer would
understand from the indication \"treatment of frequent heartburn\"? What
do you think the consumer will interpret that? And are you recommending
that the label still include the one hour or the acute relief of
symptoms indication in the dosing instructions?

DR. ZORICH: Actually what we\'ve suggested is that we think that the
relief of symptoms may be confusing to a consumer, and what we\'re
hoping to target are the appropriate consumers for this product. Those
would be, as you saw, it makes up about a quarter of the population of
people using the product for relief.

These would be people who know that they have heartburn more than once a
week.

CHAIRMAN BRASS: So to clarify, so your expectation would be that it be
only used for prevention?

DR. ZORICH: It would be used for prevention in anybody. This product is
like the H2 RAs in that it could be used whether you only have heartburn
when you eat pumpkin pie on Thanksgiving or it could be used for
treatment in those persons who had heartburn on a more frequent basis or
somebody who has heartburn kind of clustered, bouts of heartburn.

CHAIRMAN BRASS: I will open it up, but again, I think that
differentiation is confusing to me and may be very hard to convey on a
label to a consumer as to exactly what those differences are.

DR. ZORICH: Okay.

CHAIRMAN BRASS: Dr. D\'Agostino.

DR. D\'AGOSTINO: Before you take that slide down, you look at the
numbers and you have statistical significance, but the effects are quite
small. Are you \-- I mean how would you interpret that? This is a large
study, a large number of subjects and so forth and 14 days. You have
significance, but as I say, very small effects.

DR. ZORICH: Yes. I would say that this is not an unexpected finding in
heartburn trials. In these \--

DR. D\'AGOSTINO: Well, I would have expected twice as much.

DR. ZORICH: Yeah, but you know, you actually don\'t get twice as much.
If you look across some of the other therapies, it\'s not uncommon to
find deltas of only about ten percent. The bigger deltas ‑-

DR. D\'AGOSTINO: Those aren\'t ten percent.

DR. ZORICH: Well, in 095 \--

DR. D\'AGOSTINO: I would expect like 12, 13 percent.

DR. ZORICH: Yeah, really \--

DR. D\'AGOSTINO: This committee lived through all of those H2
antagonists.

DR. ZORICH: Yeah.

(Laughter.)

DR. ZORICH: With heartburn?

DR. D\'AGOSTINO: With heartburn.

DR. ZORICH: Yes.

(Laughter.)

DR. D\'AGOSTINO: And we weren\'t making money on it.

DR. ZORICH: I think Don Castell would tell you that he often doesn\'t
make any money either, but \--

DR. D\'AGOSTINO: Those may be a lot of questions, but I think I\'ve made
my point and you\'ve made yours.

DR. ZORICH: I would like to say though that I think I would ask you to
consider that these people in general had mild to moderate, and if you
extend that to the population, if you look at trials in GERD patients,
which are not these patients, I\'m talking about people with very severe
symptoms. You get much bigger deltas.

And so I think as you move to a population with lower severity, you
don\'t see the deltas, and as you move to greater severity of symptoms,
the deltas are higher, and I think that may be one of the explanations.

DR. D\'AGOSTINO: Again, can I just make one comment and not a question?

DR. ZORICH: Yes.

DR. D\'AGOSTINO: I think the word \"treatment\" takes us away from how
to interpret the studies because there\'s prevention; there\'s relief;
and then treatment leaves us in a very ambiguous place, and I think
that\'s what Eric was saying.

The other question I have, and then I\'ll step aside, is if I understand
the studies correctly, it was an enriched population, those individuals
who H2 antagonists were, in fact, effective, was one of the selection
criteria. How do we interpret \--

DR. ZORICH: Any OTC, not just H2s.

DR. D\'AGOSTINO: Well, any OTC. So how do we interpret it? Is it that it
isn\'t necessarily those individuals who aren\'t ready for a physician,
but still don\'t have luck on other OTC medications? How do we interpret
what\'s going to happen with those individuals?

DR. ZORICH: What the requirement was is that in the past they ere able
to gain relief of symptoms with over-the-counter medications, and so
what we were trying to do \-- well, first of all, that\'s 80 percent of
all heartburn folks. So that is the majority of the population.

What we were trying to do was to really make sure that we didn\'t have
the severe patients.

DR. D\'AGOSTINO: I\'ll step aside.

CHAIRMAN BRASS: Dr. Uden.

DR. UDEN: Yeah, I just have a more fundamental question on that slide.
In your presentation, you had complete relief and that was an hour
before and two hours after or three hours after. I didn\'t get a good
definition of what sustained adequate relief was. It was referred to in
the presentation that this was what other products had done, but I
couldn\'t find it in your material or you didn\'t really define what
sustained adequate means.

DR. ZORICH: It means that one hour after dosing they appreciated some
reduction in the level of their heartburn and that that reduction was
maintained for a subsequent two complete hours.

CHAIRMAN BRASS: Dr. Elashoff.

DR. ELASHOFF: In the 24-hour prevention trials, did you record whether
they used back-up medication and what were the results if you did?

DR. ZORICH: Yes, we did, and we can show those, I\'m sure. Across all
dosing, 171 and 183.

We did. I guess we\'re looking for it, but in general, back-up
medication use correlated throughout all six. We collected it in every
trial, and it was best correlated if you looked at the overall
assessment, and I guess so it was consistent.

So if the overall assessment was numerically superior to placebo, then
you were very likely to see a comparable decreased use in back-up
medication.

DR. ELASHOFF: But I\'m wondering about the absolute level.

DR. ZORICH: Yeah, I\'m trying to find it. We don\'t have it?

Well, we can get it out of our hard copy and share it with you.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: I have a couple of questions concerning safety. I think that
you have shown that there is a small beneficial effect of ten
milligrams. I think that is shown, although it is a small one.

But I would go back to safety and that concerns the use of omeprazole in
general. Dr. Castell referred to a recent review concerning safety, and
that review happened to be an answer to a review that I wrote that had a
completely different conclusion.

And I must say that in contrast to Dr. Dent there was no writing by the
editor or any association with industry after my review \-- after
Dent\'s review it was.

Since gastric carcinoids were described in rats in their eggs, there
have been a consistent question of the danger of neoplasia after PPI
use. I should like to ask if our side (phonetic) killed the rats at the
age of six months at that time and examined the stomach, wouldn\'t they
have found exactly the same findings as you find in humans today?

And if you think of the life span of rats compared with humans, I think
that it is every indication that we see the same sequence in man as in
rats.

I have also noticed that nobody of you have taken into consideration the
role of the ECL cell in gastric carcinomas in children. We have
published three or four studies describing ECL cell differentiation in
gastric carcinomas, and every time you have ECL cell involved in
neoplasia, the role of gastrin comes up.

And also at that AGA meeting in \'96 or \'97, it was described that the
increased risk of gastric carcinoma in patients with Helicobacter pylori
was due to the increase in serum gastrin diseased persons, and that
increase in gastrin is within the level, the load level. So it is no
threshold for a danger of hypergastrinemia.

And my final point will be what is the role of gastric acid. It is to
destroy marker organisms, not only bacteria. Do you have any information
on the destruction of viruses, prions, and so on? Do we know anything of
this, that is, diseases with long incubation time?

So I feel that risk over the contra of over pathology (phonetic) is
dangerous to the public.

DR. LEVINE: Regarding the first issue that you raised, in the
development program for Rx Prilosec, there were other studies done in
rats in which very high doses were administered to the rats for one
year, approximately half their lifetime, and in those experiments, in
fact, ECL cell carcinomas were not identified. So that apparently the
effect in that particular species was only seen in lifelong duration.

Regarding issues, I think that a point that you can raise regarding
follow-up, we have identified the ECL cell and the stomach as the target
organ in our pre-clinical studies, in our clinical studies, and in our
post marketing, and what we\'ve done is to continue to be vigilant
prospectively in studies that have extended for a long period of time
and have not identified any significant abnormalities in people or have
received post marketing reports of the same.

DR. CASTELL: Can I have a comment?

Your serious concerns certainly are acknowledged, and I think something
we\'ve all, those of us who have used these drugs and used them
chronically have considered and worried and watched very carefully.

I think you also are aware of the fact that most of the world that
practices gastrology has become increasingly comfortable with the
regular use of PPIs over the last two decades, and the data such as I
showed from Dr. Klinkenberg, I think, are the ones that we really relied
greatly on. Her yearly endoscopies and careful screening and
observations of these patients was very, very important to us.

And to date, as you also know, we have not seen anything that has given
us concern. So that\'s basically, I think, how the evolution of our
comfort level has occurred over the last two decades, but your concerns
are certainly appreciated.

CHAIRMAN BRASS: Dr. Shuster.

DR. SHUSTER: I\'m interested in knowing how you would differentiate the
frequent episodes of heartburn from GERD and how would you educate the
patients and the population as to that? That\'s one question.

DR. LEVINE: I respect the concern and the question that\'s obvious about
what the definition of GERD is, and as you well appreciate, there are a
variety of criteria that physicians will use to diagnose GERD.

Heartburn is a symptom that can be seen in GERD, but I think the issue
that we\'re trying to bring is the appropriateness for consumers who
would not know what GERD is, but certainly we know can recognize
heartburn, and that\'s really where we wanted to direct the discussions.

I recognize certainly the importance of the question intellectually, but
I think perhaps as we work through the day and perhaps this afternoon
we\'re willing to address what are the concerns about OTC use of this
product in consumers who recognize their own heartburn who may or may
not have GERD.

DR. SHUSTER: Could I ask also why did you exclude people who did not
respond to over-the-counter medications? It seemed to me that you would
strengthen your proposal if you included that group and demonstrated
that you had a more potent drug here that would handle that population.

I realize that you are not making a comparative study between your drug
and other over-the-counter drugs, but you did make a comparison in terms
of adverse events with ranitidine, for example.

Because a lot of consideration has come up. There are cost
considerations which will be handled in the marketplace to a large
extent by managed care, I guess, and ease of administration and so
forth. But I would like for you to address particularly the exclusion of
that group.

DR. ZORICH: We are not targeting an audience of people who have failed
their current therapies. So that\'s one reason I think that we did not
choose to study patients who had failed, and I think importantly as Dr.
D\'Agostino pointed out for us these drugs actually at these doses in
this population are not more efficacious than other therapies out there.
I think there\'s some degree of a halo effect for omeprazole because
they are very good drugs at the prescription level and the prescription
doses, which have been 20 and greater, in populations where there\'s
been substantial use.

But in the OTC population at the doses that we studied, I did not see
evidence that they were, in fact, as Dr. D\'Agostino has pointed out,
they\'re not substantially better than other therapies using comparable
models.

CHAIRMAN BRASS: I just want to remind the committee that there will be
plenty of time for further discussion this afternoon. So I want to focus
the discussion now on aspects of the studies and data presentation.

Dr. Cohen.

DR. COHEN: Yes, I have several questions to clarify the presentation.
Firstly, data was presented on acid inhibition for the 20 and 40
milligram does, and nothing was shown for the ten milligram dose except
the pH monitoring, which is not as quantitative as acid inhibition.

And the second question that perhaps you want to answer is was there any
studies done on the ten milligram dose to look at healing of mucosal
erosions in the esophagus over the period of recommended dosing, that
is, the ten-day dosing. Does it heal the mucosa? How does it heal it?
And is that a sustained response or no response?

DR. LEVINE: I can address both questions. Could I have slide 34?

I\'m going to refer you to some studies from the development program
where we\'ve done another type of study. This is a dose ranging study
looking at inhibition of peak acid output.

For those who are not familiar, this involves in a controlled laboratory
situation administering a secreter called pentagastrin and then
measuring acid output and then the inhibition of that acid output before
and after treatment.

And what you can see here is we had dose ranging from five to 40
milligrams, and I could show you table after table, but we basically
believe that five milligrams was really subtherapeutic, but you could
see if you focus on the percent changes certainly a dose response.

So within the development history we\'ve looked at, you know, basal acid
outputs as well as pH.

Next, if I could go to slide 46, again, this is not in the OTC setting.
These are data from the Rx trials because in the OTC setting these
consumers were not endoscoped to see whether or not they had esophageal
erosions, but this is data actually from the Prilosec Rx label and were
part of the pivotal studies for approval of omeprazole for acute healing
of erosive esophagitis.

And what we demonstrated \-- excuse me. These are maintenance of healing
studies. My apologies. This is the best data that I have. We were able
to show certainly a dose effect in maintenance of healing of erosive
esophagitis where there was a dose response.

DR. ZORICH: But they had been healed.

DR. LEVINE: They had been healed before with 20 milligrams.

DR. ZORICH: Four weeks.

DR. LEVINE: Over four weeks, yes.

DR. COHEN: Well, there are no data then at the ten milligram dose for
healing of established erosions, not maintenance, but healing?

DR. LEVINE: I would have to ferret those data out. I don\'t have those
with me today. Sorry.

DR. COHEN: And the inhibition data for ten is a rather modest, if not
small, acid inhibition, 20 percent.

DR. LEVINE: Yes. Clearly it\'s above zero. It\'s clearly less than 20
milligrams.

CHAIRMAN BRASS: Dr. Shapiro.

DR. SHAPIRO: There is good epidemiological evidence that the histamine
antagonists do not increase the risk of gastric cancer. I\'m bringing up
this question because of the issue that has been raised a little
earlier, rather solid evidence confirmed by the International Agency for
Research on Cancer, which reviewed this about ten years ago.

Have some of the data been developed for the use of omeprazole?

DR. LEVINE: I don\'t believe that similar studies have been performed
for omeprazole as have been with the H2s.

DR. SHAPIRO: It seems likely, based on the H2 antagonist data, that
suppression of gastric acid secretion does not seem to increase the risk
of gastric cancer. Would you be willing to infer that this might be the
case for your product?

DR. LEVINE: Yes, absolutely.

(Laughter.)

DR. SHAPIRO: Well, I\'m surprised.

CHAIRMAN BRASS: Dr. Sachs.

DR. LEVINE: Well, you know, we have to make our best medical judgments,
and based on the available evidence, I would say it\'s true.

DR. GEORGE SACHS: It\'s very difficult to define an exact threshold
between patients who are suffering moderate or mild versus relatively
more severe. What\'s very clear from all the data on omeprazole, that
you look to see a very nice change in the degree of acid inhibition on a
24-hour basis between ten and 20 milligrams as you showed, and this
would argue very strongly that given the difficulty of quantitation of
what patients should put themselves under OTC treatment, that 20
milligrams would be the appropriate dose based on acid output studies.

Secondly, I do want to point out that the risk of gastric cancer due to
Helicobacter pylori is suppression of acid secretion and ingestion of
intestinal metaplasia in the fundus and has nothing to do with increased
gastrin levels.

DR. LEVINE: I\'d like to address the first point with slide 45, please.
Again, we\'ll take advantage of the Rx development program for
omeprazole, and again, these are data from the label.

Clearly, in a scientific setting we have a better ability to measure
acid or acid inhibition, and there are a number of vagaries in either
reporting or interpretation of patients\' symptoms, and we perhaps lose
some of the exactitude, but we do want to point out that, again, in our
pivotal studies for the claim for the treatment of symptomatic GERD,
again, in the Rx setting, these were patients who were endoscoped and
found not to have erosive disease.

We did do dose ranging studies and found that either in all comers or in
individuals who we say had confirmed GERD based on a positive pH
monitoring test showing acid exposure in the esophagus, either way that
you look at the patient subsets, 20 milligrams was performing better
than ten milligrams.

Now, I would point out it\'s interesting. These studies, although they
were carried out for four weeks, not ten days, they used similar
criteria for rating symptom response. I think it\'s interesting that at
least in medically established GERD over a four-week period, one can see
a difference between these two doses, and yet in the OTC trials that we
performed in consumers, we were not able to show really substantial
difference between ten and 20 milligrams.

And whether that has to do with trial design, the nature of the
heartburn or the difference between heartburn in consumers and medically
diagnosed GERD patients I think is something to ponder.

CHAIRMAN BRASS: I think I\'m going to stop the questioning now because
of the hour and remind everybody that there will be plenty of
opportunity to extend this discussion both after the FDA presentation in
the context of anything they may bring up, as well as this afternoon.

We will reconvene at 10:15 promptly.

Thank you.

(Whereupon, the foregoing matter went off the record at 10:07 a.m. and
went back on the record at 10:19 a.m.)

CHAIRMAN BRASS: We will now continue the morning session with the
presentations by the FDA. I think Dr. Goldkind will be beginning and
managing the FDA presentations.

DR. GOLDKIND: I\'m Dr. Larry Goldkind, a gastroenterologist at the Food
and Drug Administration, and I will be discussing the efficacy of the
submission.

Dan, let\'s see if we can move this forward.

This is the outline of my presentation. I will briefly discuss the
pharmacodynamics of omeprazole; then the review of the efficacy trials;
a discussion of the current prescription usage of Prilosec for GERD and
associated heartburn; briefly discuss definitions of GERD vis-a-vis
heartburn along the lines of discussions earlier this morning; and then
I will review the current over-the-counter template for heartburn
medications and the proposed and updated proposed Prilosec I OTC label.

Next slide, please.

As was discussed earlier, the pharmacodynamic half-life of omeprazole is
quite short, and this is in distinction to the pharmacodynamic
properties which are, in fact, slow in onset, developing with multiple
doses over time, and following a single dose of omeprazole, only 50
percent of the maximum potential inhibition is achieved at 24 hours
following that first dose.

The long acting pharmacodynamic effects are also reflected in the time
to return to baseline acid secretion, which requires several days to
achieve.

This slide is from a study presented by the sponsor and uses
intragastric pH associated with a sham meal, which may be a more
physiologic setting than the peak pentagastrin stimulated acid output
that was presented earlier. On this slide you see the intragastric pH
versus time following a single dose of either omeprazole ten milligrams,
20 milligrams, or famotidine ten milligrams, a currently approved,
over-the-counter heartburn remedy.

Can you back up to the previous slide?

As you can see, over the five hours post dose, there is little to no
change in the intragastric pH associated with the ten and 20 milligrams
of omeprazole, while there is a fairly rapid rise in intragastric pH
over the three hours following dose and then a fairly rapid fall off
back towards baseline.

Next slide.

This slide is from a study, a reference submitted by the sponsor, and
this does use the mean pentagastrin stimulated peak acid output as the
endpoint, and this is intended to show that there is an effect following
a single does.

However, to maximize the pharmacodynamic effects of omeprazole, one
needs to go out multiple doses. This study was done with a 30 milligram
dose, although a similar pattern would be expected for other doses as
well.

Next slide.

Now, I\'d like to discuss the heartburn relief trials. To briefly review
the demographics, these were frequent heartburn sufferers with a mean
frequency of heartburn of 60 percent of days during the pre-study
period. The average heartburn severity of participants was in the
moderate range on a zero to three scale with zero being no heartburn and
three being severe. Over 50 percent of the subjects had moderate to
severe heartburn.

This slide shows the primary efficacy endpoint of sustained complete
relief for the first episode and first dose of drug, and as you can see,
the percent of subjects with sustained complete relief is not
meaningfully different between placebo, omeprazole ten and 20 milligrams
in both studies.

Next slide.

Secondary endpoints for the first dose were inconsistent at those
endpoints of sustained adequate relief, complete relief within an hour,
adequate relief within an hour, and overall assessment.

And I would want to add here that while sustained adequate relief was a
primary efficacy endpoint in previous heartburn submissions, it was not
the only evidence to form the basis of approval and the totality of
other submissions out of context is difficult to compare to a current
submission.

Next slide.

The sponsor has discussed the secondary analysis of all treated
episodes, and before we can really fully understand the meaning of those
results, and that question has been alluded to earlier today, one needs
to consider what the extent of exposure to drug was over the 14-day
study period.

Almost 90 percent of subjects in these studies took more than three
doses of medication during the 14-day period, and as we\'ve discussed,
results beyond the first episode will be confounded by the
pharmacodynamic carryover effects from prior doses.

As the next slide will show, no benefit was seen for the episodic cases.
The agency requested that the sponsor do an additional analysis of all
episode that were separated by at least four days from a previous dose
of omeprazole. This was felt to allow for inclusion of as much data as
possible, but also minimizing the extent of carryover pharmacodynamic
effect and acid suppression that would be associated with prior doses
for the indication of occasional relief of episodic heartburn.

And as this slide shows, the percent of subjects with sustained complete
relief was not meaningfully different between placebo, omeprazole ten
and omeprazole 20 milligrams at this analysis.

There were additional heartburn relief studies submitted to the IND.
There were three. These were large studies with a total of over 11,000
subjects, and no efficacy was demonstrated at the study endpoints that
included sustained complete relief, sustained adequate relief, overall
assessment of study medication, and back-up medication usage.

In summary, there were five studies of episodic heartburn relief which
failed at the primary analyses. The all episodes analysis, taking into
account carryover effect, failed to demonstrate efficacy for the
occasional episodic usage.

Next we\'ll discussion prevention of the meal induced heartburn studies.
This slide shows the primary efficacy endpoint for four-hour post meal
heartburn free period, and similar to the display earlier, study 006
does show a relatively small therapeutic gain with statistical
significance, while study 005 has a yet smaller therapeutic gain which
does not achieve statistical significance for either dose.

Next slide.

Secondary endpoints included overall assessment of medication, maximum
severity score, back-up medication use, average symptom severity, and
reduction of maximum severity score. There was some supportive data \--
some supportive results at the secondary endpoints for the 20 milligram
dose. However, the ten milligram dose had some support only for the
endpoint of maximum severity score, with the other four endpoints noted
here, lacking any support for the ten milligram dose.

In conclusion, Prilosec I at a 20 milligram dose may have marginal
efficacy for the prevention of heartburn when taken one hour before a
heartburn inducing meal, while the ten milligram dose lacks replicated
efficacy for primary and most meaningful secondary endpoints.

Outstanding issues include the lack of replication of results; the small
therapeutic gain that has been alluded to earlier today compared to
placebo; the potential for consumer confusion, which I think has also
been alluded to earlier in judging a product that may be approved for
prevention of heartburn where there\'s a lack of efficacy for treatment;
and finally, the pharmacodynamics as discussed do favor chronic usage of
this product.

Next we\'ll review the 24-hour prevention studies. This is in fact, a
new indication, the concept of 24-hour prevention of symptoms over a
period of time, and of course, the question must be asked: is this, in
fact, management of GERD or occasional episodic heartburn?

The entry criteria for these subjects included heartburn of greater than
one month\'s duration and heartburn at least two days per week. As has
been mentioned earlier, subjects had to have been responsive in the past
to antacids or over-the-counter H2 receptor antagonists for enrollment
which does enrich the population for response.

Demographically, the subjects were, in fact, more strongly enriched for
what we might call GERD sufferers with 80 percent of subjects having a
baseline frequency of heartburn greater than 50 percent of days. Mean
severity was between mild and moderate.

The primary efficacy endpoint, heartburn free over the 24 hours
following the first morning does, did show meaningful differences
between placebo and both ten and 20 milligrams of omeprazole.

Next slide.

The results on day 14 following 14 cumulative doses of omeprazole
likewise showed meaningful difference between the placebo and omeprazole
groups in both studies.

In summary, there were replicated, statistically significant differences
compared to placebo for both doses, and as one might expect from the
pharmacodynamics, the efficacy as measured by the therapeutic gain
compared to placebo did increase over time. On day one, going across
studies and across doses, the gain was nine to 17 percent compared to
placebo, while by day 14 the therapeutic gain was between 23 and 30
percent compared to placebo.

This slide has been displayed earlier and does point to the fat that the
efficacy is lost over the two to three days following discontinuation of
a 14-day therapeutic course of omeprazole, and it of course then begs
the question: what does the consumer do following day two or three when
they have return of their underlying chronic symptoms with an OTC
product labeled for limited usage?

In conclusion, these 24-hour prevention studies were successful at
demonstrating prevention of heartburn symptoms with both ten and 20
milligram doses. The efficacy did increase over time with the
therapeutic benefit lost within three days of discontinuation of the
study medication.

I\'d like to briefly discuss prescription versus OTC, GERD versus
heartburn. The current prescription Prilosec label for GERD states that
the recommended adult oral dose for Prilosec for the treatment of
patients with symptomatic GERD and no esophageal lesions is 20
milligrams for up to four weeks.

For those patients with erosive esophagitis and accompanying symptoms
due to GERD, the dose is the same, but the duration is longer, extending
from four to eight weeks.

Next slide.

Within the submission, the sponsor defined GERD as representing a
distinct physician diagnosed chronic disease characterized by acid
reflux and attendant symptoms, usually heartburn, and requires four to
eight weeks of treatment with omeprazole.

A little further in the submission episodic treatment of heartburn in an
attempt to distinguish from GERD is different from the treatment of
GERD, although it\'s not well clarified how one would differentiate
heartburn from GERD on a spectrum and how the treatment would best be
approached.

Going outside the submission, Dr. Castell has alluded to these
definitions. One appears in the American Society of Gastrointestinal
Endoscopy guidelines for practice of endoscopy, and a prominent
gastrointestinal disease textbook edited by Schlesinger and Fortran both
point to the fact that GERD may be defined as symptoms and/or tissue
injury related to the reflux of gastric contents into the esophagus with
heartburn being the typical symptom of GERD.

Next slide.

In an attempt to look at an operational definition of the practitioner,
one may look to studies of GERD and heartburn to see how the clinical
investigators define the population to appropriately reflect the
population for extrapolation.

And in a recently published study in the [Archives of Internal
Medicine]{.underline}, entitled \"Efficacy of Omeprazole for the
Treatment of Symptomatic Acid Reflux Disease Without Esophagitis,\" the
entry criteria required the patients have a history of heartburn for
over 12 months and episodes of moderate to severe heartburn on four or
more days of the seven days prior to endoscopy and enrollment.

In summary, heartburn is the cardinal symptom of GERD, while GERD is a
chronic condition that does require some medical judgment to assess and
to differentiate from what might be operationally defined as a mild
occasional heartburn, and likewise management of GERD is based on
medical judgment, taking into account severity, chronicity and frequency
of symptoms.

The rationale that underlies the current over-the-counter treatment of
episodic heartburn can be described by the points on this slide, that
is, the episodes for treatment should be discrete and occasional. The
symptoms have to have been shown in analysis to be responsive to low
dose therapy in an attempt to distinguish it from a chronic prescription
therapy for GERD, and the currently approved over-the-counter H2
receptor antagonists are approved at one-eighth to one-quarter of the
daily prescription doses.

The OTC products are all effective for both relief of acute symptoms, as
well as prevention, with no repeat carryover dose effects required for
efficacy, and the limitation to usage on the label is for two weeks
consecutively.

Currently the approved products, as noted earlier, include relief of
episodic symptoms and prevention for symptoms that may occur in
association with food or beverages that are known to cause heartburn for
that individual, and it\'s clear that the indication is linked to
specific episodes of heartburn.

The proposed Prilosec label includes relief of symptoms for which the
submission is not demonstrated efficacy, as well as 24-hour prevention
taken any time during the day. The studies that were submitted were
morning dosing and would require extrapolation to assume that dose taken
any time of day would give the same results.

The label further goes on to say that if preferred, one hour before
those events that are associated with occasional heartburn, such as
consuming food and beverages, where there was marginal efficacy
supported, the next point the revised label addresses that.

Next slide.

The 24-hour prevention is noted, is a new indication for OTC heartburn
treatment, which is not episode based. Dosing any time of day is an
unsupported new dosing instruction which also pulls the consumer away
from the concept of episode based management and the non-meal related
symptoms we skip.

And in the original proposed dose is the prescription dose. The new
proposed dose is certainly closer to the prescription dose than the
other over-the-counter remedies that are approved.

Next slide.

Overall conclusions, the pharmacodynamic properties of omeprazole would
predict no efficacy for acute, short-term relief with progressive
improvement in efficacy for prevention over time based on the delayed
pharmacodynamic effects of the drug.

The results of the clinical studies do follow these predictions with a
lack of efficacy at acute treatment of episodic heartburn, marginal
efficacy at prevention when taken one hour before a h inducing meal, and
a prominent optimal role in the prevention of heartburn over time in the
management of GERD, which as the sponsor stated is currently a physician
diagnosed chronic disease requiring four to eight weeks of therapy.

And as Dr. Castell has alluded to, moving along a spectrum from
occasional heartburn to GERD would be a difficult item to label if one
were to move from the occasional heartburn to GERD arena for
over-the-counter management.

Thank you.

DR. CHIN: Thank you.

Testing. Can you hear me in the back?

Good morning. I trust you\'re still heartburn free for the FDA
presentations.

My name is Dr. Chin, and I\'m from the Division of Over-the-counter Drug
products.

These slides were prepared by Dr. Shetty and myself.

A very brief overview of actual use studies. Typically actual use
studies have the following characteristics. They are all comer studies
with minimal inclusion and exclusion criteria, with minimal health
professional involvement and intervention.

Actual use studies are conducted for the purpose of demonstrating that
the consumer can self-select and use the drug appropriately according
only to the label.

Next.

In support of the Prilosec switch, there were five studies conducted
under OTC-like conditions, and they can be grouped as self-selection and
usage studies which are study 003, 067, and 022, and marketing and usage
studies 014 and 091.

This is a summary slide, and I\'m going to skip it.

An extensive list of inclusion and exclusion criteria were applied to
the enrollees before they could participate in the actual studies. The
ones of more relevance to this presentation include age limitations and
prerequisites for use of heartburn medications.

The only thing of note is that study 067 recruited specifically for
adolescents age 12 to 17, and they had to be treated with antacids or H2
blockers in the last month.

In study 014, there had to be use of oral OTC heartburn medications in
the past three months, and in study 091, antacid, acid reducer use was
of at least two times per week in the last 30 days.

Almost all of the risk conditions on the proposed label was screened
out, including pregnancy, medical conditions such as peptic ulcer
disease, continuous abdominal pain, dysphasia, known hypersensitivity to
omeprazole, and the medications listed here.

Female subjects had to undergo two or three urine pregnancy tests before
and during the study and sign an agreement that they would use a
reasonable contraceptive during the study.

Next.

A key feature of actual use studies is to demonstrate the subject\'s
ability to self-select and use appropriately. Note that the subjects in
studies 014 and 091 did not determine for themselves if the product was
appropriate for them to use.

Studies 003 and 022 were the only studies where subjects did
self-select. The rest of this presentation, therefore, will focus only
on studies 003 and 022, as well as 067 which provided information on
adolescents.

Proposed uses for OTC Prilosec are for prevention and relief. Directions
were provided for prevention of systems for 24 hours for any time during
the day or for one hour before associated events, as well as for relief
of symptoms. Regardless of use, the directions state do not take more
than one tablet a day. Do not use for more than ten days in a row unless
directed by a doctor.

The primary objective of these studies you know already, and these are
measured by the primary endpoints which are the percent of subjects who
take only one tablet per dose, take no more than one dose per day and
take no more than ten consecutive days.

Demographics. Only study 003 recruited for subjects with low literacy
levels. There were about ten percent in the ITT population. There was
racial diversity in studies 003 and 022, and in all studies about 60
percent were female.

These studies were useful in telling us about the kind of OTC consumers
who would use this product. As far as heartburn history, most of the
subjects in this study had heartburn of longstanding duration.
Two-thirds to three quarters of the subjects had heartburn for more than
two years, and only about eight to 15 percent had heartburn for less
than a year.

More than half of the subjects had heartburn at least two times per
week.

Usage patterns. Users were also characterized by their use of the
product. All subjects had to record the reason for product use in the
product use journal. Subjects checked prespecified boxes that were
marked, taken any time during the day, taken one hour before the event
or taken for relief of symptoms. These data were compiled resulting in
the distribution of subjects by these five mutually exclusive groups.

Over half of the subjects used the product for prevention and relief.
About a third of the subjects used it for relief only, and about ten
percent used it for prevention only.

I\'d like to make a note here that the three prevention subgroups,
prevention any time, prevention one hour before, and dual prevention had
very few subjects involved. So they will be considered as one group from
here onwards, as a prevention only group.

The results on correct use. As a reminder I\'ve put up the three dosing
directions. Subjects are assessed as consistent only if they complied
with all three directions, and the overall results for consistency are
58 percent to 75 percent across all three studies.

I\'d like to make a comment here about sponsor\'s data that was
presented earlier. The results presented were by dosing day and by
dosing occasions. The results that are presented in this slide are by
subjects. So you can see about three percent to 22 percent of subjects
did not use correctly according to any one of the dosing direction.

Conversely \-- can you just go back one second? Okay. I get extra time.

(Laughter.)

DR. CHIN: Conversely, in totality, if you take all the subjects in the
studies, 78 to 86 percent of all subjects did dose correctly according
to any of each of these directions.

If we focus only on those who exceeded the ten-day limit, this graph
shows across all three studies \-- oops. Sorry. Okay. I\'m sorry. There
was a mix-up in the order here.

If we focus only on those who exceeded the ten-day limit across all
three studies and if you look at the usage groups of those who use it
for prevention only, 64 percent of people in this group exceeded the
ten-day limit on use.

The people who used it for relief only very rarely did that.

Next slide.

Now, if you look further at the maximum number of sequential days that
the product was used, this slide graphically shows you the pattern
between the prevention only users and the relief only users. Prevention
only users are in yellow. Relief only users are in orange.

Eighty percent of the people who used it for relief only used it for one
to two days consecutively.

Among the prevention only users, the profile is reversed. Over 51
percent took the drug for more than 25 sequential days.

Next slide.

So in summary, these are the specific conclusions from these studies.
Fifty-eight to seventy-five percent of subjects in the three studies
dosed according to all three dosing directions. The relief only users
were more compliant than the prevention only users. Prevention only
users were most noncompliant with the ten-day sequential use limit.

Study participants had heartburn of frequent occurrence and longstanding
duration. I\'d like to offer that the study results may be biased since
two to six percent of subjects with a risk profile were further excluded
by criteria or study personnel. Another 18 to 25 percent of subjects
were excluded from the ITT population for failure to return the product
use journal or failure to complete certain elements of the product use
journal.

One could postulate that the subjects who did not return or complete the
use journal may be less motivated and may be more likely to be
noncompliant, and if included in the ITT population would have impacted
on the overall consistency results negatively.

Given the possibility that study results may be overly optimistic, the
overall compliance with all three dosing directions is not impressive.
It is of concern that the direction to exceed ten days of consecutive
use was the one direction that was most ignored, especially among
prevention users, the majority of whom were using it for beyond 25 days.

This is the final slide. The 24-hour any time prevention claim has, in
essence, changed the nature of using this drug product for episode
linked prevention to prevention of any number of episodes of heartburn
within a set time period. Therefore, people using it for this purpose
may, in fact, have more frequent and longstanding heartburn suggestive
of GERD.

Our concern is that if people with self-treating for GERD, the proposed
label does not provide adequate information for such use. The question
is: what potential harm, if any, may affect OTC consumers from chronic
long-term use without benefit of a learned intermediary in such areas as
possible misdiagnosis, delay in diagnosis and treatment, and/or
suboptimal treatment of a chronic condition that may result in much more
serious consequences.

Thank you for listening.

DR. AVIGAN: Good morning. My name is Mark Avigan. I\'m a medical officer
in the Division of Gastrointestinal and Coagulation Drug Products.

Next slide, please.

As you just heard from a number of our presenters, there are a number of
characteristics of omeprazole and the proposed indication for OTC use
which point to a rather strong likelihood of chronic or intermittent
long-term use by some consumers. These include, first, the proposed
labeling does not warn against long-term intermittent use.

Second, actual usage studies that have been performed by the sponsor
indicate that a significant percentage of subjects did not follow the
label instructions by treating themselves beyond ten days.

Third, the maximal asset suppression only occurs after two or three days
of daily 20 milligram doses, and then there\'s this lingering effect
after cessation for a few days.

These properties are consistent with a role of the prevention of chronic
heartburn rather than immediate relief by single table of occasional
episodes of heartburn.

And finally, a significant percentage of subjects recruited into the OTC
studies, in fact, had GERD. Heartburn associated with GERD is
characterized, as we\'ve heard, by a high recurrence rate when treatment
is stopped. Therefore, we need to take into account the safety profile
of long-term drug exposure in conjunction with short-term exposure as
expressed in the labeling that the sponsor has proposed.

Next slide, please.

To pursue this the following topics will be discussed, and we will have
some overlap with what has been presented by the sponsor. First, the
safety profile of the magnesium formulation in the OTC trials is
presented in the NDA.

Second, safety issues raised by experience from the short term
administration of the prescription enteric coat formulation in which a
summary of clinical studies and the post marketing experience will be
discussed. Special topics of concern that will be addressed today will
be omeprazole induced liver toxicity, skin toxicity, bone marrow and
immune system.

Third, the post marketing experience with the magnesium formulation of
omeprazole will be discussed since, as was mentioned, since 1998 this
formulation has been prescribed by physicians in Sweden, and special
issues that we will discuss today in collaboration with the sponsor, the
potential for drug-drug interactions between omeprazole and other drugs.

Next slide.

In addition, we\'ll make some reference to special populations,
particularly pregnant women, and then the second part of this
presentation will be an analysis of special concerns that have been
raised about long-term continuous or intermittent administration of
omeprazole.

We\'ve somewhat arbitrarily defined this to mean continuous or
intermittent exposure to the drug for more than 12 weeks and in some
cases longer than the year or longer than that even.

The special topics that will be covered include masking of medically
significant diseases, tumorigenicity and the implications of gastric
acid rebound upon cessation of drug administration.

Finally, a summary of the conclusions that we have drawn surrounding
these issues will be given.

There are four databases that are relevant for the short-term exposure
analysis. First, the magnesium formulation clinical trials, the OTC NDA,
that form the body of this application. Eight thousand one hundred and
seventy-nine subjects were exposed to daily ten milligram or 20
milligram doses of the magnesium formulation, 5,000 of these to the 20
and 3,000 to the ten.

In most subjects the duration of treatment range between one and 14
days. A second database relevant to short-term omeprazole exposure is
that derived from the clinical trials of the prescription formulation,
and as was mentioned, 5,700 patients with specifically GERD, esophagitis
and dyspepsia on doses between ten and 40 milligrams who are treated
over the duration between one day and 12 weeks are in this database.

And finally, there are the two post marketing databases that have been
alluded to, the SafeTNet database, which is a compilation of adverse
events until 1998, a lot of adverse events from the inception of the
prescription by the sponsor, and then the database about the magnesium
formulation in Sweden, 1998 and 1999.

So in that database there is a small number of adverse events that so
far have been recorded in a background of over 11 million prescriptions,
as the sponsor has mentioned.

Now, safety information gleaned from the OTC omeprazole magnesium
clinical trials is limited by the following characteristics.

First, there is brief exposure to the drug.

Second, there is short-term monitoring of adverse events.

Third, the relatively small number of subjects precludes comprehensive
assessment of rare adverse events since these may not be detectable in
this size of a group of exposed individuals.

It has to be pointed out that there was negligible representation of
specific demographic groups, and I think the sponsor has already alluded
to the adolescents, and in addition, Asian Americans only represented
one percent of the exposed individuals, and as has been alluded to, this
particular group has a higher rate of slow metabolizers, and I\'ll come
back to this point in a moment.

The findings in the omeprazole magnesium clinical trials for the OTC
indication are that the profile, a general profile, common adverse
events, is similar to the prescription formulation, but in the database
there are also cases of drug related adverse events, including serum
sickness, urticaria, and elevations of AST, suggesting that these side
effects are not exceedingly rare.

There are no apparent dose related differences in these adverse events.
Causes for drug discontinuation in the groups included not surprisingly
headache and rash.

Next slide.

Because there are large numbers of people in the United States who may
self-medicate for heartburn symptoms only, without supervision of the
physician, it is necessary to insure that omeprazole meets a very high
stringency of safety. In the case of prescription usage, the benefit of
treatment of significant medical conditions under the supervision of a
physician outweighs the risk to develop drug toxicities, including those
that are rare.

Because the benefit gained for the symptomatic treatment of occasional
episodic symptoms is different, it is appropriate to revisit the profile
of these toxicities which were previously found to be acceptable in the
arena prescription treatment.

In synthesizing the four different sources of information concerning the
safety profile, the short-term exposure to the drug, a number of
toxicities have emerged as points for this discussion, and they\'re
listed here. These are the ones we will just briefly focus on: hepatic,
marrow suppression, angioedema and anaphylaxis, and finally drug-drug
interactions.

The sponsor has provided a liver function assessment that was performed
in four U.S. and five non-U.S. clinical trials. These studies included a
rather small group of 1,400 patients. Treatment duration with omeprazole
lasted between one and 60 weeks, and we can make the following general
conclusions from these studies.

First, that LFT abnormalities are not dose dependent, and secondly, most
of these abnormalities are mild, transient, and not related to duration
of treatment.

Nonetheless, as can be seen, a few patients with liver injury were
detected in these trials. Transaminase elevations exceeded three times
the upper limit of normal in five patients in the U.S. trials with
respect to incidences at .58 and .18 percent.

No unexpectedly, the incidence of milder elevations of transaminase in
both groups of these studies were higher. This finding supports the
conclusion that there\'s a spectrum of transaminase elevations
associated with exposure to the drug, and, in fact, the studies reveal
that between 200,000 and 500,000 treated patients developed some
transaminase elevations consistent with three times or greater
elevations of hepatitis.

Now, in the post marketing SafeTNet database, there were 33 fatal cases,
two which were assigned an A rating. This rating suggests a high
probability of omeprazole toxicity since no other explanation of
causality could be identified.

Of the 227 liver toxic serious adverse events, four were assigned an A
rating, and it has to be pointed out that two of these four cases
redeveloped hepatocellular necrosis after drug rechallenge,
demonstrating the unequivocal linkage to omeprazole.

According to the FDA adverse event reporting system, two of 57 domestic
toxic liver events linked to omeprazole have required liver
transplantation. Therefore, the range of liver damage associated with
omeprazole rarely includes individuals who have developed severe
toxicity and organ failure, and, again, it is a rare event.

Unfortunately, the incidence of omeprazole linked liver damage and
hepatic failure and death cannot be extrapolated from a voluntary
reporting system because of the nature of such a system.

Next.

With regards to omeprazole associated toxic epidermal necrolysis and
Stevens-Johnson Syndrome, there are variable time intervals between drug
exposure and onset of symptoms. In the post marketing database there are
49 cases of this severe form of toxicity. Two have an A rating, and a
nonfatal case redeveloped skin lesions upon drug rechallenge showing the
strong linkage to the drug.

The incidence of white cell suppression by omeprazole is high enough to
be detectable in relatively small clinical trial populations. With
regards to granulocytopenia in U.S. short-term trials that have been
analyzed, the incidence was .2 percent, and in U.S. long-term trials it
was .7 percent. For leukopenia, the incidence in U.S. short-term trials
is .9 percent and in long-term trials 1.5 percent.

Related to these observations the intensive medical monitoring program
in New Zealand and one-year follow-up of omeprazole treated patients
revealed that .03 percent developed granulocytopenia. In fact, there was
a case of aplastic anemia.

It\'s important, again, to emphasize that cause and effect is not \-- is
provided for each of these cases.

Now, the post marketing database \-- next slide \-- SafeTNet has
revealed that there are 122 reported cases of omeprazole linked with
suppression of white cells. These include 26 fatalities.

Of the 26 fatal cases, five were assigned an A rating. Of the 96 serious
nonfatal cases, 35 were assigned an A rating.

So, in summary, similar to the other toxicities we visited so far,
significant marrow suppression associated with granulocyte counts less
than 1.5 times ten to the ninth per liter occurs with an incidence
between .3 and five per 1,000, and in fact, there are very rare cases of
fatal agranulocytosis.

As is the case of these other events, omeprazole exposure has been
associated with hypersensitivity reactions in clinical trials. In these
trials at least there are four cases of angioedema and one of
anaphylaxis. Three fatalities also occurred that were associated with
drug hypersensitivity.

But much more commonly the incidence of urticaria has been measured to
be between one and two per thousand.

Similarly, the reported incidence of hypersensitivity reactions,
including angioedema and urticaria in omeprazole users has been detected
in New Zealand.

Not surprisingly in the post marketing SafeTNet database there were 134
cases of angioedema and anaphylaxis. Seven of these were fatal, and nine
of the nonfatal cases were assigned an A rating. Again, the A rating is
the high probability linkage.

Next slide.

In summary, immediate hypersensitivity reactions, which include
urticaria, angioedema, wheezing and anaphylaxis are linked to omeprazole
exposure. In the number that I\'ve given most of those are on the milder
end of the spectrum.

Next slide.

As I mentioned, omeprazole magnesium has been used as a prescription
drug in Sweden since 1998, and there\'s a database of 219 voluntary
reports. The only thing I want to say about these is that we see a
similar pattern of side effects, including hypersensitivity reactions,
angioedema, urticaria, anaphylactic shock, and there are some liver
toxicity reports.

Other serious adverse events include toxic epidermal necrolysis and
interstitial nephritis. Finally, cases of agranulocytosis have been
reported.

Although substantial differences between the safety profiles of the
enteric coated prescription formulation and the magnesium formulation
have not emerged, it should be pointed out that subtle differences in
formulation associated risk to develop rare adverse events cannot be
measured because of undefined reporting biases and the relative short
time that the magnesium formulation has been marketed.

Now, I\'m going to just go through this quickly. This has been alluded
to before that omeprazole is metabolized by CYP 2C19.

Next slide.

An important influence on omeprazole clearance is the presence of a
polymorphism, which inactivates the isoform, and this slow metabolizer
phenotype is identified. The homozygous genotype actually is identified
in only three percent of Caucasians, but it\'s present in 15 percent of
Asians.

Other factors as has been mentioned which decreased clearance or aging
and liver disease.

Again, the concept is that a reduction in clearance of the drug may be
linked to two effects: first, a longer circulating half-life of the
drug; and, second, increasing circulating drug levels when it\'s at
steady state.

Because of the relatively short half-life of omeprazole, modest effects
on clearance usually have small effects in circulating drug levels.

Alterations of activities of other drugs by omeprazole occur by two
distinct mechanisms. One of these, changes of drug absorption, occurs
due to the effects of the PPI and gastric liminal pH, and pertinent to
this mechanism, there is increased absorption of digoxin and nifedipine,
which in normal individuals is a modest phenomenon.

However, it should be pointed out that certain individuals, such as
those with renal failure, might be susceptible to digoxin toxicity, for
example, even with subtle changes in blood levels.

In the opposite direction, decreased absorption of the anti-fungals by
as much as 80 percent during treatment with omeprazole has been
observed.

The second mechanism by which omeprazole interacts with some other drugs
is through the inhibition of CYP 2C19, leading to their reduced
clearance. Drugs which are cleared by this enzyme include diazepam,
phenytoin, R-warfarin, and tolbutamide.

And during omeprazole treatment in study subjects, decreases in
clearance of these drugs has ranged between ten and 55 percent. In the
case of diazepam, an omeprazole induced reduction of this magnitude may
be clinically significant in individuals who are particularly
susceptible, such as those with liver disease.

Although omeprazole reduces clearance of these drugs only modestly in
normal subjects, the potential for more pronounced alterations in
individuals who are slow metabolizers taking multiple drugs in which
alternate clearance pathways have been saturated or in individuals with
underlying medical conditions, such as liver disease, has not been
entirely ruled out.

Let\'s move on. The adolescent point I think we both agree on, and I
think we can just move forward.

Thank you.

Currently omeprazole is not approved for prescription use during
pregnancy. There are a number of concerns regarding the use of
omeprazole during pregnancy. These include the following points. The
drug is associated with embryo fetal lethality in rabbits and reduced
fetal weights in rats. In some experiments the drug has been found to be
classed eugenic, and I will discuss this in a moment.

Nonetheless, it has to be said that voluntary reporting of females of
child bearing age who have been issued 14 percent of the total
prescriptions in the U.S. before, during, and after pregnancy has not
revealed a signal consistent with human embryo-fetal toxicity.

With these observations, there is a need for a prospective or nested
(phonetic) case control studies in pregnant women to confirm safety of
embryo-fetal exposure.

Now, let me switch gears to talk about the safety issues that surround
long-term exposure of omeprazole, defined as exposure for more than 12
weeks, in some cases longer than a year. These include the masking
phenomenon that we\'ve heard about or in the delay of diagnosis of GERD
related complications or conditions which require medical treatment.
Such conditions include Barrett\'s esophagus, advanced stages of erosive
esophagitis, esophageal dysplasia and adenocarcinoma.

A second issue is the undefined tumorigenic potential of drug induced
prolonged hypergastrinemia and genotoxic properties related to the drug.

Finally, a concern has been raised about the potential for rapid and/or
exaggerated rebound of gastric acid secretion after cessation of
treatment that is tied to recurrence of reflux symptoms and/or mucosal
inflammatory changes.

As I alluded to, it is likely that the long-term use of omeprazole will
be common among undifferentiated OTC consumers with heartburn since,
first, the proposed labeling does not warn against long-term
intermittent use;

Second, actual usage studies revealed longer than ten-day use in a
significant percentage of people who use the drug for prevention;

Third, the pharmacodynamic properties of omeprazole lend themselves to
this phenomenon;

And, finally, the history of symptoms of many of the OTC users, in fact,
was that they had GERD.

Moreover, the concern about masking of underlying disease is justified
from a number of anecdotal voluntary post marketing SafeTNet reports,
which indicate that delay in diagnosis of gastric malignancy can occur
due to temporary alleviation of symptoms or improvement in the
appearance of gastric lesions.

In four of 49 cases of omeprazole linked gastric adenocarcinoma, there
was a one to 12 month delay in diagnosis after treatment was started.

Here I\'m just going to reemphasize a point made by the sponsor that the
incidence of GERD complications is not trivial. Complications include
Barrett\'s esophagus. You heard a ten percent number, that studies range
anywhere from one to six percent of people with longstanding hypernon
(phonetic).

And, again, as was mentioned, the symptoms of Barrett\'s esophagus
really are not distinguishable from the undifferentiated population,
which is a problem, but the conundrum, the hook is that current medical
practice includes regular endoscopic surveillance in these folks for
dysplasia and cancer.

A different complication of GERD is the composite of advanced stages of
erosive esophagitis whose incidence ranges between 2.4 and 47 percent,
depending on the studies. These individuals are at increased risk to
develop clinically significant strictures and other fibrotic changes,
and they\'re currently treated with aggressive pharmacotherapy to
suppress acid.

Another complication that we\'ve heard about today is the dysplasia and
cancer complications where the problem of delay in diagnosis may have an
important impact on outcome. These individuals are less than one percent
of the total pool of people.

Next slide.

Because of the complications that I have mentioned, effective triage of
individuals with GERD who require further diagnostic testing plays an
important role in their management. The current standard of medical care
includes the following features.

Early physician referral is recommended for individuals with one or more
of the following: dysphagia or odynophagia; persistent symptoms despite
treatment; hematemesis, melena, rectal bleeding, or anemia, weight loss,
anorexia, unexplained chest pain, chronic cough, hoarseness, asthma,
chronic symptoms in patients at high risk for a Barrett\'s esophagus and
finally need for continuous therapy.

Therefore, early physician evaluation of individuals with GERD who have
features that put them at risk for underlying diseases is part of the
current standard of medical care in the United States. Endoscopic
evaluation may be warranted in many of these individuals.

In summary, physician referral after a failed treatment course or
recurrence of GERD symptoms after cessation of therapy is thought to
provide an important margin of safety to exclude significant underlying
diseases.

Consistent with this perspective, the sponsor has made the following
statement, and you can read it. In order to avoid the risk of possible
complications \-- and I think they basically said the same thing today
\-- that there has to be adequate warning, and that consumers should be
made aware of the indications, dose and duration of therapy, and in
addition, they should have a clear understanding of when to seek medical
attention

Issues of concern that have been raised that pertain to a potential
carcinogenic effect of omeprazole in a large population of chronic
users, even though ambiguity still surrounds some of these issues, it is
important to raise them since the proposed treatment of occasional
episodic heartburn requires an appraisal of risk relative to a newly
calibrated benefit.

The concerns are based on the following proposed mechanisms. First,
omeprazole induced hypergastrinemia has an atrophic effect on not only
ECL cells, but other cells both within and outside the GI tract.

There is a potential by omeprazole induced hypergastrinemia to cause
exaggerated growth promoting effects in the gastric mucosa of H. pylori
infected individuals.

And finally, the genotoxic properties of omeprazole to susceptible cells
both within and outside the GI tract may promote carcinogenesis.

Omeprazole induced hypergastrinemia is characterized in the following
manner. Many individuals manifest a two to fourfold increase in serum
gastrin concentrations above baseline during chronic administration of
the drug. This reverses upon cessation of treatment.

Increases of this magnitude are not observed during administration of
low dose H2 receptor antagonists that are used to treat heartburn over
the counter. A small percentage of individuals develop pronounced
responses with greater than a fourfold increase of serum gastrin
concentrations, some well above the upper limit of normal. These
individuals may be particularly vulnerable to drug related cancer risks.

Factors which may increase serum gastrin responses to omeprazole in some
individuals include H. pylori infection, the CYP 2C polymorphism, both
the heterozygous, as well as the homozygous genotype. High dose and
increased dosage infrequency of omeprazole and medical or physiologic
conditions in which there is a reduced level of pretreatment gastric
acid secretion.

The genotoxic potential of omeprazole is predicated on the following
observations. First, [in vivo]{.underline} and [in vitro]{.underline}
clastogenic effects have been noted in drug exposed mouse and human bone
marrow cells.

Second, chromosomal aberrations in omeprazole exposed human lymphocytes
have been noted. Increased sister chromatin (phonetic) exchanges in
peripheral lymphocytes of treated subjects have been reported in one set
of experiments, but similar reports subsequently have not been
forthcoming.

Despite these findings, DNA mutagenicity testing is measured by Ames
Salmonella typhimirium tests, has been consistently negative.

Taken together in the face of positive results that omeprazole has some
clastogenic properties, it is not possible to rule out genotoxicity
associated with long-term exposure to the drug that may be linked to an
increased risk of malignancy.

Now, taking a step back and analyzing the carcinogenic potential of
omeprazole in humans, there are a number of significant limitations in
our analysis. These include the size of controlled studies of
individuals treated for longer than one year are small; precluding
detection of rare drug related tumors. There\'s a lack of prospective or
nested cohort studies to track patients treated with the drug over a
very long period of time.

Detection of malignancy is limited by a predicted long lag phase after
drug exposure, and in some cases high background rates of certain GI
malignancies, for example, colon cancer are expected to drown out weak
signals.

The SafeTNet, as needs to be emphasized, relies on a voluntary reporting
which is not comprehensive. So we don\'t really get incidence figures
out of SafeTNet data.

Finally, there\'s a lack of definition of groups that may be especially
vulnerable to the carcinogenic effect of omeprazole. We heard that from
the table. Such subsets of the population may be diluted by individuals
who are not at increased risk for malignancy when exposed to the drug.

Nonetheless, taking these deficiencies into account, at present based on
the composite of the clinical studies, the SafeTNet data and the
literature, the development of omeprazole induced ECL cell hyperplasia
in humans, unlike rats, has not been linked to progression of carcinoid
tumors with the caveats that I\'ve mentioned.

There is no apparent causal relationship between omeprazole and
carcinoid tumors, gastric adenoma carcinoma, colorectal adenocarcinoma,
and other malignancies.

And finally, in H. pylori infected subject a clinically significant
contribution by omeprazole to the development of gastric mucosal
atrophy, intestinal metaplasia and dysplasia, which are the precursor
lesions to cancer, has not been apparent.

Finally there has been concern about rebound of gastric acid secretion
after cessation of omeprazole. This is based on the following points.

First, cessation of treatment is associated with rapid reappearance of
inflammatory changes in individuals with erosive esophagitis.

Second, acid rebound is reflected by increases in both basal and
pentagastrin stimulated acid secretion. This effect is variable, usually
in people who have been on treatment for longer than a month, but it\'s
not unique to PPIs. It also occurs with full dose H2 blockers.

And, lastly, acid rebound is self-limited after discontinuation of
treatment with omeprazole. No information has been provided by the
sponsor to determine whether acid rebound plays a role in some subjects
to extend the duration of continuous OTC self-medication with
omeprazole. Therefore, at this time it is not possible to assess whether
conditions which affect acid secretion, such as H. pylori, for example,
may influence the development of acid rebound after cessation of
treatment.

In addition, pronounced acid rebound in a subset of susceptible
individuals cannot be excluded. Such a phenomenon would not necessarily
be detected in studies which are in real small numbers of test subjects.

In conclusion, associated with the omeprazole magnesium application,
there are a range of liver toxicities, toxicities idiosyncratic, usually
mild, self-limited, and reversible upon drug withdrawal.

However, the drug does cause significant hepatocellular necrosis in a
small percentage of individuals and has been linked to a few deaths.

Causality of significant hepatocellular damage has been confirmed and in
a few cases with rechallenge by rechallenge with omeprazole.

Omeprazole is also associated with toxic epidermal necrolysis and
Stevens-Johnson Syndrome. Although very rare, some cases have been
linked to death.

The drug has been linked to agranularcytosis and other disorders of
marrow suppression. Life threatening suppression of leucocytes by
omeprazole is very rare. Usually drug induced marrow suppression is
reversible upon drug withdrawal.

Drug hypersensitivity occurs in some cases in which symptoms of
urticaria, wheezing, rash, anaphylaxis and angioedema after omeprazole
exposure have appeared, and the causality in some cases has been proven
by drug rechallenge.

The incidence of these responses that have been detected in clinical
trials may be as high as .5 per 1,000 users of the drug.

Now, even if serious adverse events and the fatalities related to them
are rare, and I think we all agree that these are rare events, in a
background of millions of OTC consumers per year, a significant number
of these events are expected.

For example, if there are ten million OTC courses of omeprazole
magnesium issued in a year and the rate of an SAE is one per 10,000,
then 1,000 SAEs are predicted to occur. SAE, that is, serious adverse
events.

We can skip that.

Currently omeprazole is categorized as a Class C drug because of
embryo-fetal toxicity in an animal model. In addition, there are
concerns about the clastogenic properties of the drug. Nonetheless, off
label use is not demonstrated to omeprazole linked loss of fertility or
teratogenicity in humans.

With regards to long-term exposure, omeprazole may mask clinically
significant GERD, complications which require early diagnosis and
specific management. These include Barrett\'s esophagus, advanced
erosive esophagitis, dysplasia, cancer, and gastric cancer.

The drug may induce significant hypergastrinemia and/or manifest
toxicity in some individuals. Hypergastrinemic responses to omeprazole
may be more pronounced in those with H. pylori infection or in slow
metabolizers.

However, based on voluntary reporting a tumor association with
omeprazole administration has not yet emerged. The possibility that
there are oncogenic effects of the drug in susceptible groups who are
exposed to the drug for very long periods of time has not been ruled
out.

Rebound of acid secretion may encourage long-term usage in a subset of
consumers. Upon cessation of treatment, rapid relapse of heartburn
symptoms and/or esophageal inflammatory change is predicted in some
individuals with GERD.

Taken together the prescription use of omeprazole has relied on the
presence of a professional health care provider for patient assessment,
triage, and for further diagnostic testing and recognition and
management of significant drug toxicity.

In the OTC setting there is no learned intermediary to enact these
functions so that safe and effective use entirely depends on the effect
on effective consumer labeling.

We want to be convinced that serious omeprazole magnesium induced
toxicity even when rare is outweighed by the benefit of OTC treatment by
symptomatic heartburn.

Furthermore, we are concerned whether serious toxicity will be
recognized and effectively managed by OTC consumers without physician
supervision.

Chronic empirical therapy prior to physician referral is inappropriate
for a significant number of patients with GERD. We are concerned whether
omeprazole magnesium can be targeted in an OTC setting to only those
consumers for whom self-medication will have a meaningful benefit in the
absence of a significant risk for serious adverse events.

Conversely, we are concerned whether there are adequate safeguards
protecting those for whom physician referral is indicated to justify OTC
approval.

(Pause in proceedings.)

DR. LECHTER: Good morning. I\'m Karen Lechter with the Division of Drug
Marketing, Advertising, and Communication.

I\'m going to talk as fast as I can. I understand our time is running
out. I\'m going to be talking about the label comprehension study and
the addendum study, and to give you a little context, I\'d like to point
out that the regulations require that OTC labels be written in such
terms as to render them likely to be read and understood by the ordinary
individual, including individuals of low comprehension under customary
conditions of purchase and use. For this reason, sponsors for switched
products often perform label comprehension studies.

For Prilosec, there was one main label comprehension study and an
addendum study. I won\'t go over the details of this. The sponsor has
already discussed those, but I will point out that there were four
cohorts, one of which were persons who should not use the product
without referring to a doctor before use. They were taking medications
that were indicated on the label as requiring medical consultation or
they were pregnant or nursing.

I will just present the most important results, not all of the results.
When asked the purpose of the product, 99 percent said that it was
prevention or relief. Sixty-five percent mentioned relief only. Eighteen
percent mentioned prevention only, and 16 percent mentioned prevention
and relief.

These results indicate that when asked what the product is for, most
consumers think in terms of relief.

The information listed here was only moderately understood. I will not
go over all of these with you. If you can read them fast, you will
understand that there are some issues that were understood only in the
low 80 percent range and could benefit from improvement in the labeling.

There was a significant troubling result. Seventy-five percent of Cohort
IV, the persons who should see a doctor before using the product,
incorrectly said that they would use the product to prevent and relieve
heartburn. There were two questions on this issue, one for prevention
and one for relief. Only 21 percent of persons in that group were
correct in saying that they would not use the product.

Because of this troubling result, an addendum study was conducted to
determine if the wording of the question about self-use in Cohort IV
contributed to the high rate of incorrect responses. The addendum study
compared responses to the original self-use question with responses to a
new self-use question. In this study there were 58 participants, 29 in
each arm. All should have asked the doctor before using the product.
They were pregnant, nursing, or taking the drugs mentioned on the label.

The addendum study questions were as follows. One arm was asked the
original question: if you wanted to present heartburn, would you use
Prilosec I yourself? They were also asked an identical question about
relief.

The other arm was asked new questions. If you were a heartburn sufferer
and you wanted to prevent heartburn, would it be okay for you personally
to use Prilosec I yourself or not?

A similar question was asked about relief. It did not use the word
\"personally.\"

The new questions did improve the results. For the original question
about prevention, 35 percent were correct. With the reworded question,
69 percent were correct. For the original question about relief, 31
percent were correct, with the reworded question, 59 percent were
correct.

However, even with the reworded question, comprehension about self-use
was low among those who should see a doctor before use.

There were additional questions asked. If the prior responses were not
correct in this study, they dealt with whether the persons were actually
taking the medications on the label, and they also were leading
questions. Is there anything you would do prior to taking this product
or not? And considering your current health and medications you are
currently taking, would it be necessary for you to contact a doctor
prior to using this product yourself or not?

The results of the leading questions have uncertain value, and
therefore, we do not use those results in interpreting the responses to
the questions.

The conclusions from the addendum study are that the group that should
consult a physician before use has problems understanding that they need
to see a physician first. Only 59 percent to 69 percent of this group
responded correctly to the new question about self-use.

Now I\'ll briefly talk about the product label. The label changed
substantially after the label comprehension test, and the new label has
not been tested. The committee members have copies of the tested label
and the NDA label in their packets. It\'s two sheets stapled together if
you want to refer to those.

And then there\'s a more recent label that was submitted recently that
we have not had an opportunity to review. I\'ll just briefly go over
some of the differences in these labels because of the time constraint.

The NDA label, as opposed to the tested label had causes of symptoms,
prevention, and allergy warning, a \"do not use\" section, a statement
about not using with acid reducers, and some other additional
information that did not appear on the tested label.

The NDA label specified the number of days in which to see a doctor,
changed the number of days, said that to see a pharmacist as well as a
doctor for certain questions; changed the wording about trouble
swallowing, pregnancy, directions for use, and storage instructions;
reversed the order of other information; and bolded one of the warnings
and included a symbol.

Therefore, there were many changes to the label after the label
comprehension test. Because the new label was not tested, we don\'t know
how well it will be understood by consumers.

In summary, consumers associate this product with relief. The fact that
most consumers associate this product with relief is troubling,
particularly since efficacy for this indication is questionable.

The data suggests a substantial use by persons who should consult a
doctor first.

Some information is not strongly communicated. They were listed on the
prior slides. I won\'t go over all of those at this time, and the most
recent label has not been tested. It varies significantly from the
tested label, and in light of the changes that the sponsor presented
today, we particularly don\'t know if consumers will understand what the
product is for.

CHAIRMAN BRASS: Thank you very much.

We now have time for questions from the committee to the FDA. I would
again like to remind the committee that there will be ample opportunity
for general discussion this afternoon, and I would like to focus the
discussion now on clarification of issues directly relevant to the
FDA\'s presentation.

Dr. Sachs. Microphone.

DR. GEORGE SACHS: Three hundred and forty-five points on these
presentations. (a) \--

CHAIRMAN BRASS: Round it off to one.

DR. GEORGE SACHS: Right. Any genotoxic studies that have been performed
on omeprazole [in vitro]{.underline} have shown it to be negative unless
there\'s an extremely high dose with conversion to the actual active
drug.

Two, in pernicious anemia patients, there is no history of increased
gastric cancer or increased carcinoids, and the gastrin levels in PA
patients is much higher than you see with omeprazole treatment.

CHAIRMAN BRASS: Any comments from the FDA?

Okay. Ms. Cohen.

Microphone. Thank you for making me feel needed.

DR. AVIGAN: I think that the hypergastrinemia point is an excellent
point. The only caveat to that is the time line of when the
hypergastrinemia occurs in life.

Someone else at the table has raised the problem of what about early in
life exposure to high gastrin levels. PA is a disease typically of older
people. So one of the problems with these cancer questions based upon
the way we understand the disease is the long lag phase and the
multiplicity of mutations that have to accrue in particular cells over
time to get the phenotype.

So, again, I agree with the statement, but there is a caveat.

CHAIRMAN BRASS: Ms. Cohen.

MS. COHEN: I have one question, but since I\'m the only consumer member,
I hope I\'ll have time this afternoon to address my questions to the
presenters, but I do have a question for the FDA in regards to what Dr.
Waldum said about the studies of rats and the study of humans, and I
don\'t think there was any answer. Now, do you feel that what he has
presented in terms of his study, that there is a causation that you can
track between rats and humans? Is this something that\'s essential to
our understanding of what needs to be done?

I\'m glad I asked the question.

CHAIRMAN BRASS: Could you identify yourself, please?

DR. DeGEORGE: Joseph DeGeorge, Associate Director for Pharmacology and
Toxicology.

Actually, I don\'t think we can answer your question specifically about
any causal link or any specific link between the animal findings and
humans. There is, it\'s my understanding, evidence of a hyperplasia
across species, but the next step is the link that people would like to
know the answer to. We just don\'t have that data.

CHAIRMAN BRASS: Dr. Mirsalis.

DR. MIRSALIS: Yes. I\'d like to ak a question or a clarification about
the statement that was made that there is [in vivo]{.underline}
genotoxicity. It\'s stated one place in the briefing book and again in
the presentation you say [in vivo]{.underline} chromosomal aberrations,
and yet in FDA\'s own briefing book they state no significant increase
in chromosomal aberrations were noted.

I did a National Library of Medicine search and can\'t find anything in
the peer reviewed literature. In fact, the data is overwhelming in the
literature that there is no [in vivo]{.underline} genotoxic response,
and data hasn\'t been provided to us.

I\'m just curious what that statement is based upon.

CHAIRMAN BRASS: Thank you all.

DR. CHOUDARY: I\'m Jaspi Choudary, a pharmacologist from
Gastrointestinal and Coagulation Drug Products Division.

Those statements are there in the labeling also. The [in
vivo]{.underline} tests referred to the chromosome aberration test in
the mice and the micro nucleus test in the mice. Those are all there in
the NDA labeling for omeprazole, and those stand up.

DR. MIRSALIS: Could I comment on that then? We haven\'t been provided
that data at all to look at.

DR. CHOUDARY: That is there in the labeling that has been reviewed
already in the NDA review dating 11 years back, and it still stands.

CHAIRMAN BRASS: Thank you.

Dr. Robinson.

DR. ROBINSON: For a long time we\'ve all been told about the dangers of
drug-drug interactions and not only with the potential drug-drug
interactions with this drug, but other drugs as well, and I want to know
whether either the agency or the sponsor has any data on the actual
occurred on drug-drug interactions with omeprazole because it seems to
me if we\'re going to talk about this as a risk, we need to have some
idea of what kind of quantitative risk this might be.

DR. AVIGAN: Well, I think we were not \-- I was not really disagreeing
with what the sponsor has said. Again, it was a caveat that I was
mentioning, which was that these drug-drug interactions have been tested
in a very confined way to specific kinds of subjects.

My concern is that when you take this drug out of the arena of a learned
intermediary and you have an outlier individual who has multiple
simultaneous reasons for abnormal clearance, there may be an additive or
a synergistic effect, which is not measurable in a more simple case
where there\'s just two drugs being tested in a normal background.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: I have a couple of comments. First, on pernicious anemia, I
think that it is quite clear that you have a two to three times
increased risk of carcinoma in patients with pernicious anemia, and
it\'s also well documented that you have an increased risk of ECL cell
carcinoids. I think there\'s no doubt about that.

And so it\'s difficult to me to understand what you mean when you say
that there is no indication that hypergastrinemia in UCC cell lumas
(phonetic) in man because also patients have Zollinger-Ellison Syndrome
not only as a part of endocrine neoplasia, but also chellery (phonetic).

So patients \-- every condition with hypergastrinemia in whatever
species you know do develop ECL cell tumors when they have
hypergastrinemia for a long enough time. It\'s well known that the
studies on mice and dogs, that two low doses were used and, therefore,
you had not adequate inhibition of gastric acid secretion, and
therefore, you didn\'t see any tumors.

That\'s my first comment, and the second is relating to Helicobacter
pylori. Since Dr. Sachs didn\'t know this Norwegian-British study about
gastric carcinoma and the Helicobacter Pylori and gastrin, I suppose he
does know that transgenic mice, moderately hypergastrinemic, when they
develop gastric carcinoma and when they are infected with Helicobacter
pylori, the gastrin value increases and the incidences of gastric
carcinoma also increases.

So you have this connection both in man and in animals, and I have a
question concerning this. It is claimed that you haven\'t seen any ECL
cell tumors in patients treated with omeprazole. If you look at the book
from page 131, there are 14 cases.

CHAIRMAN BRASS: I\'m sorry. Which book are you referring to?

DR. WALDUM: This white one.

CHAIRMAN BRASS: The sponsor\'s book.

DR. WALDUM: Yeah. On page 131, they stated that there were 14 cases of
gastroduodenal carcinoids where they could not determine whether the
patient had Zollinger-Ellison Syndrome or pernicious anemia, and they
also state that some of them obviously have acid hypersecretion. I guess
that they had gastric hypersecretion due to rebound, acid hypersecretion
secondary to treatment, and also that actually these patients, these
tumors actually show that the ECL cell tumors have been developed after
treatment.

So it would be very interesting to have an independent look into these
tumors, I think.

CHAIRMAN BRASS: Comment on that?

DR. AVIGAN: I think both the sponsor and the FDA would agree that
sorting through these cases is very difficult, and when you read the
narratives and look through them, just my general impression is that
there are some cases which are, you know, clearly the diagnosis is made,
and in other cases there\'s still an open question mark.

So I think to be fair at this point it\'s a theoretical possibility, but
I have not really so far, you know, found, you know, clear cases that
could be linked by cause and effect, but that would be something that
could be thought about in terms of how that could be looked for.

CHAIRMAN BRASS: Dr. Shapiro, did you have a question?

DR. SHAPIRO: I have 346 questions, but one of them was taken up already.
The drug and drug interactions is one. My basic question is this: is
that agranularcytosis, aplastic anemia, anaphylaxis, acute liver
failure, and toxic epidermal necrolysis, and Stevens-Johnson Syndrome
have all been mentioned as case reports possibly linked to the use of
omeprazole. Case reports are notoriously unreliable. In my view they are
sometimes, and then only occasionally, reliable for the generation of
hypotheses. Beyond that, they tend to be systematically biased and
exceedingly unreliable, and in all instances, they have to be confirmed
by epidemiological data.

Are there any epidemiological data to indicate that omeprazole was
associated with an increased risk of agranularcytosis, aplastic anemia,
anaphylaxis, et cetera? And if so, what is the magnitude of the
association, and what is the incidence of these conditions among people
who use omeprazole?

We know, for example, that the baseline incidence of aplastic anemia is
two to four per million per year in the general population, and
incidentally, none of your incidence figures included the time dimension
at all, which makes them rather difficult to interpret.

Assuming even that there were an increased risk, what would be the
public health implications of that increased risk for a drug which may
turn out to be very useful in the management of heartburn?

CHAIRMAN BRASS: I will allow them to answer in just a second, but sine
it\'s fresh on many of our minds, I would just like to reemphasize that
the burden of proof of safety is on the sponsor, and that there\'s no
burden on the FDA to provide lack of safety if a concern exists.

DR. SHAPIRO: Mr. Chairman, if the allegations are made that there may be
a lack of safety, we need data to show that those allegations have some
foundation.

DR. AVIGAN: As I alluded to, for those four rare events that were
discussed, they were actually rated by the sponsor according to a
lettering system A through D for causality, and I was not trying to
build a case for numbers because I think we actually all agree that
these are very rare events.

The most compelling A cases, which are the ones where causality has been
linked, are ones where there is rechallenge, that is, single drug. For
example, hives, zero to cariad (phonetic), a very clear example where
there are cases where the drug is given. Hives develop within 12 hours.
The drug is stopped. Hives disappear, and then the drug is given again
as a rechallenge and the hives reappear.

There are similar cases, again, as anecdotal for each of the side
effects that I mentioned, and the question about incidence is a fair
question. On a population basis, clearly these events are rare. The
reason why they were raised in this setting is that we\'re moving from a
learned intermediary setting where rare complications might be
recognized and managed to one where the OTC consumer has to take
liability for recognition and for doing something about it.

And so it\'s a conceptual point that bears some thought not on a
population basis, but rather on an individual basis.

CHAIRMAN BRASS: Dr. Cantilena.

DR. CANTILENA: Yes. I just have two questions on the issue of drug-drug
interactions, and the first one is I guess I\'m hearing you say that
you\'re not sure of the clinical significance of what could be up to,
you know, 50 percent decrease in clearance as a result of the inhibition
of CYP 2C19.

And I guess I heard you sort of qualify that by saying there could be
subsets who have, you know, liver disease, et cetera, et cetera, but I
guess I would like to sort of ask you then are your, you know,
qualifications saying that in all likelihood that magnitude of a change
for drugs such as phenytoin or, you know, diazepam are not likely to be
clinically significant?

That is, you know, the first, you know, question because as I think all
of us saw, there was a change in the label from the original label which
had a couple of these drugs in there, and, you know, the final label or,
you know, the one that\'s on the table now has, you know, dropped those
drugs, and I\'m hoping that they weren\'t dropped as a result of the FDA
saying they\'re unlikely, you know, to be clinically significant.

DR. AVIGAN: Let me clarify that point. There is a margin of safety in
terms of the CYP ISO enzyme ability to metabolize. That\'s clear, and
the sponsor is absolutely correct, I guess, in their data on test
subjects to show that slow metabolizers still based on theoretical
considerations can basically get rid of drugs through other alternate
pathways.

But the problem is in a large population of users when you amplify the
usage to people who have other reasons to not clear, then you have to
consider different kinds of scenarios in terms of saturating those
alternate pathways, and the potential that you run out of that margin of
safety.

In cases where you have underlying liver disease, for example, as a
concept point or people who are on multiple drugs. The idea there is if
you have a learned intermediary, and I raise this as a question only,
would that learned intermediary at least know or think about those
issues in a patient who is a problem patient?

DR. CANTILENA: So if I could just follow, so are you in support of, you
know, dropping that from a label because of, you know, low likelihood
that it will be a problem?

DR. AVIGAN: I don\'t want to take a position on that now. I think I
would rather keep away from the remedy because I would rather that that
be discussed by the committee and later on.

DR. CANTILENA: Okay. Then the follow-up question is in someone who is,
you know, homozygous, you know, PM for the enzyme, is, you know, the
pathway that then becomes the most important, is that CYP 3A4 and are
there questions in terms of interactions with substrates of the CYP 3A?

DR. AVIGAN: There might be.

CHAIRMAN BRASS: Dr. Steinberg.

DR. STEINBERG: Could you give us an estimate, if there is one, of the
difference in toxicity as where it is between omeprazole and the data we
have on that, and other medicines that already have been approved for
OTC products, such as the H2 receptor antagonists, such as NSAIDS, et
cetera?

Is this drug more dangerous, less dangerous? It appears to me it\'s a
lot less dangerous than NSAIDS, which the FDA has approved, and multiple
NSAIDS, if I\'m correct, and H2 receptor antagonists have similar rare
toxicities, to my knowledge.

DR. AVIGAN: You\'re correct, and I don\'t want to get into that
argument.

CHAIRMAN BRASS: Well, can you comment on the order of magnitude
comparisons of frequency, I think, which was \--

DR. AVIGAN: Yes.

CHAIRMAN BRASS: \-- I think, just in terms of information?

DR. AVIGAN: At first blush because, again, the problem that you\'re \--
if you\'re asking me to be scientific, I don\'t have incidence data. We
see with post marketing data there\'s a large pool of users and signals.
We have no idea what the reporting bias is. So these are not incidence
data. So it\'s a database from, let\'s say, one of the H2 blockers and a
database for this. They\'re not really scientifically comparable.
That\'s a very important point to realize.

But having said that, the general gestalt is for these acute effects
which probably is not all that much difference in terms of the gestalt
of it from what I see.

DR. STEINBERG: From the H2s, for instance.

DR. AVIGAN: Right. The separate issue of the longstanding exposure,
chronic hypergastrinemia, that\'s slightly distinct and the way the
pharmacodynamic properties of the drug work; that\'s a slightly distinct
issue.

DR. STEINBERG: I have another question of a toxicity that hasn\'t been
or an adverse effect that hasn\'t been raised, and that is there have
been reports of vitamin B12 malabsorption from the use of acid
suppressors. Vitamin B12 as we take it is protein bound, and acid is
needed to separate the B12 from the protein.

What information do we have on long-term use of omeprazole and
clinically significant vitamin B12 problems, and has it been looked at
even?

DR. AVIGAN: It has been looked at. There\'s a series of papers on that,
and a general impression, and there are some experts here who could
probably tell more about it than I can, but that there is not a problem.

CHAIRMAN BRASS: Dr. Lam.

DR. LAM: Is there actual safety data whether it is positive or negative
in poor metabolizer that are described on the omeprazole? And if the
data is negative, what would be the effect of specific inhibitor of CYP
2C19, and especially in terms of converting them into a poor
metabolizer, and if that case they\'re more reliant on a CYP 3A4 pop way
(phonetic), what would be the effect of adding a CYP 3A4 inhibitor,
which as erythromycin, which is available over the counter \-- I mean
not over the counter \-- which is widely available to the regimen?

DR. AVIGAN: That was the point I was raising. I\'m not aware of data
about that. Again, the way the subjects are tested is that, you know,
theoretically if you don\'t saturate the alternate pathways, then the
patients or people who are slow metabolizers should have no effect on
the drug because they don\'t even use that pathway.

The problem is starting to speculate about what happens when you sort of
spill over and saturate pathways, and that, again, is just an open
question.

DR. LAM: Okay, but we have no safety data in specific poor metabolizers
at all whether it is negative or positive?

CHAIRMAN BRASS: Dr. Neill.

DR. NEILL: I\'m going to go to a slightly different subject. I\'m
curious about whether FDA has had submitted to it to review data from an
efficacy study designed for the new use label that the sponsor is
proposing, specifically prevention due to food or beverage when taken
only on days heartburn is expected, because I haven\'t seen any efficacy
data about that specifically.

And the second question is I have not heard any label comprehension data
on this new proposed use, and I trust that\'s because you\'re hearing
about this for the first time today as well. Can you confirm that?

DR. GOLDKIND: My understanding is the same as yours. There\'s no
currently labeled products have that indication as you described it.

CHAIRMAN BRASS: No, I think the question was whether any of the existing
submitted from the sponsor efficacy data are relevant to the indication
as proposed.

DR. NEILL: Actually it\'s not whether they\'re relevant because we\'ve
got several studies that may be relevant, but none that are specific
that were designed to answer the question: is the medication as proposed
effective?

And while I would guess that that study, if done, might show a degree of
effectiveness, my concern is for those intermittent users who might have
more than a two or three day lag time between doses, who I\'m
extrapolating from the data that I have would not see much
effectiveness, and then on the contrary, for patients who might be
taking it daily, I\'ve got data that suggests that they\'re going to
take it daily for a long time, and my concern in those people is they
are a category of patient who would not be appropriate for OTC use
because of the inability to self-select and to self-monitor for
important co-morbid conditions, specifically GERD and Barrett\'s and are
then not going to present for endoscopy and that learned intermediary
intervention.

I\'ve got no data on efficacy for the proposed indication at all.

DR. GOLDKIND: The data that would be relevant from these submissions
would be the data on day one of the 14-day prevention studies. There was
a difference between placebo in both doses for the percent of subjects
who would be heartburn free for 24 hours following a dose at 8:00 a.m.

CHAIRMAN BRASS: Dr. Lechter, do you want to comment on the label
question?

DR. LECHTER: The only label that we\'re aware of that was tested is the
one that I described. You have the two in front of you. One was a tested
label, and the other was the one submitted with the NDA, and now the one
that they\'re discussing today is an even different one. We have not
seen that one.

DR. NEILL: Just to follow up about the efficacy data, while I agree with
you that that might be the most appropriate piece of data that we have
in front of us, my concern is that that data derives from a study in
which that first use was not up to the consumer to choose, and the label
that I have in front of me as proposed is on days when heartburn is
expected.

And I don\'t know that my patients have the ability to know when to
expect heartburn, and if that\'s not the case, then I would have
expected studies like 171 and 183 where we would tell patients who have
a history, \"Don\'t try and predict whether it\'s coming. Take it every
day for ten to 14 days.\"

DR. GOLDKIND: I share that concern and agree.

CHAIRMAN BRASS: Dr. Sachs, you had an additional comment?

DR. GEORGE SACHS: Yes.

CHAIRMAN BRASS: Microphone.

DR. GEORGE SACHS: Ms. Cohen asked a question about comparison of rats
and people, and remember as well just incidentally that there are four
such drugs now available on the market in the U.S. that have been
subjected to not only a variety of animal studies at very high doses,
approximately 100 times, even sometimes 1,000 times of what\'s given to
people, and rats consistently give this ECL cell carcinoid carcinoma
eventually because that cell in the rat continues to replicate and
doesn\'t stop replicating. It is not an end cell, and there\'s much data
in the dog, the mouse and man that ECL cells are end cells and,
therefore, do not continue replication beyond a certain point of aging
and maturation.

So I think it\'s very clear, given not just omeprazole from the early
days, but with pantoprozole, lansoprazole, and rabeprazole, that the rat
ECL cell rapid formation of ECL cell carcinoids and metastasis is a rate
selector problem independent of dose given to any other animal species,
and of course, all of those PPIs have had two year carcinistic studies
in at least two species.

CHAIRMAN BRASS: Dr. Geller.

DR. GELLER: Hearing everything I\'ve been hearing, what is the ideal way
to take this drug if you have, indeed, heartburn and not GERD?

CHAIRMAN BRASS: If the FDA would like to answer, but again, I don\'t
want a general discussion. I want focused on are there any issues about
the FDA presentation that we can get addressed now. If you\'d like to
make a comment, feel free.

DR. GOLDKIND: The proposed label doesn\'t really address the efficacy
data well, and I think a challenging discussion would be how one might
label this product following the efficacy data. I don\'t have a solution
to that problem.

CHAIRMAN BRASS: Do you have a rebuttal to Dr. Sachs or do you have a
question for the FDA?

DR. WALDUM: No, only a remark.

CHAIRMAN BRASS: No. Save it for later, please.

Dr. Cohen, a general question for the FDA?

DR. COHEN: My question really focuses on the last question I was asked
and a question to the FDA. Are you trying to make a distinction between
GERD and heartburn? I don\'t see how you can do it. I don\'t know a
difference, and I think if you filled the room with a group of Talmudic
scholars I don\'t think they can tell you the difference.

There is no difference. GERD or gastroesophageal reflux is manifested by
heartburn, and heartburn is the cardinal symptom of GERD. So it\'s the
same, and I can\'t see how you can go about trying to argue this point.
It\'s the same situation, same condition.

DR. GANLEY: Can I answer that or try to answer that?

CHAIRMAN BRASS: Yes.

DR. GANLEY: Yeah, I think that\'s what we\'re trying to point out here,
is that the current OTC market is for the treatment of episodic
occasional heartburn or meal induced heartburn. This is going down
another path.

I think we\'re coming to that agreement here. It\'s going to pull in
people that have GERD. Our question to the committee is: is that
acceptable?

We\'re taking a neutral position. We\'re asking your opinion on it.
We\'re not taking a position. I think that\'s what the presentations
have tried to pull out. So that\'s a question for the committee to
answer. Is that an acceptable OTC use? And if it is, how do we
appropriately label for that?

CHAIRMAN BRASS: And that will be the focus this afternoon.

Dr. Shuster, question for the FDA?

DR. SHUSTER: Yeah. First of all, I just wanted to ask Dr. Cohen what he
thinks a good Jesuit priest might do with that question.

(Laughter.)

DR. SHUSTER: But I did want to address the question which had been
raised here and which I had in mind which really concerns me, and that
relates not to content, but to process. Here we are now being presented
with something which none of us have really directed our attention to.

When I read these tomes here, I usually have a targeted concept, a
targeted approach to it, and I think that many others would, too. For
example, the group now that is being proposed, which really essentially
is the prevention only group for the labeling, is the group which was
most noncompliant, which most misunderstood the directions. Sixty-four
percent of them did.

Now, we are also given a new dosage form, and I would have to go back to
all of this focusing now on ten milligram dosage rather than a 20
milligram dosage.

So what I\'d like to ask is can \-- and I address this to all of the FDA
representatives as they\'re standing there, and actually it\'s a
question that could be addressed to all of the committee members as
well, and that is do you feel that you are competent at this stage to
make recommendations about the new labeling or would you have to go back
to look at this in a totally different sort of fashion.

I\'m new to this committee and, as a matter of fact, so new that I\'ve
been disenfranchised because I haven\'t been vetted appropriately yet,
but I would like to ask whether the process should not be a rather rigid
one; that if there is a change in labeling, and that wasn\'t determined
yesterday, I presume, that that change be submitted to the FDA and to
the committee so that they could pay attention to it.

CHAIRMAN BRASS: Well, let me respond to that and then, again, Dr. Ganley
or the committee or anybody else can comment, too.

I think that the points you raised are extremely important and, in fact,
will be reflected in both the questions and discussion that we will have
this afternoon about reacting to this information, and I think the FDA
has asked our opinion not only with respect to the studies and issues
that have been presented, but because this is an evolving area, our
input at this stage might be helpful to both the agency and sponsor in
focusing that evolution in the future.

But I think the points you\'ve raised are germane and recognized by all,
and Dr. DeLap.

DR. DeLAP: Yeah. I think that this is a not terribly unusual
circumstance for us when we\'re dealing with something that is a little
different paradigm than what\'s gone before, and there is a natural
back-and-forth between the sponsor and the agency over the course of the
review of an application in this kind of situation, and in fairness to
the sponsor, you know, it\'s not their fault that they come up with some
new ideas in the course of the review process because we\'re asking them
to come up with some new ideas a lot of times.

Having said that, this did seem to us to be a good time to look at at
least a large portion of the issues in the application and to get some
advice from the committee rather than, you know, trying to get
everything totally ironed out before it comes to you.

And, again, in terms of like labels for things, it\'s not unusual if the
label gets changed from what was studied. That usually triggers the need
to do another label study, but, again, that\'s not unusual.

I think there are some questions that have come up today, as you say,
that we\'re not really competent to address because we haven\'t thought
about them exactly in that fashion, but there are a lot of good
questions, I think, that have been thought about, and we\'ve tried to
capture some of those for the committee here, and I think we\'ll be very
pleased if we can get some good discussion and ideas about the questions
that we have addressed here. That will really help us with the process.

CHAIRMAN BRASS: With that segue, I will adjourn us for lunch to
reconvene at 1:05. I don\'t ant to shortchange your lunch.

(Whereupon, at 12:08 p.m., the meeting was recessed for lunch, to
reconvene at 1:05 p.m., the same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:09 p.m.)

CHAIRMAN BRASS: If we could begin the afternoon session, after the
presentations of this morning a number of issues were identified, and
what I would like to do is we have been given or will be given shortly a
very broad spectrum of questions quantitatively and qualitatively from
the FDA to discuss, which I think encompasses the broad range of these
issues, and by using the questions to focus our discussion, I think we
will be able to be more productive and yet cover that broad range of
issues.

So at this point, I\'d like to ask Dr. Katz to give the charge to the
committee.

DR. KATZ: Good afternoon. I hope everyone can hear me back there. Can
you hear? Okay.

At this point in time, I\'d like to welcome everyone back to the final
session of our committee meeting, which is the deliberation portion of
our meeting.

Before going on to kind of address some of the questions, I\'d just like
to go back again and just kind of remind everybody where we\'ve been.

As part of the background, currently available now we all know that
there are two products out on the OTC marketplace for the indication or
symptomatic relief of heartburn. Those would be the antacids and the
acid reducers, also known as the H2 receptor antagonists.

The H2 receptor antagonists also have an additional indication, that of
prevention for meal induced heartburn symptoms at a specified period of
time depending upon the nature of the drug.

Today we have heard from Procter & Gamble, who has proposed moving
omeprazole, Prilosec, to the over-the-counter marketplace. Currently, as
we know, Prilosec is approved for 20 milligrams as a prescription drug
for the treatment of gastric and duodenal ulcers, erosive esophagitis,
GERD, and for treatment as well of pathologic hypersecretory conditions.

Today also we have heard that an additional proposal has been discussed
for an additional indication, and in fact, at the time of the filing of
the NDA, the three indications that I have here for acute symptomatic
relief of heartburn, for prevention of meal induced heartburn, and the
new indication of a 24-hour heartburn prevention due to a variety of
causes was proposed.

Earlier today we\'ve heard about a modification for the labeling which
would be for the treatment of frequent heartburn and a change in dosage
from 20 milligrams to ten milligrams.

When you go back to deliberate over some of the questions at hand, what
I\'d like to remind you about are some of the important issues that go
into some of the decision making process for looking at drugs that are
going over the counter. These would include the benefit-risk for the
population that we\'re talking about; consumer\'s ability to treat, to
self-diagnose and self-treat; consumer\'s ability to understand the
labeling instructions, including monitoring, follow-up care, and other
associated treatment that they might need to receive; ability to
recognize that they\'ve attained a goal and what that goal is; and the
ability to recognize toxicity.

In today\'s discussion, what I\'d also like to do is to focus you on the
areas that we\'ve heard about, which is that we\'ve had different
studies that have been presented to look at efficacy, and in fact,
we\'ve heard about five studies that have been presented for the acute
symptomatic relief of heartburn where both ten milligram and 20
milligram a day doses have been looked at.

For relief, we\'ve also heard that there really has not been a
significant benefit shown for either the ten or the 20 milligram tablet.

We\'ve also been presented two trials to look at prevention of meal
induced heartburn, both the ten and 20 milligrams, one which was
successful, one which trended but did not show statistical significance,
and two additional studies for the prevention of 24-hour heartburn due
to a variety of causes.

In addition, there were five actual use studies that were performed to
evaluate use patterns in dosing compliance, but these were not designed
specifically to look at efficacy.

We also have heard further about the indication as to GERD, and in part
of your deliberations today, we\'d like you to look at is GERD an
acceptable OTC indication, and this gets us from the acute versus the
chronic realm, and is this appropriate?

When we consider GERD, remember again we consider chronicity of therapy,
safety consequences, any rebound effects, and suboptimal treatment, and
by this I mean the fact that the label itself will be labeled if as we
saw it for ten-day use and what do consumers need to do if the symptoms
persist beyond the ten days\' duration, and this, again, should be
something that should come out in some of the discussion.

The safety issues we\'ve heard a great deal about, and at this point in
time rather than spending a lot of time here, I just want to focus you
on short-term versus chronic intermittent use, and in going through to
the deliberations and trying to answer the questions, to have you focus
on those terms, and also, again, to let us know in any of the areas that
we\'ve discussed today, such as anaphylaxis, angioedema, urticaria,
liver toxicity, bone marrow disorders, severe skin reactions, and other
safety concerns, which of these are of import for an OTC marketplace and
which we should pay more or less attention to.

We\'re also coming down. Two would be the drug-drug interactions.

Finally, we get to the last area, which is that of actual use and label
comprehension issues, and this is where some of the data, again, we kind
of try to synthesize the whole over-the-counter picture together.

We\'ve heard about that it\'s important for consumers to be able to
appropriately self-select, to know which population of consumers should
use this product and which should not, their ability to use the product
correctly, having the correct dosage for the time specified in the
label, their ability to identify when to go see a physician or other
health care provider, their ability to identify serious adverse events
and what needs to be done about them, their ability to avoid interacting
drugs, and whether or not populations who should not use the drug can
adequately identify that they should not be taking this product.

We\'ve also identified for you some areas of concern in that 65 percent
of a subset of subjects using omeprazole for prevention only used it
more than the ten consecutive days that was a limit placed on the label
itself.

In addition, about 19 to 22 percent of consumers using omeprazole for
both acute symptoms and prevention also exceeded the ten-day limit.

The best results did seem to go in the individuals who used it for
relief only. However, again, we\'ve heard that the product was not very
effective for relief only.

At this time, again, in closing, I would just like to once more focus
your attention that what we were talking about here is a new indication,
as well, that would take over more of a chronic realm, and that should
focus in as part of your discussion in deliberating the questions at
hand.

Thank you.

CHAIRMAN BRASS: Thank you.

We will now proceed to the questions, and again, because we have several
guests, I just want to go over a few of the ground rules.

First of all, when it comes to voting, only official panel members will
be able to vote, and therefore, the following people will be excluded
from any voting, though they will be able to participate in the
discussions. Specifically, Drs. Mirsalis, Sachs, Robinson, Blewitt,
Douglas, Waldum, Shapiro, Shuster, and Cohen as all excluded from the
voting.

Second, I think because of the breadth of material we need to cover this
afternoon, I think it\'s extremely important that we stay focused in our
discussion on the issues relevant to the questions, each question as it
comes before the committee.

It will obviously be important for us to discuss these in as much depth
as possible, and I would encourage committee members to ask questions of
either sponsor or the FDA for clarifications on issues relevant to those
questions.

So with that preamble \-- yes?

DR. SHAPIRO: Just a point of order, Mr. Chairman. On my handout, I\'m
listed as a voting participant. Is that incorrect?

CHAIRMAN BRASS: I will ask for help.

DR. TITUS: You\'re Dr. Shapiro?

DR. SHAPIRO: Yes.

DR. TITUS: I need to check.

CHAIRMAN BRASS: We will look into that and try to get an answer prior to
the first vote. Thank you for clarifying that.

So the first question is: in studies 092 and 095, those two studies
specifically, the primary endpoint for efficacy was the occurrence of
sustained complete relief of the first treated episode of heartburn.
Based on the primary measure of efficacy, is there a clinically
significant improvement of acute symptomatic heartburn in either the ten
or 20 milligram omeprazole groups as compared to placebo? Please explain
your answer.

I have been told that Dr. Shapiro does, indeed, get to vote officially.

Dr. D\'Agostino.

DR. D\'AGOSTINO: The data is quite clear. The studies did not attain
statistical significance.

CHAIRMAN BRASS: Other comments or observations?

I personally would agree with that assessment, and that on the primary
endpoints there was no reason to believe that there was efficacy. Would
anybody else like to comment on that issue?

Yes, Dr. Steinberg.

DR. STEINBERG: That appears to be clear for that particular question,
but there were the secondary outcomes where some of this is muddied,
where there is statistical significance for sustained adequate relief.
Is that an important consideration?

CHAIRMAN BRASS: It\'s potentially important. But I would point out that
in 095 it was only the 20 milligram dose, and neither dose in the 092 is
my understanding for that endpoint.

DR. STEINBERG: I have all treated episodes.

CHAIRMAN BRASS: I see. The all treated episodes, that\'s correct.

DR. STEINBERG: It was the ten milligrams for both studies appear to be
statistically significant.

CHAIRMAN BRASS: Dr. D\'Agostino.

DR. D\'AGOSTINO: I think we could have an interesting discussion that
they picked the wrong endpoints and the primary endpoint, and I think
that when you look at the sort of array of endpoints, at the secondary,
and then though the FDA sort of took them to task for it, when you look
at what other studies, other products have done, that there may be
something of interest going on with the secondary endpoints. The
question focuses on the primary, and my response was to the primary.

CHAIRMAN BRASS: Dr. Cohen.

DR. COHEN: In looking at the data, if I read this correct, with the 60
percent placebo response, I think that\'s beyond what \--

CHAIRMAN BRASS: Which endpoint are you referring to?

DR. COHEN: Well, the sustained adequate relief. I think 60 percent
placebo response is beyond what we generally see in GI diseases where
you\'re looking for symptomatic improvement. So I would think that we
brought in a lot of patients, and it\'s very insensitive in separating
out the two groups.

DR. STEINBERG: But I think it seems that industry set a very high task
to get complete \-- that primary endpoint which they established was
very admirable, but very tough to achieve. I think most of us in
practice would be very happy if we controlled symptoms. It would be
great if we could eliminate them, but make them better. It appears that
the data shows that it make the people better, but not completely
better.

CHAIRMAN BRASS: Well, I think part of the issue in the endpoint
discussion, which I think both of you have highlighted, and I tried to
bring out earlier is whether in the endpoint that you are referring to,
whether or not it is truly acute relief that\'s being detected or
prevention, and it is more similar to some of the other studies, and I
think that\'s also what Dr. D\'Agostino is referring to in terms of
differentiating the endpoint.

DR. STEINBERG: I don\'t think you could separate those two probably.

CHAIRMAN BRASS: But I would submit separation is important if the
product was to be labeled directly so that consumers would understand
which endpoint they were trying to treat.

Yes, Dr. Blewitt.

DR. BLEWITT: Yeah. Frankly, I don\'t think that you can ask Question A
in isolation as far as the primary endpoints are concerned. I think that
really you have to find out what the studies told you, and I would
suggest that there were significant learnings from the studies when you
look at adequate relief compared to complete relief. Maybe complete
relief was too high a bar.

And so I would suggest that the Question A be taken also in the context
of the secondary endpoints.

CHAIRMAN BRASS: Yes. I would encourage such a discussion. Obviously for
the purposes of the vote, we will focus on the primary endpoint, but I
think your point is an excellent one, and I\'m trying to bring that out
in the discussion so that it would help provide insights relevant to the
later questions, et cetera.

Yes.

DR. ROBINSON: My comment would be that I don\'t think anyone in this
room would argue about the efficacy of this product in the disorder for
which it\'s intended, and the only issue really is: is it possible to
use this product in the OTC environment in a way which is easily
understandable by patients or by people in the community who would want
to use such a medicine.

And they really answered that question in this study, it seems to me,
and I think the sponsor pointed this out quite well when they asked for
the appraisal, the overall appraisal of was this a useful medicine for
you for this condition for which you took it.

And in that situation it clearly was very \-- deemed by the takers of
the medicine who, after all, are the only arbiters who are important in
this situation as being very useful, indeed.

So I think that\'s really the \-- from my perspective at least, that\'s
the final point in this story, and that is this is a lot of semantics
about whether we\'re talking about acute heartburn or relief of
heartburn or treatment of heartburn, but really the bottom line for all
of this is are these subjects being satisfied by a medicine that they
are taking for a condition, an unpleasant condition which they are
experiencing?

CHAIRMAN BRASS: Dr. Geller.

DR. GELLER: I would like to disagree with the previous speaker. I think
we\'re talking about a disease that\'s both self-limiting and has a
placebo effect.

Now, the primary endpoint here was clearly negative. The P values
aren\'t even close, and I\'d like to make an additional \-- to .05 \--
I\'d like to make an additional comment that since there were
essentially two studies using the same control group, a rigorous
clinical trialist will assess these data at the .025 level, not at the
.05 level, and in that setting a P value of .035, which is the last
treated episode P value for the 20 milligram versus placebo dose or the
.032 which is the totality of evidence over the two weeks would not be
considered statistically significant. At best they would be borderline.

CHAIRMAN BRASS: Dr. D\'Agostino.

DR. D\'AGOSTINO: It\'s the same comment, that basically the placebo
effect is so large, I mean, it\'s probably a badly run study as opposed
to indictment of the drug, and I think that\'s really what the issue is.

CHAIRMAN BRASS: Dr. Sachs.

DR. GEORGE SACHS: I think you should remember that this class of drug
actually made its name by its ability to treat GERD or heartburn as
compared to H2 RAs, and that was its launch pad, but it\'s very clear
from any study that had been done on this class of drug that to expect
to get complete symptom relief with first dose simply isn\'t within the
mechanics of the way this drug works.

However, in taking the drug by the second dose you see the effect, and
you see the effect also, in fact, in the evening better than H2 RAs.

So if they ask the question complete symptom relief, almost nothing does
that even in long-term studies, but in terms of improvement for the
patient by the first dose, second dose, that sort of question, I think,
would be answered positively.

CHAIRMAN BRASS: Dr. Sachs on my right.

DR. HARI SACHS: Dr. Hari Sachs, P. Mandrix (phonetic).

In my looking at the data, actually looking at clinical significance,
where I have a little trouble is at best they\'re showing ten to 15
percent over placebo. So I don\'t see this as being clinically
significant in answering this, you know, for efficacy at all. Even
though there may be some improvement, it\'s really very marginal over
placebo.

CHAIRMAN BRASS: Ms. Cohen, did you have a comment?

MS. COHEN: Well, I don\'t know \--

CHAIRMAN BRASS: Microphone.

MS. COHEN: Thank you.

I think you\'re going to shoot me down, but as a consumer member, I\'ve
heard a lot of things. There are almost 50 million Americans in this
country that don\'t have health care. Therefore, they\'re not even going
to be able to see a doctor.

This is a multi-cultural country, and I saw that you had 86 percent
Caucasians in your study. Did you advertise in different languages to
find people from different backgrounds and different cultures? How are
these people going to understand something if it\'s not going to be in
their language? No one has interviewed them in their language.

Did you do focus groups in different languages for different people?
Because the one thing most of us, I do, I\'m a perfect example of
heartburn and GERD. How do you know how these people \-- it\'s the one
thing that everybody is going to say. In the advertising that\'s going
to happen, and all of a sudden everybody, everybody is going to think,
\"Well, I can come take this medication.\"

Well, there are all kinds of preemptive information that they need to
know, and I, frankly \-- this is the real world of all those Americans
who aren\'t going to be able to go see a doctor, and we\'re talking
about all of these things, and the end result is the kind of information
that is given to consumers that\'s it\'s plain and concise, plain
language in Spanish.

Is someone going to answer the phone who speaks Spanish or another
language? Is there going to be someone at the phone at your place?

I\'m sorry. I feel that these are issues that are very important and the
heart and soul of the end product, which is the information you\'re
going to give to people, and the advertising if this thing is passed is
going to be voluminous, and I\'m worried about all the people that
can\'t go to a doctor, and they continue to take it and what\'s going to
be the end result?

Thank you. I appreciate your allowing me to say that, but I\'m
disturbed.

DR. SCHACHTEL: I couldn\'t agree with you more, and there are several
\-- as you know, I\'ve been involved in neighborhood health centers for
years, and I entirely agree with you about concern for people who may
not be as literate as others, whose ethnic backgrounds or even language
background may be different.

We did look at the benefits for them, as well as their compliance with
the label in different ways, and I can provide you in great detail if
you want looking at the different stratifications. Maybe there can be a
few that can be thrown up that might satisfy you.

For example, looking even at educational level, which is a reasonable
handle I think you\'ll agree for literacy \-- we actually have it. Good.
This one I don\'t know how to work. Oh, there it is. Good, okay.

Looking at the percent of dosing days compliant by whether a person has
had a high school diploma or a GED or less versus some college and
greater than a college degree; looking at whether they took one tablet
per dose, one dose per day, and the overall doesn\'t matter. Do you have
it for the ten days, please? Because I think that\'s a critical issue,
too. No, that\'s not a critical issue to you? I thought it would be.

MS. COHEN: Is that where you go from Hispanic areas and you go into
black areas and you find that everybody has that educational level? You
know, we\'re all educated in this room, but this is not real America
either. There are all those people out there who are not college degree
or don\'t have advanced degrees, who really \-- I mean I just saw what
you gave. I mean, is that typical of the United States and in many areas
of this country?

I don\'t think so. I\'m worried about people that have to understand
what they\'re taking, what they\'re taking it for, how long they can
take it. I\'m worried about they might have symptoms that really are far
more serious than just indigestion or GERDS

I mean, this is a serious thing, and if you\'re going to go OTC, you\'re
going to start advertising, and I\'m worried about the people who have
symptoms that are going to be masked by other things.

I think showing me the educational level is not telling me about
America.

DR. SCHACHTEL: But, in fact, the shopping centers that we purposely
selected represent lower socioeconomic, Hispanic sections. If you looked
in the reports \-- perhaps it\'s not in the dossier that you received
\-- we did that intentionally, and that\'s why the averages for
socioeconomic level through different indices are intentionally low.

What I was particularly interested in is that it doesn\'t really matter
as much as some people believe because if a person wants to take a
medication for their heartburn, they will learn how to use it correctly
either because, in fact, they are literate or because there are other
people in the home who are, and that\'s what I\'ve learned at least over
the past, well, 13 years that I\'ve been doing this kind of research.

And I don\'t consider this study to have been any different, in fact.

CHAIRMAN BRASS: I want to bring us back to 92 and 95 and the question on
the table. So we\'ll come back if there is a question about the label.
We can do that.

Dr. Geller?

DR. GELLER: I was going to say that I don\'t think you can make a very
strong argument in defense of efficacy based on these trials. In fact, I
think the argument is extremely weak. In fact, the people sitting around
this table did not make the decision of what the primary outcome should
be. The company chose this because they thought they were going to get
success on this endpoint, and that\'s a reasonable line of thinking.

But I don\'t think anybody here should make the case that there\'s
efficacy based on this trial, and I think we should go on to the other
trials where you can make some argument of efficacy.

CHAIRMAN BRASS: Dr. Shuster.

DR. SHUSTER: My area of special interest in gastroenterology is
gastrointestinal disorders or functions, sometimes called functional
gastric disorders there, disorders in which there is disturbed motility
and disturbed contraction of sphincters that prevent reflux and so
forth, and what we see in a number of these disorders of function is a
very high placebo response, up to 60 percent.

Now, I think you need a pretty darn good drug to best a 60 percent
placebo response, and even ten or 15 percent above that I think is a
significant response. That\'s number one.

Number two, had these studies been carried out further, they may have
shown a more impressive result because the placebo response tends to be
somewhat self-limited, and if you can write out that response, I think
that it might have shown we don\'t have that data, but I think it is a
consideration.

CHAIRMAN BRASS: Dr. Neill?

Any other comments before we vote on \-- yes.

DR. ELASHOFF: Well, in terms of sustained adequate relief, the
difference between the ten milligram dose and the placebo is five
percent in one study and two percent in the other. It\'s not ten or 15.

CHAIRMAN BRASS: Okay. I\'m going to call the first question, and again,
specifically in reference to 092, 095. Based on the primary measure of
efficacy, is there clinically significant improvement of acute
symptomatic heartburn in either the ten or 20 milligram omeprazole
groups compared to placebo? The options are yes, no, and abstain.

All who feel the answer is yes to that question, please raise your hand.

(No response.)

CHAIRMAN BRASS: All those who feel the answer is no to that questions,
please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: All abstentions, please raise your hand.

(Show of hands.)

DR. TITUS: Okay. We have zero for yes, 12 noes and one abstention.

CHAIRMAN BRASS: Can we see the \--

DR. STEINBERG: But I would like to add that that\'s not the only
question that should have been asked for these studies.

CHAIRMAN BRASS: I understand, and hopefully the discussion will have
brought out the information on those other points that are not ignored,
and I agree they are important.

Do you want to count again.

DR. TITUS: I think the count must be, unless someone on the committee
wants to correct me, one abstention and 13 noes. Anybody want to correct
me? Okay. I have to get a count of 14.

CHAIRMAN BRASS: Okay. Second question: in studies 005 and 006 the
primary endpoint for efficacy was the percentage of subjects heartburn
free over the entire four-hour period after a provocative meal. Based on
the primary measure of efficacy, is there a clinically significant
improvement of heartburn symptoms in either the ten or 20 milligram
omeprazole groups compared to placebo?

Then we will also specifically discuss are the analyses of the
prespecified secondary endpoints supportive of the primary study
outcome. Do they add information regarding clinically significant
treatment effects?

Yes, Doctor.

DR. UDEN: The product now that we\'re going to be approving is a ten
milligram product. I am confused why we would be voting on the 20
milligram dose.

CHAIRMAN BRASS: I think that to the degree it helps both the sponsor and
the agency in future decision making, I think it would be useful
information unless the agency would like to withdraw that question.

DR. DeLAP: No, I think we\'re interested in it. The question as it\'s
phrase, I think, refers to both doses, and you can tell us what you
think.

DR. UDEN: So are we going to be splitting our votes up?

CHAIRMAN BRASS: If the discussion so dictates, I am more than happy to
split votes.

Dr. Geller?

DR. GELLER: The second study seems to show a significant difference and
the first did not, and I\'m kind of curious about the difference between
the patients in the first and second study, say, with respect to the
frequency of heartburn during the run-in period.

CHAIRMAN BRASS: Could you be more specific between first and second? Do
you mean \--

DR. GELLER: I presume 05 preceded 06.

DR. ZORICH: They were run concurrently, and just for the matter of
convenience designated with two different numbers, and we have asked
ourselves that question, of course, and cannot account for why there\'s
a difference in the placebo.

The difference in those two studies is not the treatment effect. It\'s
the placebo groups, and we have not been able to account for why
there\'s a difference in placebo response.

CHAIRMAN BRASS: Other observations about these two studies?

DR. GELLER: Could I get an answer to the question about the number of
days of heartburn?

DR. ZORICH: Yes, that\'s what I was trying to answer. We have
specifically looked for parameters, and that being one of them. We\'ve
looked at every parameter we had available to us to try to account for
was there some disbalance, unbalance, and had not found any.

CHAIRMAN BRASS: Yes, Dr. Elashoff.

DR. ELASHOFF: Well, I would argue that whether significant or not, the
actual observed differences are five percent and four percent in one
study and nine percent and eight percent in the other study, and if we
assume that the truth is somewhere in between, we\'re talking about
maybe a six percent or seven percent difference, which I don\'t think I
would regard as clinically significant even were they both statistically
significant, which they are not.

DR. STEINBERG: Unless you were one of those seven percent that got
relief.

(Laughter.)

CHAIRMAN BRASS: Dr. Sachs.

DR. SACHS: Again, the issue is this is day one initial treatment, and
it\'s very clear from any comparative study against any other form of
heartburn or GERD treatment that the incidence improves day two, day
three.

In terms of patients who can\'t go see doctors, the 20 milligrams if
that becomes available OTC will be the only effective medication for
those people in terms of treating any form of GERD relative to H2 RAs.
And it\'s not the first day. It\'s also the continuation of treatment
that really makes the difference.

So the six or nine percent that Elashoff sees the first day translates
to 20 or 30 percent by third day.

CHAIRMAN BRASS: Let me try once more to try to justify why these
differentiations are being made explicit in the context of the questions
and in the context of understanding the studies.

Ultimately if this product is to be approved for over-the-counter use,
it will have to have a label indication that will tell a consumer
realistically when they can take it and what they should expect to have
happen and how likely it is to have happen almost in fact.

And to the degree that a comparison to the other labeled products for
the same type of relief of heartburn have taught consumers an
expectation that when they have heartburn they can take the medication
and get relief, if that is not the case for this medication, then we
have to both understand that and deal with that in terms of ultimately
what the instructions to the consumer might look like.

Dr. Cohen.

DR. COHEN: The provocative meal is equivalent to a stress test, and the
stress test here is to provoke heartburn in a high percentage of
patients, which it\'s done.

The very low placebo response would indicate that it was a very, very
aggressive stimulus and that the drug at this dose was not adequate to
overcome that, but as Dr. Sachs said, perhaps if the patient was treated
longer, it probably would have prevented it.

But what we were given here with this very low placebo response or very
provocative meal, it didn\'t have a clinically effective response.

CHAIRMAN BRASS: Dr. Johnson.

DR. JOHNSON: I guess I am having a little trouble following some of the
arguments from the other side of the table because, as I understand it,
this isn\'t something that is going to be recommended to be taken day
after day after day. So I accept that maybe on third day they would have
good benefit, but that\'s not how we\'re asking these people to use this
drug. So I\'m not quite sure what the relevance to continuous use is in
the over-the-counter setting because we don\'t want them to use it
continuously, unless I\'ve missed something and it is supposed to be
used continuously.

DR. COHEN: That was just an editorial comment. It was a negative study.

CHAIRMAN BRASS: Dr. Robinson.

DR. ROBINSON: Obviously we\'re sort of doing this in a peculiar order
because it seems to me that the bottom line, of course, is what kind of
label if this product were to be approved will it have, and it\'s quite
likely, it seems to me, knowing what we do about the pharmacology of
omeprazole, that any label that made any sense for this product is not
going to be for single, one time use.

So if we are looking at the question of should it be approved for
single, one time use, the answer does appear to be no.

CHAIRMAN BRASS: Yes, Dr. Geller.

DR. GELLER: Once again, I need to remind the people on the other side of
the table that the trial \--

(Laughter.)

DR. GELLER: \-- the trial was designed as a single dose, meal induced
heartburn trial. We didn\'t tell them what to feed them. We didn\'t tell
them what does to use. These are decisions they made.

And, of course, if they had had a winner, if this had been
overwhelmingly successful in both trials, then we would not be having
this discussion, of course.

But we only can evaluate what we\'re presented with, and I think the
rest is extrapolation beyond the data.

CHAIRMAN BRASS: With that I\'m going to call that part of Question B. So
specifically for study 005 and 006, is there clinically significant
improvement of heartburn symptoms in either the ten or 20 milligram
omeprazole groups compared to placebo?

All who feel the answer to that question is yes, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: All who feel the answer is no, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(No response.)

DR. TITUS: Thirteen noes, one yes, zero abstentions.

CHAIRMAN BRASS: We would like to now have some discussion on the
secondary endpoints that were used in 005 and 006. Are the analyses of
the prespecified secondary endpoints supportive of the primary study
outcome? Do they add information?

And, again, here we would like to get insight into what can be learned
from those assessments that were made that might be useful in the
context of the therapeutic use of this in the OTC setting.

Dr. Johnson.

DR. JOHNSON: I have a question that I\'ve been sort of waiting, and it
looks like this might be a good time to ask the company, and that is the
decision to go from 20 to ten, and I understand there\'s this sort of
historical perspective, but, again, if you look down the list, if I\'m
looking at the right Table 5.9, clear down the list there\'s efficacy at
20, and there\'s clear down the list, except for one or two exceptions,
not efficacy at ten.

So I\'m curious if you can tell us a little bit about that decision
apparently fairly late in the game.

DR. ZORICH: Okay. Thank you.

It is a unique opportunity to come in after many precedents have been
set. For instance, I think the last vote just set a very interesting
precedent because when you look, in fact, at the meal induced study for
H2 RAs, and Dr. D\'Agostino who has lived through those can help me
remember, because my recollection is that, in fact, for the H2 RA meal
induced trials these differences have never been overwhelmingly
clinically kind of knock your socks off.

So I think what we are working with is really looking at the
over-the-counter appropriateness for drugs for heartburn within the
context of everything that has come before, and in that context, it
seems to me that if you look at the considerations that were given to
the H2 RAs, you\'ll see very similar kinds of discussions about efficacy
vis-a-vis dose, and sometimes there were dose effects; sometimes there
were not.

And at the end of the day it all came down to what is the most
appropriate, lowest effective dose that you would put into an OTC
environment, and so we felt, as you said, that if you just look at the
numbers in the absolute, 20 often is numerically superior, but then when
you start really to ask a more comprehensive question, as but does that
mean that ten wouldn\'t be an appropriate dose, we found ourselves
unable to give an affirmative answer.

And so in keeping that many of these same questions had been asked and
wrestled with I\'d say sincerely and still remembered five years later,
that in that context ten was an appropriate dose for serious
consideration, and we thought it had to be, and in consultation with the
agency, we thought we really had to talk about both.

And so I think that\'s what we\'re doing today.

CHAIRMAN BRASS: I would just like to comment about the dose issue
because I think it\'s one that has a lot of impact in how we think about
these issues.

From our perspective, the rationale for picking the minimally effective
dose for an OTC preparation is in the context of dose related toxicity,
and to balance the risk to benefit into the OTC setting, and that if
presented with a product that had little or no dose related toxicity, in
fact, the interest would be in maximizing efficacy, not minimizing
efficacy, and so that the concept that we always need to have the lowest
dose that bumps at all may be doing everybody a disservice, including
you by making it more difficult to demonstrate statistically significant
effects.

So I think that is a blanket concept, is not one I am comfortable saying
is a biblical law, and I don\'t know if I\'ve just committed a sin.

(Laughter.)

DR. DeLAP: No, we are very interested that consumers get benefits from
products, and I think you don\'t want to focus on a low dose unless
there\'s really a good reason for doing that. I mean, there\'s no reason
for someone to get 20 if ten does the job, but on the other hand, if 20
looks better and there\'s not some real big safety issue that makes it
clear that that\'s not a good idea, then I think we have to look
seriously at the 20.

CHAIRMAN BRASS: Dr. D\'Agostino.

DR. D\'AGOSTINO: I don\'t recall the exact numbers of the previous
products and so forth, but one of the things that we did and did quite
consistently is before we talked about clinical significance, we had to
assure ourselves that there was statistical significance, and also
you\'ve separated nicely the primary from the secondary. There was lots
of multiple testing, and so I think the answer to the first question,
the first part of this question has a lot to do with the fact that
differences are small clinically, but they\'re also carrying with them
some statistical insignificance, and from that point of view we\'d have
to say that the difference could possibly be zero.

So I think that we are being consistent, and I do think that there were
larger differences, but, again, they were statistically significant.
Then the question became how big must the difference be.

CHAIRMAN BRASS: Dr. Johnson.

DR. JOHNSON: I agree with Dr. Brass\' comments about dose, and I\'m just
wondering. I really haven\'t heard anything about dose related
toxicities. I mean this is really a very unique compound in terms of its
kinetic dynamic relationship. Can you tell us more about \--

CHAIRMAN BRASS: Can we save that for the safety questions?

DR. JOHNSON: Oh, sure.

CHAIRMAN BRASS: Thank you.

Dr. George Sachs.

DR. GEORGE SACHS: Yeah, I absolutely agree with what Dr. Brass said.
This type of drug when it came on to market, the issue was 20 versus 40.
At that time there were safety issues. Every subsequent drug has been
introduced \-- annexium (phonetic) that just had its approvable letter
is either 30 or 40 milligrams. Ten milligrams in study after study when
it was being put on the market, you know, not as a prescription drug
showed very, very little, if any, benefit over OTC Zantec. I think it
would be a mistake for the consumer to be offered ten milligrams when 20
milligrams is clearly to me the minimal effective dose for treatment of
GERD.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: I would support George Sachs and that comment because I
think that \--

DR. GEORGE SACHS: No, no, no, please.

(Laughter.)

DR. WALDUM: A large proportion of patients do not get any effect at all
on ten milligrams. I think the company should come up with that because
I think more than 50 percent do not have any inhibition of gastric acid
secretion at all because you have such a steep concentration response
curve for omeprazole. It\'s a drawback because you have this virtually
none or complete inhibition of gastric acid secretion, but ten
milligram, many patients without an effect at all.

CHAIRMAN BRASS: And again, you want to remember this is in the context
of looking at those secondary endpoints in these trials which had
suggested that relationship which Dr. Johnson pointed out.

Yes.

DR. ROBINSON: Just to remind people here, actually our data which came
to the agency for omeprazole at the time that omeprazole got its
original approval showed that ten and 20 milligrams were, in fact,
different, and the problem was that although ten milligrams did work, it
didn\'t work in as large a number of people. That is, each time you
elevate the dose, you decrease the number of people that failed to
respond, and we showed, and that was one of the reasons that 20
milligrams was chosen, that 20 milligrams was clearly pharmacologically
superior to ten milligrams. So I would agree that if I were the company
I\'d pick the 20 milligram dose as well.

CHAIRMAN BRASS: Other discussion of the secondary endpoints that were
used.

Dr. Geller.

DR. GELLER: I would fee much better able to assess the differences shown
on page 52 of the white book if I had actual P values, not just that the
P values were less than .05.

CHAIRMAN BRASS: Do we have those available?

PARTICIPANT: We have a subset of it.

CHAIRMAN BRASS: Well, I guess any actual P values would be helpful. Is
that fair?

DR. ZORICH: Then I would say study 006 then would \-- an overall
assessment even at the .025.

CHAIRMAN BRASS: I\'m sorry. Table 5.9 on page 52 has a number of
endpoints which are not on it.

DR. ZORICH: Right, and the only ones I have here are the last two in
that list of five.

CHAIRMAN BRASS: Okay.

DR. ZORICH: Overall and back-up, and study 006, even with the
consideration as you said of a more stringent P value, both doses, and
005 only 20 milligrams.

This is overall assessment. This is a secondary variable. You asked
about it. It\'s the fifth. ON page 52, it\'s the bottom.

CHAIRMAN BRASS: Dr. D\'Agostino.

DR. D\'AGOSTINO: I agree 100 percent with the notion of the P value and
the size, but there is a consistency, and I think it should get into the
transcript that there is a consistency across the secondary endpoints,
which is quite pleasant to see and so forth, and I don\'t think that it
\-- it doesn\'t support \-- I think the way the question is worded it\'s
kind of hard to answer. We said we don\'t buy the primary and now we\'re
supporting something that we don\'t buy, but I do think the secondary
showed that something is going on with the drug, and maybe it\'s a bad
design. Maybe the requirements of having the relief within an hour and
sustained for two hours, all of those things are working against the
drug and the study, but I do think that we can\'t ignore the consistency
of these secondary endpoints.

CHAIRMAN BRASS: And just for the record, that is a consistency towards
drug benefit.

DR. D\'AGOSTINO: Towards drug benefit, yes.

CHAIRMAN BRASS: Other comments about the secondary endpoints? Yes, Dr.
Johnson.

DR. JOHNSON: Well, my only comment would be that the consistency of
benefit is only at 20 milligrams.

DR. GELLER: There\'s no question about that.

CHAIRMAN BRASS: Okay. I don\'t think we need to take a vote. I think the
discussion on that point addressed the issues.

We now move to studies 171 and 182. The primary endpoint revocacy was
the complete prevention of heartburn between the first two doses of
therapy. Based on the primary measure of efficacy, is there a clinically
significant improvement of heartburn symptoms in either the ten or 20
milligram omeprazole groups compared to placebo?

(Pause in proceedings.)

CHAIRMAN BRASS: Thank you, Dr. D\'Agostino.

DR. D\'AGOSTINO: Nobody wants to say it.

The primary endpoint is quite significant, and I think clinically
significant.

CHAIRMAN BRASS: Would somebody like to \-- since this is looking at the
first episode, would we infer something about the pharmacology or
biology here, why this one was positive compared to the previous
negative results? Is this expected, unexpected, logical, illogical?

Dr. Neill.

DR. NEILL: My understanding is that this is daily dose not in response
to meal; take it first thing in the morning. You\'ve had it on board for
several hours, and certainly if the assessment is 24 hours in, then
that\'s for reasons that have already been explained \-- do I have that
wrong?

DR. ZORICH: The assessment is whenever heartburn occurred, covering a
full 24-hour period with a specific assessment of nocturnal. So any
heartburn that is occurring is collected in real time, and then of
course, within 24 hours there is a final assessment, and there was also
an assessment of the nighttime experience.

So there actually is ongoing assessments throughout the full period. So,
for instance, there was time to heartburn, and it was on a continuum,
not just a static assessment at the end of 24 hours.

DR. NEILL: So thanks for clarifying that.

So my presumption, and maybe you could confirm this \-- I think you did
earlier \-- is that the majority of the benefit that\'s seen within that
first 24 hours, given the studies that we\'ve already seen, does not
come from the first four hours.

DR. GEORGE SACHS: Sorry. Can I ask for clarification as well?

DR. ZORICH: I would like to suggest that the only thing that we can say
with clarity, and I think, Dr. D\'Agostino, I would ask you to see
whether or not you see this fits any kind of test of reasonableness.
Since we agree that at 20 milligrams there was something in that
previous one hour before the provocative meal study and ten \-- I think
we had debate, but at least in one study there was significance at one
hour before a meal. Then I would say that if the drug was taken prior to
an hour, I think that that\'s about the most I think we can limit.

So I don\'t think we could say three hours, four hours. It seems to me
that one hour is just about where you\'re on the edge.

DR. D\'AGOSTINO: I\'m going to throw that over to the other side of the
table and let them answer it.

CHAIRMAN BRASS: Dr. Cohen?

DR. GEORGE SACHS: Can I get clarification? With the previous studies,
the patient had heartburn and swallowed omeprazole.

DR. ZORICH: Not with the ones we just talked about.

DR. GEORGE SACHS: No, no. I\'m just talking about the previous ones.

DR. ZORICH: Oh, nine, two and 095.

DR. GEORGE SACHS: Yes.

DR. ZORICH: Yes.

DR. GEORGE SACHS: Now, here I assume the patient wakes up, takes his
capsule, then has breakfast, and then records his heartburn for the next
24 hours.

DR. ZORICH: They were instructed to take it in the morning, yes.

DR. GEORGE SACHS: So your dosage system is different.

DR. ZORICH: Yes.

DR. GEORGE SACHS: Here you\'re following what we would prescribe
omeprazole and how you take it, half an hour before breakfast to give
you the maximal effect day one and then day two and day three.

Your previous studies sort of on the spot swallowing omeprazole have a
different design.

DR. ZORICH: Right.

DR. GEORGE SACHS: And your pharmacokinetics of the drug as your acid is
switching on are completely different. So this is the way the study
should be done.

CHAIRMAN BRASS: Dr. Cohen.

DR. ZORICH: This study was done that way.

DR. COHEN: This is a very positive study, and it mimics the way patients
take the drug in real life, and the ten milligram dose to my looking at
this is highly efficacious. It\'s the way patients would take it.

The provocative meal, although very sexy, is also very artificial, but
this is the way patients live, and they take the medication, and in this
dose range you also have an appropriate placebo response which you would
expect in the 30 percent range, not 60 or 70 percent.

So to me this is a very positive study and a very real life circumstance
as how a ten milligram does would be taken.

CHAIRMAN BRASS: Was there a dose ranging analysis, not necessarily
statistical significance between the doses, but just a dose ranging
analysis between \-- a trend analysis \-- in either 171, 183 or in the
combined population to look at whether there was a dose response
relationship?

DR. ZORICH: Could you please put up the first day and be ready for 14
days?

We actually saw in both of these studies ‑- in one study, if applying
statistical test \-- and, of course, this is now after the fact. I
don\'t want to, you know, pretend it was planned in. These were both
separately compared to placebo, and then after we had the results, we
did see differences in 171, but as you can see and not surprising, there
are not differences in 183.

Now, when you look across all 14 days, what you see is in 171 there
really are not differences, and there\'s a suggestion of difference in
183.

So this is what I was talking about in reference to wrestling with this
question of dose. In this design, ten and 20, you\'d be hard pressed to
say definitively 20 was better.

CHAIRMAN BRASS: Well, I wouldn\'t be surprised if a trend analysis, not
a two arm comparison, but really a three point trend analysis would not
have confirmed that there was some kind of dose relationship across that
range.

Ms. Cohen.

MS. COHEN: Being as we tend to eat all kinds of foods that are bad for
ourselves, did you take the worst case scenario in foods and what people
might eat? They take the dosage, and then they eat something that\'s
pretty \"gucky\" and pretty bad. Did you test it under the worst
conditions, not under the best, but under the worst?

DR. ZORICH: The previous studies 005 and 006, I think it was pointed out
here that the low placebo response rate \-- these were a highly \--
these diets were really design to provoke reflux, and so, yes, we did
test it under high fat, other stimulants of reflux, caffeine, and these
people were living freely in their homes. So we did do both, free
living, but as you know, abusing themselves nonetheless, but just on
their own time.

CHAIRMAN BRASS: Dr. Neill.

DR. NEILL: I\'ll preface my comments by saying that I think that the
answer to the question is, yes, there\'s some efficacy shown here.

Having said that, I have to disagree that this is how people take this
medicine in real life. This is how people take \-- let me correct
myself. This is how physicians think patients take the prescription
medicine, but the studies of that show that even for single dose
medicines, patients at best comply only 75 percent of the time, and when
the instruction is something like 30 minutes before a meal and that meal
is morning time, trying to keep people from drinking their coffee,
putting food in their mouth for 30 minutes, and insuring that they get
the medicine beforehand doesn\'t happen.

Now, so as not to sound overly negative, the nice thing about this
medicine is once a patient has been on it, it doesn\'t matter because
the pharmacodynamic effect will remain.

My concern is that in the OTC setting, none of the current parameters
apply. It\'s not prescription. It\'s not continuing therapy. There are
others that we\'ll get to later.

And so I just felt the need not to let stand the comment that this is a
study of how people take it now because I have no data to support that
assertion.

DR. ZORICH: Let me say though that I think I would just like to make a
correction, that I think we\'re over applying instructions to the
patients that were, in fact, not applied. They were told to take in the
morning before breakfast, and if they didn\'t eat breakfast or if it get
late, just take it before noon.

So, in fact, this is not a study that is a strict clinical design, and I
think we tried to make it more naturalistic and take it in the morning,
and the reason we did that was not to try to force, again, a situation
where you\'re being very prescriptive, but because we had built in \--
and I didn\'t show you the data \-- but we specifically built in a
nighttime heartburn endpoint. We felt that we wanted to have some idea
that at least since noon people had taken it. So I just want to make
sure that we don\'t over interpret the instructions to the patient.

CHAIRMAN BRASS: Dr. D\'Agostino, you had another question?

DR. D\'AGOSTINO: I\'m not sure that the other side of the table answered
the question you addressed to me from what I heard them saying
previously, that the explanation you gave sounds reasonable, and I
gather that\'s also in agreement with other people at the table.

CHAIRMAN BRASS: And that\'s what I assumed by the discussion.

Dr. Johnson.

DR. JOHNSON: You can shut me off if you want because this may not fit
with this question, but I guess I\'d like to go back to \--

(Laughter.)

DR. JOHNSON: \-- slide ZC6 where it\'s sort of the final proposed
labeling slide.

DR. ZORICH: Yes.

DR. JOHNSON: Treatment of frequent heartburn and prevention due to food
and beverage. When would they be taking these to accomplish the ‑- I\'m
very confused about how the product would be taken.

DR. ZORICH: Well, to be honest, I mean, there\'s no criticism here
intended because truly what we\'re asking for is, you know, something
that hasn\'t been done before, but when you think about it, the whole
\-- I think the comment came over here \-- is that the meal induced
model was that. It was a model, but because it helped the consumer get
clear direction on when to take it in reference to what they predicted
would be a provocative meal, and, Dr. Neill, with due respect, ever
since \'95, we\'ve been treating predictable heartburn because you have
to predict that a meal is going to be provocative.

And so prediction of heartburn is operative, I would say, but so what
we\'re saying is that the data supports that as long as it\'s an hour
before, we\'re very clear that the pharmacodynamics of this particular
drug, you can\'t get real close to when your heartburn is going to
happen. You can\'t get closer than an hour. That 005 and 006, I think,
showed us that no closer than an hour.

Backing up from an hour is a good idea. So let\'s say that if you\'re a
consumer who is not going to have a provocative lunch but will have a
provocative dinner, then dosing in the afternoon is okay, but dosing in
the morning is okay.

It\'s unfortunate, and I\'m sure that you can understand from the side
point that someone who really thinks this is a benefit for a person,
having the luxury of knowing that today is going to be a stressful day
for a lot of reasons, it\'s a good thing to be able to take it in the
morning and have a 24-hour prevention.

So what we would be telling the consumer is to take it on the day
provided it\'s at least one hour before the meal that would provoke
symptoms. So it would have to be more than an hour removed.

But other than that, there really isn\'t any reason to specify exactly
when, and then if the person who is the 18 percent of the people that
Dr. Castell showed to us with the weekly heartburn who\'s currently
right now taking the drugs approved for episodic heartburn, it\'s just
that those episodes happen to be two or three times within a week. Our
data, we believe, shows that for that targeted consumer, not the person
taking Mylanta once every three months; for the person who identifies
with the term \-- and grant you, we have to test this for clarity \--
but for someone with frequent heartburn, more than once a week, this
person we believe is the targeted population. They currently are taking
anti-secretory therapies now, and this would be the group that we think
would benefit from this product.

And in fact, perhaps our hope would be that they would even have to take
fewer products in combination.

CHAIRMAN BRASS: I want to come back to 171, 183.

Dr. Geller.

DR. GELLER: I wanted to know what the frequency of heartburn during the
run-in period was in these studies.

DR. ZORICH: One, seventy-one and 173?

DR. GELLER: Yes.

DR. ZORICH: Do we have a slide for that?

I think over 50 percent of these folks were having heartburn at least
half of the time, but we probably have a number.

DR. GELLER: Then is it correct that this line between GERD and heartburn
is, again, blurred?

CHAIRMAN BRASS: Let\'s hold that question. Let\'s hold that one. That
one will come up later.

Dr. Cohen.

DR. COHEN: I\'m not going to get a chance to vote, but I want to say
that this is a real life indication, and I know there\'s some contention
across the table here, but I see patients, and this is the way patients
take a drug. They know when they\'re going to get heartburn, and if you
go out and you go to Tuscany for a week or you go out for dinner and you
have a cigar and a couple of drinks, people can predict this, and in
real life circumstances, this is a reasonable indication.

I don\'t think it\'s artificial at all. So I think that \-- and let me
just make one other comment \-- I think it\'s better to prevent
heartburn than to treat established heartburn. Once you\'ve had
heartburn, you\'ve already had mucosal exposure and possibly mucosal
damage. This can prevent it. This is a reasonable indication, in my
opinion.

CHAIRMAN BRASS: Do you want to show those? Do you have that data?

DR. ZORICH: Can we show that histogram? I have something that I think
\-- no, that not the right one. I\'ve got the actual number of episodes.

CHAIRMAN BRASS: Well, if you can just \--

DR. ZORICH: I\'m sorry. I apologize because I\'m not being clear.

You know the one that plot 114, 092 and 095? Ah.

What I\'ve plotted for you here, I think this is separate from the
studies because I\'m only plotting people on placebo, but it tells you
about that population of people that we recruited.

No, no. You had the right one in. Hello. I was happy. I was fine.

(Laughter.)

DR. ZORICH: Okay. We\'ll start again. What I\'m plotting here are the
percent of subjects, and \-- 092 \--

DR. GELLER: This is 092 and 095, and I guess in trying to understand why
this trial was successful and the success with the others is more mixed,
I was wondering about how much heartburn these patients had compared to
the other set.

DR. ZORICH: In general, it\'s a fair statement that because of the way
they were recruited, they\'re all pretty comparable. There weren\'t any
particular studies where they were very severe and the other ones were
very mild. These, in general, were tracking in about \-- I think were
they about 1.5?

DR. GELLER: That\'s the severity, which is clear in the book, but the
number of days of heartburn in the run-in period isn\'t.

DR. ZORICH: Well, they would have had at least two minimum to qualify.

DR. GELLER: That\'s part of your eligibility criteria.

DR. ZORICH: Right.

DR. GELLER: I think it was far higher.

DR. ZORICH: It\'s okay. How about if I go off line and I\'ll try to get
that, and I\'ll come back?

DR. GILLIAM: If you look at Table 5.4, it says that 70 percent \--
heartburn frequency of days during run-in, and it\'s running 73, 74
percent.

DR. GELLER: That\'s five days. Is that what that means? Does that
translate to five days out of the seven days of run-in?

DR. ZORICH: Yes.

DR. GELLER: Thank you.

DR. ZORICH: That\'s right. We just confirmed that, five days.

CHAIRMAN BRASS: Okay. I \-- oh, Dr. Cohen, did you want to make a last
comment?

Okay. I\'d like to call for the vote on Question C(1). In studies 171
and 183, is there a clinically significant improvement of heartburn
symptoms in either the ten or 20 omeprazole groups?

And I propose to keep them lumped, not bother with separating dose. So I
think we discussed that issue. Okay?

All in favor of yes for that question, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Noes, please raise your hand.

(No response.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(No response.)

DR. TITUS: There were 14 yeses.

CHAIRMAN BRASS: We\'re now asked to comment on the pre-specified
secondary endpoints and whether they are supportive of the primary study
outcome. Do they add information regarding clinically significant
treatment effect?

And I would just kind of ditto Dr. D\'Agostino\'s previous remarks that
there does appear to be consistency in favor of drug for those secondary
endpoints.

Would you like to add anything else?

DR. D\'AGOSTINO: No, that\'s fine, but this withdrawal, are we going to
talk about that in this context?

CHAIRMAN BRASS: Yes, please, go ahead.

DR. D\'AGOSTINO: Well, I\'d like some discussion on what that actually
means. The drug obviously holds itself up for a few days, which is
interesting, and is there any implication in terms of interpreting the
study?

There were discussions this morning. Should something get into the
transcript on that?

CHAIRMAN BRASS: Do any of the \-- yes, Dr. Cohen.

DR. COHEN: I would just comment that I think clinician knows that once
you stop the drug, the symptoms come back, and that was the whole
rationale for long-term maintenance trial, and anybody who looks at the
usage of the drug, it\'s chronic usage. So I think that\'s one of the
issues that comes up. They feel so good that they don\'t want to stop.

CHAIRMAN BRASS: That point will become very important when we talk about
the labeling and the long-term toxicity issues.

Dr. Sachs.

DR. HARI SACHS: I really was just going to mention that, you know. It
seems to me that there\'s no question this will be used chronically
because we\'re talking prevention, and if you stop it, you feel bad.

CHAIRMAN BRASS: Other comments on the secondary endpoints for 171 or
183?

If not, we will move on to Question D. Based on the types and frequency
of adverse events reported in the clinical trials and in the post
marketing adverse events database, are the safety concerns for the OTC
marketing of omeprazole able to be addressed solely by labeling,
identifying risks to consumers for short-term or chronic intermittent
use?

And let me editorialize. That question is whether or not you believe it
will actually be used that way. So I want to focus the discussion on
issues related to short-term toxicity or intermittent use that is
repetitive short-term use, and I want it answered that way because I
want to separate the issues without any short-term toxicity from the
issues with the longer term toxicity, and regardless of how we think it
may ultimately be used.

In answering this question, please consider the reports of anaphylaxis,
angioedema, urticaria, liver toxicity, white blood cell disorders, and
severe skin reactions.

DR. SHAPIRO: Mr. Chairman, just on a point of order, are you asking us
first to confine the discussion to short-term effects?

CHAIRMAN BRASS: Yes, short term as defined with ten days of exposure.

DR. SHAPIRO: Okay, but you\'re talking about effects within ten days of
exposure.

CHAIRMAN BRASS: Or later effects that would result from only ten days of
exposure.

DR. SHAPIRO: Well, that could be things like aplastic anemia and \--

DR. GANLEY: Eric, let me just interject here. I think that he\'s picked
up on some of these things. I may require longer use than ten days in,
for example, hepatitis. You know, I think there was some discussion of
when that occurred in the course of chronic therapy. So if you take it
in the context of someone using it for short-term use or for this, you
know, chronic intermittent use, you know, there may be differences in
these various \--

DR. SHAPIRO: Could I make a suggestion?

CHAIRMAN BRASS: Please.

DR. SHAPIRO: Could we consider short-term effects to be things like
nausea, vomiting, diarrhea, and long-term effects to be cancers of
various kinds, agranularcytosis, toxic epidermal necrolyzers (phonetic)
and so on?

CHAIRMAN BRASS: I was hoping to avoid the cancer issue until the next
set of questions, but I\'m open to doing it either way, and I was trying
to simplify things because I was trying to avoid the definition of
intermittent in terms of \-- because intermittent use becomes chronic
use.

Yes, you want to try and help?

DR. RACZKOWSKI: Yes, I think that the focus of this question is really
on some of this uncommon, but some of the serious adverse events that
have been associated with omeprazole use. I think both the company and
the agency would agree that there have been serious events associated
with the drug, and that they are uncommon.

But in a prescription setting, we\'ve made the determination that the
benefits exceed the risks because the potential benefits are greater,
and so the thrust of this question really focuses on serious adverse
events that are uncommon.

Are those acceptable in an OTC setting, where the benefits may not be as
great?

CHAIRMAN BRASS: Okay, but what I really want to do is separate the
issues that are defined in Question E, for those of you who have read
ahead, from those that are going to be discussed now in the context of
Question D.

So whatever language is useful to separate those two I accept
immediately.

Yes, Dr. Shapiro.

DR. SHAPIRO: Thank you.

The specific effects that are referred to here are anaphylaxis,
angioedema, urticaria, liver toxicity, white blood cell disorders, and
severe skin reactions. I think there are secure data concerning
anaphylaxis to indicate that, first of all, this is a rare outcome;
secondly, that its most common causes, apart from bee stings and wasp
stings, are actually blood transfusions, plasma infusions, and the use
of radiopaque materials, and a few selected drugs, such a penicillin.

Apart from that, the incidence of true anaphylaxis is exceedingly low,
and even if this product were to increase the risk of anaphylaxis, the
incidence would still be low. If you take a very rare disease and you
multiply it by a relative risk of three, it remains rare.

So I wouldn\'t have anxieties about anaphylaxis even if there have been
reports and even if there have been reports of the occurrence of
anaphylaxis on rechallenge.

With regard to urticaria, there isn\'t a drug on the market that
doesn\'t cause urticaria, either over the counter or a prescription, and
if one really wants to know whether urticaria or hives or conditions of
that kind are a problem, one would need to do a randomized controlled
trial and compare incidence rates. Without doing that, we couldn\'t
answer the question.

But urticaria itself is not serious, and if a patient experiences
urticaria and if it recurs on rechallenge, that patient can stop. So I
don\'t think that\'s major.

Major hepatic toxicity, liver failure, which rather than transaminitis,
I think, again is so uncommon that whether or not there should be a
causal relationship, there would not be a public health problem.

White blood cell disorders, if there\'s a neutropenia, which is
asymptomatic, it doesn\'t matter. If there is agranularcytosis, this is
an exceedingly rare disease. If this drug were commonly causing
agranularcytosis, like some of the other agents on the market, we would
know about it.

And for toxic epidermal necrolysis and Stevens-Johnson Syndrome, there
are, again, acute conditions. If they were a major public health
problem, we would know about that, too.

So what I take from all of this is what we currently know is
reassurance. If some public health problem were to arise, there are
already data banks in which these questions can be adequately examined
in well formulated case controlled studies.

CHAIRMAN BRASS: Dr. George Sachs.

DR. GEORGE SACHS: I think the issues are twofold. One, are the adverse
events, the idiosyncratic events under omeprazole more frequent than
placebo, or, secondly, are these adverse events more frequent than any
other controlled clinical trial?

And I think careful surveillance on omeprazole 12 years post launch
worldwide, I don\'t think anybody can point to any instance of where
omeprazole per se has resulted in adverse events more frequent than
those found certainly in the second category in terms of any other drug
trial that\'s going on in this area or any other area.

So I don\'t believe there\'s any issue whatever about the safety of
omeprazole relative to any other drugs, OTC or prescription.

CHAIRMAN BRASS: Ms. Cohen.

MS. COHEN: If you describe the contraindications here, would consumers
know what they are, number one? And, number two, I wouldn\'t trust a
label till I saw it.

CHAIRMAN BRASS: We\'re not talking about the label right now. Labeling
will come up later.

Dr. Cantilena.

DR. CANTILENA: Yeah. I guess I would not sort of share the opinions just
expressed concerning the toxicity to the liver. I think there seems to
be, albeit very small, but a clear signal, and I guess we have some
fairly well documented cases, and I was going to just ask the FDA one
follow-up question that I didn\'t get a chance to ask this morning from
the safety presentation.

Your slide number 11 talked about some of the cases were classified as
Category A, which means that you\'re fairly tight in terms of causality.
In looking at those reports, can you tell us in terms of, you know,
genetic, you know, polymorphism or anything that might suspect, you
know, mechanisms in terms of the toxicity?

And as you\'re thinking about that, but if you just look at that list, I
mean, there\'s a significant number of, you know, fatal cases and, you
know, nonfatal, serious, not just, you know, trivial, and I guess I\'m
not as comfortable as you seem to be in the issue of hepatic toxicity,
especially for treatment of, you know, a condition that is not, you
know, life threatening.

So just to sort of put that out there, but I am extremely interested in
finding out whether or not we know more, you know, about these
apparently well documented cases.

DR. STEINBERG: If I\'m looking at that same slide you are, you said
slide 11. You said there are two cases of fatal that were A rating and
two and four of nonfatal. Are those the numbers that you\'re talking
about that I find disturbing?

DR. CANTILENA: Right. Overall, you know, 33 fatal, 227 nonfatal,
serious. But I was just asking if we knew more about the cases that had
the A rating.

CHAIRMAN BRASS: Yeah, let\'s let the FDA response.

DR. CANTILENA: right.

DR. AVIGAN: The point I would make is that the A cases generally have
had the luxury of rechallenge in some cases at least, two of the four
cases that were the nonfatal cases, with clear association on
rechallenge, and I think that you have to understand that there is a
limitation in this kind of analysis because the information is given in
a voluntary way, and when you sort through the various kinds of cases,
the problem is not just the A cases. It\'s the B, C, and D cases, where
if you look at what is given to you in the narrative, there are a number
of potential explanations which cannot be dissected through because of
limitation information. In fact, there may be in the total aggregate
more that in reality or in truth are attributable.

So you could look at it both ways, and the second point is that this is
presumably still a very rare event, but we don\'t know the true
incidence because this is voluntary.

DR. CANTILENA: So just for a specific, if you look at that aggregate of
serious and fatal, have you examined in terms of, you know, race, if
it\'s a high, you know, percentage of like Asian, you know, population
that have that?

DR. AVIGAN: Yeah, these are idiosyncratic reactions that are not
predictable a priori by any measure that we currently have.

CHAIRMAN BRASS: Dr. Shapiro.

DR. SHAPIRO: Even when a case occurs on rechallenge, adverse reaction
reporting systems do not contain the requisite clinical information that
you really need to make a judgment about causality. You want to know
about exact timing. You want to know about other drugs that were used.
You want to know about whether that person previously had
hepatotoxicity. You want to know whether the person had Hepatitis B
positivity or Hepatitis A or Hepatitis C. Without that information, you
can reach no conclusions.

The other added difficulty here is that if there are two patients who
have hepatic failure, both of whom die, one of whom was exposed to a
drug and another was not, the one that was exposed will be reported to
the Food and Drug Administration. The one that was not exposed will not
be reported.

The bias is 100 percent the data are not interpretable.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: I tried to raise an issue previously today, but that is
concerning the biological effect of gastric acid. It seems to me that
nobody is interested in that. After all, we have preserved the
production of gastric acidity in the upper part of the alimentary tract
throughout phytogenesis, and I can\'t understand why you want to take it
away from a large million of people.

Aren\'t you afraid of that? What could happen with viruses and prions,
as I said? Do you have that information that there is this enormous,
long incubation times for these diseases?

So I\'m not \-- I\'m asking for biological.

CHAIRMAN BRASS: Dr. Cohen.

DR. COHEN: Yeah, the thing that impressed me at the ten milligram dose,
which is the recommended dose was that it was really only a very modest
effect on acid inhibition. I mean it was like a 20 percent reduction,
and the pHs did reach acidity at some time during the day.

So in a way, I\'m pleased and surprised that the beneficial effect
without having a major impact on acid inhibition is very minimal or
modest, I should say.

CHAIRMAN BRASS: Dr. Hari Sachs.

DR. HARI SACHS: In a clinically relevant question, if these drugs
actually cause relevant neutropenia and perhaps make you at risk for
infection because of gastric acid effects, is there any data on
infection, you know, incidence in people with this drug, you know, that
it\'s higher than the average?

DR. CANTILENA: The only thing that I know, and perhaps other people can
comment, is that in patients on high dose proton pump inhibitors,
they\'re somewhat more susceptible to getting enteric infections, like
E. coli or campylobacter, salmonella, and even there the association
isn\'t that great, but that\'s the only thing that I know of, but
that\'s at pretty high doses where they\'re virtually achlorhydric.

CHAIRMAN BRASS: Yes. Would sponsor like to make a comment?

DR. LEVINE: I believe Dr. Cohen as made the right comment.

DR. SHAPIRO: Could I answer that question? The incidence of
agranularcytosis in the population at large is about six per million per
year. These would be the people who are uniquely susceptible to
developing infections.

With such a low incidence, it would be impossible in any study that I
can conceive of to show an increased incidence of infection among
omeprazole users and nonusers.

Even if there were an increased incidence it would be of no public
health importance. It might be 12 per million per year.

CHAIRMAN BRASS: Dr. George Sachs.

DR. SACHS: In relation to infection and the use of PPIs, there have been
studies done in people where the incidence of overgrowth by E. coli or
other enteric organisms has been followed as a function of treatment
with acid inhibitory medication, i.e., Zantec at a clinically effective
dose of 300 milligrams b.i.d., omeprazole 20 milligrams. o.d.

And you can show in both instances a transient overgrowth which then
disappears, and remember that at this dosage nobody except for the very
slow metabolizers ever shows anything close to achlorhydria.

So the benefits that you see in terms of the 20 milligrams of omeprazole
are limited by the fact that you\'re not getting complete acid
suppression, and the pH does go down to one at night, and you don\'t get
this sort of effect at nighttime GERD that you\'d like to see.

So you\'re not generating achlorhydria. You\'re not generating gastric
infection by treatment either with omeprazole or b.i.d. 300 milligrams
Zantec.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: Yes. There\'s the question of the highest pH that you have
in the stomach does not allow us. When you eat something, when you drink
something, if you happen to have a high pH, that is what matters, not
the lowest.

CHAIRMAN BRASS: I\'d like to come back to an issue on the drug
interaction question because I think it impacts the consumer\'s ability
to discriminate.

What is \-- I\'m sorry. Do you have specific data on omeprazole-warfarin
interactions, specifically using PT or prothrombin time or INRs as the
endpoint?

And I\'d much prefer not to see mean data, but data on the number of
patients who had their INR bumped by a certain amount. In other words,
I\'m actually interested in the outliers from a safety perspective, not
the mean response.

DR. LEVINE: I can\'t provide outliers. We have mean data and did not
show any differences in coagulation parameters.

CHAIRMAN BRASS: Yeah, I think that\'s just always how it\'s shown, and
it\'s really not helpful if you\'re looking for a subset of patients who
may be at risk or have an exaggerated response when you expose a large
population. So I think having confidence that there are less than X
percent of the population who will bump their INR more than 25 percent
or something like that is much more useful than mean data.

Obviously if mean data shows a change, it\'s important, but when it
doesn\'t show a change, I think for safety purposes the outliers matter
a lot.

DR. LEVINE: May I just make one point?

CHAIRMAN BRASS: Oh, please.

DR. LEVINE: Just it\'s important to recognize that warfarin is a
racemate. It has two inantemers (phonetic), and in fact, the most active
inantemer that affects coagulation is not \-- it doesn\'t go through the
same metabolic pathways so that what we measure is with the less active
warfarin. So although we don\'t have all of the data, there are
reassuring bits of information.

CHAIRMAN BRASS: Also, I remember at some point there being discussion of
omeprazole being an inducer of certain P450s. Did I confabulate that?

DR. LEVINE: I would have to defer to my pharmacologist, but that\'s data
that I\'m not aware of.

DR. LAM: Omeprazole definitely can induce 1A2.

DR. LEVINE: Could I ask Dr. Andersson to respond to that, please? He\'s
one of our internal experts in pharmacology.

DR. ANDERSSON: That issue has been thoroughly studied in many, many
different ways with different doses and from different labs, and there
is a German group that showed that in poor metabolizers actually 40
milligram omeprazole were given over one or two weeks, had an induction
of some 30 percent 1A2, which in rapid metabolizers, they had to give
120 milligram to obtain the same degree of induction.

But those data were very variable and going from negative induction, so
to say, to some 60 percent induction, and we have tried to reproduce
those data at our own company, and almost as I\'m speaking right now, we
are going to submit a study using 60 milligram omeprazole in poor
metabolizers with an N of five, and there is no induction at all in that
study.

So I would tend to say that there is really no induction at least that
has no clinical relevance, 1A2, of omeprazole treatment.

CHAIRMAN BRASS: Dr. Elashoff.

DR. ELASHOFF: With respect to the proportion of people who might be in
some extreme area, although these studies are probably small, they also
probably have standard deviation in addition to mean, and one could make
some initial approximation to how many people might be extreme, using,
say, two to three times the standard deviation.

CHAIRMAN BRASS: That\'s assuming if it\'s a normal population. If
you\'re looking for a bimodal subset, you\'ll miss it that way.

DR. ELASHOFF: It just \-- it just gives a place to start. I\'m not
saying that it gives an answer.

CHAIRMAN BRASS: Dr. George Sachs.

DR. GEORGE SACHS: Yeah, again, with this induction of 1A2, the issue was
initially brought up as converting things to a more dangerous form, and
therefore, induction of 1A2 by implication due to omeprazole increased
the patient to the risk of carcinogenic metabolites.

But traditionally, historically all P450s are protective, and animal
studies with increased 1A2 shows actually protection against
carcinogenicity, not promotion of carcinogenicity.

CHAIRMAN BRASS: Dr. Johnson.

DR. JOHNSON: Well, I disagree. I think there\'s pretty clear literature
for certain cancers, and I can\'t remember off the top of my head, with
higher 1A2 activity or induction, but I don\'t believe that that\'s
probably clinically relevant in this situation.

I guess I\'d like to come back to the question I asked earlier, which is
the data that you might have on the relationship between toxicity and
dose.

I mean, I think one of the luxuries we have with OTC products is that
we\'ve got experience with millions or billions of prescriptions being
filled, and I don\'t see really any safety concerns, but, again, to go
to this issue of ten versus 20, is there any reason we should be more
concerned about 20 than ten other than the acid inhibition?

DR. LEVINE: I\'ve tried to make the point that what we\'ve been talking
about is risk potential with particular reference to something that the
agency has mentioned, which is specific subpopulations. We can monitor
head to head ten milligrams, 20 milligrams in controlled trials and
obviously not show any difference, and the issue, of course, is what\'s
happening in an at risk subpopulation or what\'s happening with very,
very rare events.

One of the issues that we\'ve been talking about is the potential for
drug-drug interactions. We think that the profile is safe, but the
potential if you want to stack the deck to really assure any lack is to
simply lower the dose.

But with regard to a lot of the adverse events that we\'ve been talking
about, if there is any relationship as best as we can determine it\'s
idiosyncratic. If we wish to think about theoretical risks that have to
do with disruption of gastric homeostasis, we know that there\'s clearly
a dose difference between ten and 20, and you know, from our view
looking at the studies that we\'ve seen where we did not see substantial
differences between ten and 20, that\'s why we\'ve come to the
recommendation for ten milligrams.

DR. JOHNSON: But it seems in terms of side effects, in particular, if
there was really clear dose related relationships, the people who are
poor metabolizers would jump out and have all kinds of toxicities
because they have fivefold concentrations.

My impression is they don\'t. Is that correct?

DR. LEVINE: That we\'ve not observed that. You\'re correct.

DR. GELLER: How many slow metabolizers have you studied?

DR. LEVINE: I can\'t cite an absolute number. We have chosen a number
of, you know, subjects as part of our pharmacology studies. We have
conducted studies in Japan. We have adverse event profiles from that
country, and the distribution of AEs resemble exactly what we\'ve
observed in the United States and worldwide.

CHAIRMAN BRASS: Dr. Cantilena.

DR. CANTILENA: Yes. I was wondering if you can actually show the
drug-drug interaction with your product and, say, phenytoin at, you
know, ten or higher dosages of the omeprazole, if you have that data,
and again, obviously if you have the individual data, that would be
idea, but I think even for us to see the mean with phenytoin would be
helpful for me.

DR. LEVINE: Could we pull slide 55, please?

These are the data that we\'ve been able to accumulate, and what has
been done is studies both in healthy subjects here, as well as in
patients with epilepsy who required phenytoin and to whom we added
omeprazole dosing. The dosing in these studies as you can see were high
in these, 40 milligrams over seven days, which is steady state
concentrations, and we\'re seeing this magnitude of change. There are
some differences here, and in fact, in the epileptic patients we
couldn\'t demonstrate a change.

So we feel pretty comfortable that particularly even if there were
magnitudes of changes that are, you know, in the vicinity of 15 to 20
percent, that\'s not going to be a clinically relevant issue with regard
to phenytoin levels, but actually when we went and looked at patients,
we couldn\'t demonstrate a change in phenytoin levels.

I\'m sorry I don\'t have individual data.

CHAIRMAN BRASS: Dr. Sachs, do you have a question?

DR. HARI SACHS: I just can\'t see \-- I apologize for my eyes \-- the
dose in the phenytoin patients with seizures, of phenytoin.

DR. LEVINE: That was 20 milligrams for 21 days.

DR. HARI SACHS: The dose of phenytoin.

CHAIRMAN BRASS: It was whatever they were taking, but they were at
steady state. So it was an individualized study.

DR. LEVINE: Yes, yes, I\'m sorry. I misheard you.

CHAIRMAN BRASS: Okay. Do you want to vote on D?

PARTICIPANT: I\'d like that.

CHAIRMAN BRASS: Okay. So what I\'d like to do is call the question for
D. Specifically are the safety concerns for the OTC marketing of
omeprazole able to be addressed solely by labeling to consumers for
short-term or chronic intermittent use?

All who feel the answer to that question is \-- and, again, we\'re
putting aside the issue of whether they\'re going to use it longer or
not \-- all those who feel the answer to that question is yes, please
raise your hand.

(Show of hands.)

CHAIRMAN BRASS: All those who feel the answer to that question is no,
please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: All those abstaining, please raise your hand.

(Show of hands.)

DR. TITUS: There are seven noes, four yeses, two abstentions and one
member absent.

CHAIRMAN BRASS: Dr. Neill.

DR. NEILL: Safety is shown. I\'m not sure whether the yes or no reflects
that, but my vote is cast in favor of safety having been demonstrated.

CHAIRMAN BRASS: That was a yes.

I think we\'re going to take A Cantilena break and \--

(Laughter.)

CHAIRMAN BRASS: \-- reconvene promptly at 3:00 p.m. because I don\'t
think we\'re going to get through for another little while, and I don\'t
want people getting up and walking out.

(Whereupon, the foregoing matter went off the record at 2:50 p.m. and
went back on the record at 3:04 p.m.)

CHAIRMAN BRASS: I\'d like to continue our deliberations, and I think
that the last question may have engendered considerable confusion, and
based on what comments I have received actually in both directions so
maybe it was worded perfectly, that people felt that there may not have
been clarity in what this question was trying to ask.

So I\'m going to try to reread the question with clarification, ask for
verification if my interpretation is correct, and if so, redo the vote,
and if everybody understood it before, the vote will come out exactly
the same and we will see.

So specifically, based on the types and frequency of adverse events
reported in the clinical trials and in the post marketing adverse events
database, are the safety concerns for the OTC marketing of omeprazole
able to be addressed solely by labeling to consumers?

Notice it does not say has the sponsor\'s label demonstrated that. It
does not say whether you have been provided a randomized controlled
trial on that point. It simply says based on your understanding of these
safety profiles and your understanding of labelology, whether or not it
is reasonable to expect that a label could be designed to insure that
short-term use could be done safely.

And if our answer comes out the same as no, I\'m going to ask the noes
for suggestions on what would be necessary to alleviate their concerns.

Is that fair, Dr. Ganley?

Is that clarified, Dr. Blewitt?

DR. BLEWITT: I would only add that that question be considered in the
context of existing products on the OTC market.

CHAIRMAN BRASS: I think the issue is not one of comparison necessarily
to other agents, but in terms of whether or not there are safety
concerns, whether the label is able to convey and does not even imply a
risk to benefit analysis having been made.

So I don\'t want to get into that kind of nuance if it\'s clear without
it.

DR. GANLEY: Eric, I just want to \--

CHAIRMAN BRASS: Dr. Ganley.

DR. GANLEY: It\'s not only the noes we\'ve mentioned, but the yes
because the question would be then if they do think there\'s some
problems here, could you address it in labeling, and their answer could
be yes or they don\'t think that these are a significant enough problem
to even worry about them.

CHAIRMAN BRASS: I understand the point exactly.

Dr. Shapiro, did you have a clarification?

DR. SHAPIRO: I\'m one of the people who apparently voted against his own
opinion a short while ago.

(Laughter.)

DR. SHAPIRO: So I wanted to be sure I understand you.

CHAIRMAN BRASS: If you vote yes, you believe the drug can be labeled
safely for OTC use, for short-term OTC use.

DR. SHAPIRO: What if I believe the adverse reactions may not even exist?

CHAIRMAN BRASS: Then you can raise both hands, but only one will be
counted.

(Laughter.)

CHAIRMAN BRASS: Okay. Are we ready to vote?

All those who believe the answer to that question is yes, please raise
your hand.

(Show of hands.)

CHAIRMAN BRASS: All those who believe the answer is no, please raise
your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(Show of hands.)

DR. TITUS: Is somebody missing? I have to see the noes again. The noes?
Thank you.

Three for no, meaning they can\'t do it in the label; nine for yes,
meaning the label can do it; and two abstentions.

CHAIRMAN BRASS: So apropos of trying to clarify this issue further, I\'d
be interested from the people who abstained or voted no what are their
major concerns and what would it take to reassure them on this issue.

Dr. Geller.

DR. GELLER: I\'ll give this a try. I am concerned about the slow
metabolizers and the fact that you didn\'t show us much data on that,
and it seems like we infer that you don\'t have much data. So, in
particular, in Asian populations in the U.S., I\'m concerned about that.

And I\'m concerned about that, and I\'m concerned about seeing \-- I\'d
like to see more data about drug-drug interactions and whether \-- I
don\'t know how you can show that such people will read the label
carefully.

I guess one of my concerns is that there are so many things going on,
albeit in a very low proportion of people, that that gives me a concern
about being able to cover all of this in the label.

CHAIRMAN BRASS: Are there particular populations or patients who you
think are at risk that would be critical to identify in the label?

DR. GELLER: Well, I think the possibility is raised somehow that Asians
may be at higher risk.

CHAIRMAN BRASS: Dr. Cantilena, did you want to comment?

DR. CANTILENA: Yeah, I think actually my concerns were quite close to
that. First of all, we only studied, I believe, 48 out of 8,000 some
odd, you know, Asians. So the issue of, you know, PM for CYP 2C19 is an
issue.

Then the other issue with the drug interactions, you know, my question,
you know, was not answered. When you show me averages without even
standard deviations, I actually can\'t interpret that. So it was not
answered. You really need to see individual data, and I think that
obviously is available. There\'s no clear reason why that\'s not shown.

And so then the question that I was faced with is I have a concern about
drug interactions, and we\'re not going to talk about the labeling now,
but I\'m not sure, and it certainly wasn\'t clear in terms of what
we\'ve seen for labeling whether or not we can handle that
appropriately. So it left me with sort of enough uncertainties not only
in the amount of sort of lack of information for the magnitude of
drug-drug interactions, particularly in the poor metabolizers, but
whether or not that could be handled by labeling.

CHAIRMAN BRASS: Yes, Dr. Steinberg.

DR. STEINBERG: I can\'t answer it with relation to drug-drug
interaction, but in terms of slow metabolizers, it\'s my understanding
of what must be going on with these rare events is that they\'re
idiosyncratic reactions. That\'s why it occurs one in a million.

And even a slow metabolizer who may have more drug on board would not be
expected to have a greater frequency of these rare reactions because
they\'re still idiosyncratic and it\'s not dose related. Just because
you have more drug floating around in your system doesn\'t mean you get
a rare side effect any more frequently.

DR. GELLER: You know what the statistician says to that. Show me the
data.

CHAIRMAN BRASS: Well, again, the suggested data was the post marketing
experience in Japan, which is the large cohort. Now, again, it clearly
has limitations.

DR. GELLER: Actually, we did see it, number one. And, number two \--

CHAIRMAN BRASS: Do you have that data?

DR. GELLER: \-- I\'m not sure of its relevance to the American
population.

CHAIRMAN BRASS: That\'s why they didn\'t show it to you.

DR. GELLER: I just don\'t know.

CHAIRMAN BRASS: Would you like to comment? Only turn on your microphone.

MS. COHEN: All right. First of all, in listening to the scientists
around the table, they can\'t even agree what goes on the label, and if
you can\'t agree, then how does anybody know what goes on the label?

Secondly, I\'m concerned about drug interaction, and more than that, I
would like to know in a long-term study about the people who took these
Prilosec and what happens later on. You didn\'t ask the symptoms. Did
you follow them? Did you come back six, seven, eight months later after
they took it? And was it masking some other kinds of symptoms?

So I\'m not satisfied with the information. I think it has to be more
long term.

CHAIRMAN BRASS: Dr. Johnson.

DR. JOHNSON: I really consider myself a pharmacokineticist by training.
So I feel fairly confident in making some of these statements.

I really don\'t see much reason for concern about drug interactions.
There\'s two kinds of drug interactions here. One is inhibition of other
drugs by omeprazole, and there are really not a lot of substrates for
CYP 2C19. They\'ve covered most of them, and albeit they are mean data,
they don\'t really appear to be important effects in that direction.

So the other concern then is effects of other drugs, which is going to
be those same diazepam, et cetera. There\'s not really good evidence of
that, which to me really leaves one category for potential drug
interactions, which is poor metabolizers so that they don\'t have CYP
2C19 activity, which means the major enzyme is CYP 3A4, and then if they
have an interacting drug on board, and again I\'m not convinced because
the poor metabolizers have fivefold elevations in their concentrations,
and it doesn\'t appear to matter. I just don\'t think we\'re going to
see drug interactions of a magnitude similar to what we see with the
genetic abnormality.

CHAIRMAN BRASS: I think there is one drug interaction that we all agree
is important, and that\'s the ketoconazole-itraconazole (phonetic), and
I think that in terms of labeling, it\'s clearly incorporated on the
label or the proposed new label, but I think it\'s an example where a
different kind of comprehension study is very important.

We have talked about asking patients with the label in front of them
whether they know if they\'re taking itraconazole or ketoconazole and
whether or not they can take this drug, and 90 percent say, \"No, I\'m
not supposed to.\"

I don\'t think we know what percentage of consumers who are taking
ketoconazole know and could identify whether or not they\'re on
ketoconazole so that even if they read the label they would know not to
take it, and I think that link for any of the drug interaction warnings
on the OTC products to my satisfaction have never been cemented.

And because we\'re talking about a from mild to moderately severe fungal
infection, I think it would be very important to know with some
confidence that a patient using one of those products was not going to
lose the efficacy of their antifungal agent by buying this
over-the-counter product.

Please.

DR. LEVINE: May I just address one question that\'s been raised in the
poor metabolizers?

What hasn\'t come across in the presentation is what happens in them,
and it\'s the concept of affinity. Omeprazole has a strong, very strong
affinity for 2C19 and a weak affinity for 3A4 so that in a poor
metabolizer who doesn\'t have 2C19 function and who undergoes \-- has
the omeprazole metabolized by 3A4, what\'s more likely is that other
drugs that go through 3A4 may inhibit the metabolism of omeprazole and
not the other way around.

That\'s obvious to some people, but may not be to others.

CHAIRMAN BRASS: Dr. Cantilena.

DR. CANTILENA: Yeah, if I could just follow that, so have you done a
study in a poor metabolizer for CYP 2C19 to look at the effect of your
compound on, say, cyclosporin?

DR. LEVINE: That has been done, and my understanding is that there is no
interaction. What I thought you were going to ask is whether that\'s
been done with diazepam, and there\'s no effect on the diazepam levels
in a poor metabolizer.

DR. CANTILENA: In the presence of omeprazole?

DR. LEVINE: In the presence of omeprazole.

DR. CANTILENA: There\'s no change in the individuals or in the mean?

DR. LEVINE: In the mean, but it\'s because of the metabolism. If you
don\'t have 2C19 function, the diazepam is going to be metabolized
normally as if the omeprazole isn\'t there because diazepam isn\'t
metabolized. You know, its dominant metabolism is 2C19.

DR. CANTILENA: Right, but, again, when you talk about the mean
information, I\'m uncomfortable with that, and I think that you need to
know that I\'m used to looking at individuals, and the outliers as, you
know, the chair, you know, suggested. So I appreciate that.

When you look at the overall effect and where you\'re obviously for your
statistical analysis, but it is important, and I think just, again, I\'m
just commenting in response to, you know, the reasons why I voted the
way I did is in that there is information out there that when you\'re
using this as an alternate pathway, it\'s possible for you to have
interactions, and there\'s a whole host of interactions that we haven\'t
explored on the 3A side.

And if, indeed, the data show that those are extremely, you know, small
and there are not outliers, then I\'m a lot more comfortable, but I
haven\'t seen that data and, you know, when I ask for it, I only hear
about averages, and so that\'s the reason I voted the way I did.

CHAIRMAN BRASS: Dr. Robinson.

DR. ROBINSON: Not to cast aspersions on any part of the table, but it
does seem to me that this all sounds very remarkably like what I heard
when I was here with omeprazole the first time. Only the difference now
is the 380 million prescriptions that we\'ve heard about, and if all of
these low metabolizers and people with other problems existed, doctors
have been thinking about drug-drug interactions. We are all focused on
that. All the other pharmaceutical companies have told us to be focused
on it. We are looking for it, and if it existed, we would have seen it.

So looking for the one or two cases that might exist under some
extremely peculiar set of circumstances doesn\'t strike me as a very
productive enterprise.

CHAIRMAN BRASS: I guess we don\'t all share your opinion of the
conscientiousness of the surveillance system.

DR. CANTILENA: And I would also say in addition to that that you\'re now
shifting into an uncontrolled environment, and that\'s really the issue.
So it isn\'t quite the same.

CHAIRMAN BRASS: Is there anybody who would like to keep Question D on
the table or shall we move on to Question E?

Dr. Ganley.

DR. GANLEY: Yeah, for the people who said yes, was there a specific
adverse event that they believe a consumer should know about?

CHAIRMAN BRASS: Well, that\'s why I mentioned the drug interaction
education as a yet vote or as something that I think it\'s important to
verify that the label can communicate effectively to that population
who\'s been prescribed ketoconazole, itraconazole, that they know not to
take it.

Dr. Sachs?

DR. HARI SACHS: I would probably add some stop use, which probably seems
obvious to people at the table, but, for example, if a rash develops and
persists, abdominal pain, nausea, vomiting, things like that.

CHAIRMAN BRASS: Dr. Neill.

DR. NEILL: There aren\'t other things that I would add to the label, but
I think that\'s different from whether they should be added to a package
insert that\'s included and whether or not information that would be
included on the label is going to influence a decision to buy or not.

For many of the drugs that are already available over the counter, I
can\'t imagine that adding agranularcytosis, some of these
extraordinarily rare things, agranularcytosis, some of which patients
aren\'t going to be able to monitor for anyway \-- that there would be
any value in doing that both because they occur so rarely; also because
they occur very rarely in comparison to the drug that\'s sitting right
next to the Prilosec on the shelf.

DR. GANLEY: Yeah, I think if you were worried about agranularcytosis,
you would label it that if you developed fevers or chills or things like
that or, you know, if you were worried about hepatitis, if your eyes got
yellow. I think that\'s how we have to label it for consumers. If you
think it\'s so rare that we don\'t have to tell \-- and believe me,
it\'s amazing what you do have to tell people sometimes, although
you\'re probably aware of that \-- but that\'s what I\'m trying to get
at.

If there was one there, a concern, that we need to incorporate in
labeling, that\'s what I was trying to address.

CHAIRMAN BRASS: Dr. Neill?

DR. NEILL: I\'m trying to imagine any circumstance where as a family
doctor I would want you telling more of my patients to call me if they
get chills or a fever.

(Laughter.)

DR. NEILL: And I can\'t.

CHAIRMAN BRASS: Moving on to Question E.

DR. GANLEY: Would you be asking them whether they\'d be taking OTC
drugs?

CHAIRMAN BRASS: Both in the context of the charts you\'re amused, but
because there will undoubtedly be discussion about more chronic use of
this product if it is made available in the OTC setting, there are a
series of issues that have been identified in Question E which we would
also like to hear discussed because of their relevance in how much we
should be concerned about that chronic use in terms of its OTC use.

So specifically, do other safety concerns affect acceptability of the
OTC marketing of omeprazole? In answering this question, please consider
the questions raised by the FDA reviewer regarding:

One, the making of serious disease;

Two, the potential for genotoxicity, tumorigenicity, and fetal and
developmental toxicity;

Three, rebound hyperacidity reported in the literature with
discontinuation of therapy;

And, four, hypergastrinemia that may be associated with the chronic or
chronic intermittent use of omeprazole.

And I would add to that list any sequelae, including alterations in
cobalamin metabolism that might be associated with chronic suppression
of the gastric environment.

Dr. Shapiro.

DR. SHAPIRO: Mr. Chairman, one of the reasons I\'m here is that I was
contacted by the Food and Drug Administration in August asking me to
look at fetal and developmental toxicity, and I was provided with three
papers and then subsequently with an unpublished paper which I reviewed
for the FDA.

These papers were not perfect by any means in terms of their
methodology, and they suffered from weaknesses, particularly in terms of
their statistical power and their informatively, but collectively they
showed no increase, no overall increase in the risk of major
malformations, although some increase could not be ruled out. They gave
no indication of any evidence to suggest delayed development or I\'m
trying to think of \-- small for deaths. There was no evidence of an
increased risk of spontaneous abortion or whether there were major
methodological problems concerning that.

And also when I reviewed the evidence of which they provided relevant
papers, this drug causes fetal loss and fetal death at high doses in
rabbits, and it causes fetal loss at even higher doses in mice. It does
not cause birth defects. So there\'s no plausible biological evidence to
suggest that there should be an increased risk of birth defects.

Now, of course, in principle any drug is capable of being a teratogen,
and sometimes the correct experimental model for observing the
teratogenic effect is the human being as with, say, thalidomide, which
was more effective in producing birth defects in human beings than in
any other species that I know of.

But beyond that general caveat, this product ought to be monitored for
birth defects as thoroughly as any other drug on the market. I could
find no special reasons to single out omeprazole, and my conclusion was
that this drug poses no greater public health hazards in terms of the
risks of birth defects than any other drug which is currently on the
over-the-counter market.

With regard to tumorigenicity, we\'ve already this morning discussed the
findings which have been found regarding the H2 blockers, which have
shown quite substantially and quite unanimously that there is initially
an increased incidence of gastric cancer which appears to be due to
misdiagnosis, people being labeled as having some indication for the
drug who, in fact, already have gastric cancer, and that as the
follow-up continues of long-term use, the relative risk declines to one
and stays there after a year or two.

And I think the unanimous opinion now is that there\'s no increase in
risk. If one extrapolates and says that suppression of acid secretion
does not appear to increase the risk of gastric cancer, that presumably
would apply to omeprazole, but it could also be proven.

In addition, there do exist databases that if there was some hypothesis
concerning an increased risk of tumors, those databases could be
examined and one could assess whether there\'s an increased risk, as
well.

And also if there were some specific birth defect which was alleged to
be caused by omeprazole as opposed to just an increase in the risk of
all birth defects, once that hypothesis exists and appears to be
reasonably based, that, too, could be explored in existing databases.

CHAIRMAN BRASS: Dr. Cohen.

DR. COHEN: I don\'t have great concerns about any of the questions
raised here in E, but now at almost 3:30 in the afternoon, we\'ve talked
about a dose of a drug of ten milligrams, and we\'ve talked about a
whole bunch of peripheral effects, but there\'s been no discussion of
what the effects of ten milligram is on the esophagus, which is the
organ that we\'re treating, and I would like to know if ten milligrams
of omeprazole taken for two weeks or longer has any healing effect on
the esophagus. Does it heal partially, does it heal completely, does it
lead to more Barrett\'s epithelium, or does it protect against
Barrett\'s epithelium?

And that to me is the critical issue. I think these peripheral issues
are obviously important, but I think the critical issue is the
esophagus.

CHAIRMAN BRASS: I\'m going to hold that question because we can stay
focused on E and hopefully it will come up in some of the final
efficacy.

Dr. Elashoff.

DR. ELASHOFF: Yes. With respect to fetal problems, I\'m always
especially concerned with a drug that sounds like it\'s good if your
stomach is not feeling good in pregnancy because I think people are more
likely to take this kind of drug in pregnancy because of the common
stomach problems.

The issue of whether the data are reassuring or not has to do very, very
strongly with sample size because unless you study 1,000 people or rats
or whatever it is, you\'re not very likely to see events that occur one
in 1,000 or two in 1,000.

So I personally am not reassured unless studies have been very, very
large in this area.

CHAIRMAN BRASS: Dr. Shapiro, I assume those studies you referred to are
registry type studies, combined exposure in them?

DR. SHAPIRO: One of them was from the GERD database in England. That\'s
an automated database. The numbers were small nevertheless.

Another one was from the combination of data from Canada and Italy. This
was more ad hoc.

But just to answer your comment, I think it\'s inconceivable that a
prospect of study could ever be large enough to answer these questions.

There was earlier talk about case cohort studies and about nested cohort
studies. A nested case control study is one in which the cases and
controls are drawn from a follow-up study and one just samples a
proportion of the non-cases, a small proportion.

But they could never be large enough. One has to use case control
methods.

There are case control data in existence in this country concerning
omeprazole. The prevalence of omeprazole exposure is high enough that if
there is any specific birth defect, let\'s say, an encephaly (phonetic)
or spina bifida or cleft anomalies or phocomelia that could be evaluated
quite rapidly and quite efficiently in existing databases or that could
be evaluated pretty soon in case control studies.

DR. ELASHOFF: But apparently has not been, according to your comments.

DR. SHAPIRO: You really need a prior hypothesis first. I mean there is a
whole array of 10,000 different birth defects, and you can\'t go just
fishing for one of them because if you fish you\'ll find something. Just
on ordinary probability theory, you need a plausible hypothesis, and as
far as I\'m aware none exist.

CHAIRMAN BRASS: Dr. Uden.

DR. UDEN: Given your comments about the risk in pregnancy, right now as
the NDA label has on it, the one that has been submitted, if pregnant or
breast feeding, ask a health professional before use. then it says,
\"May cause damage to your unborn or nursing child.\"

Those two, it would seem to me that that first statement shouldn\'t go
along with the second statement, that it would be \"do not use if you
are pregnant.\"

DR. SHAPIRO: Yeah, there\'s been reference to the one. So this is
another reference. No one today would dare market a drug without a
warning to pregnant women even if there\'s no evidence that it\'s
dangerous for pregnant women.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: I will make some comments. First, comparing H2 blockers and
PPI, I think there is a great difference between these agents, although
they both inhibit acid secretion. It\'s a question of efficacy and also
a question of tolerance. You have a tolerance of an H2 blockers that in
a way is protected for long-term use. You have not the same degree of
acid inhibition. That was my first comment.

Then I will comment on what this danger is, hypergastrinemia. I think
that it was published in the late \'80s by a Finnish group concerning
the occurrence of ECL tumors in patients with pernicious anemia, and it
was not so that patients having higher gastrin values than 500 picamolar
had more frequent \-- higher frequency of ECL tumors. They occurred
already at 100 picamolar. It was a question of the degree of
hypergastrinemia after a certain level and the duration of the
hypergastrinemia.

Then I would say to Dr. Sachs again that in the eight \--

CHAIRMAN BRASS: I called on you because he wasn\'t in the room.

(Laughter.)

DR. UDEN: Okay. It was a study in the late \'80s showing that loxtadin
(phonetic), a so-called unsurmountable H2 blocker, induced ECL tumors in
mouse. So it is not correct that you don\'t see such tumors during
hypergastrinemia in rat species.

And then my last comment will be on rebound acid hypersecretion because
I was the first to describe it. It may be rather high acid
hypersecretion, and one of the patients had also an increase in acid
secretion from 40 to nearly 70 micromolar mL, which is values that you
only see in patients with Zollinger-Ellison Syndrome.

CHAIRMAN BRASS: I\'m sorry. Are you talking about one patients from
these studies or one patient from your previous experience?

DR. UDEN: I have described this patient in my paper.

And the duration of acid hypersecretion, it seems we have done a study,
but we haven\'t published it. It lasts for about two months. It is
declining from two weeks to two months.

CHAIRMAN BRASS: Dr. Steinberg.

DR. STEINBERG: My only concern as a gastroenterologist is the issues of
the masking of disease, and that is Barrett\'s esophagus, and clearly
the data have shown that there are going to be a certain percentage of
these patients who get efficacy who will stay on this drug and not
according to the labeling.

And so the question I have is to the esophagologist. Perhaps Dr. Castell
can address this. What is the danger if a large number of users of ten
milligrams of Prilosec over a long period of time; what is the danger,
the public health danger of not diagnosing a certain small number of
Barrett\'s patients who might then not be found to have dysplasia, and
so forth and so on there? Do you have any feeling for this?

DR. CASTELL: Thank you, Bill.

As you know, this is from my approach is the issue about masking as
Barrett\'s and whether we\'ll miss something, and it\'s as you know a
highly controversial area. There are some people who say that we
shouldn\'t even bother to look for it because it doesn\'t make any
difference anyway in what you find.

We know that it\'s out there. We know that we miss it in people that
don\'t get in for endoscopy, and you and I would like to endoscope
everybody that has any heartburn because we think it\'s important to
find it, and that\'s why I said earlier I would hope that is a drug like
this were available over the counter that we could label it in such a
way that it would hopefully get more people that we\'re missing now into
the gastroenterologist. I don\'t know if that will work.

Now, I haven\'t answered your question yet. Whether it will make a
difference or not, I don\'t know. Ten milligrams doesn\'t do much in
terms of acid control, but it does a little more probably than the
already available over-the-counter drugs.

But as I showed you from that Duke study, many patients with Barrett\'s
have milder symptoms than patients with erosive disease. We\'re already
missing them with the available over-the-counter medications.

CHAIRMAN BRASS: Well, I think this also makes Dr. Cohen\'s question now
very germane because, in fact, if you\'re exposing these patients at ten
milligrams and they either heal if they have an erosive process or have
the same treatment that they would get if they went to a
gastroenterologist, you\'re masking nothing.

The question is whether there is an in between situation.

DR. STEINBERG: The question I have, Don, though is: would more of them
come in to see a gastroenterologist or would fewer because a certain
percentage will go on to take this medicine? Over 50 percent did not
follow the labeling advice and won\'t ever come in because now they have
a drug to help them.

DR. CASTELL: Yeah, and again, obviously I don\'t know the answer to that
because I don\'t know what I don\'t know, and only time would tell us
that.

I think, first of all, I want to acknowledge the agency for even being
willing to discuss this question of a drug like this for treating GERD,
if you will, because that\'s what we\'re talking about here, and the
sponsors for bringing the question to the agency.

I would hope that we could find a way if the drug is going to be
approved to make the labeling effective so that it would, in fact,
result in what I think should happen: more patients coming for
evaluation rather than less.

DR. LEVINE: Could I just introduce Dr. Brian Reed (phonetic), who is
another Barrett\'s esophagus expert?

DR. REED: Hi. I\'m Brian Reed from the Fred Hutchinson Cancer Center.

I would like to suggest that the situation would get better. We would
see more patients with Barrett\'s esophagus than we do under the
existing circumstances. Why do I say that? Because the published data
now say we only see five percent of the patients with Barrett\'s
esophagus who are out there who can be detected by autopsy studies.

We only see at most five percent of curable cancers. They usually come
in with incurable cancers, and so there\'s a huge 95 percent that
aren\'t coming in, and I think that an appropriate labeling could
increase that.

So relative to what we\'re doing now, there\'s very little down side
risk and a lot of potential with good labeling.

DR. STEINBERG: But people aren\'t following the labeling. That\'s what
the study shows so far. A greater percentage of those that are using it
to prevent illness are not following the labeling.

DR. REED: Are you referring to these studies here?

DR. STEINBERG: Yeah, the study that was shown here.

DR. REED: Just two comments. Even if the percentage were what it is and
they did follow the labeling, that would be an enormous increase over
five percent, and I think people are talking about revising the
labeling, but I\'m not involved in those discussions.

CHAIRMAN BRASS: Well, maybe I can pose the issue a slightly different
way as a standard of care issue. Let\'s say a primary care physician or
gastroenterologist had a patient with heartburn that was suppressed with
a pump inhibitor. When they went off the pump inhibitor they had
recurrence. Put them back on the pump inhibitor, they\'re fine.

Would that patient require any additional therapy other than
continuation of the pump inhibitor?

DR. CASTELL: Are you suggesting after they\'ve been seen by a physician?

CHAIRMAN BRASS: Yes, or a physician has seen them and says, \"Here\'s
your piece of paper. Go take your\" \-- you know, if it makes it go
away, make it go away.

So if the patient feels better on a pump inhibitor, clearly doesn\'t
feel good when they\'re not on a pump inhibitor; so they have some
disease, whatever label you want to call it. But if they are
symptomatically relieved by a pump inhibitor, is that fine? Would a
physician simply continue the chronic use of the pump inhibitor, or does
the standard of care require further diagnostic evaluation of that
patient?

Because to me that\'s the central question. If there\'s chronic use in
the out-patient setting, you get better and you recapitulate what\'s
seen by a physician. If you\'re seen by a physician, no problem. And if
you\'re not relieved, then you\'ll go see the physician.

My concern is if we\'re denied standard of care by giving symptomatic
relief or not.

Dr. Cohen.

DR. COHEN: And that\'s really one of the important issues, and I don\'t
think you can answer that question at this point without knowing the
effect of the ten milligram dose, which is very efficacious. It\'s very
good in preventing the symptom of heartburn at that dose for the
two-week period.

But what I\'m asking is what is the effect on the mucosa in the 30 to 40
percent of patients that Dr. Castell said may have erosions, and that
would help us know what the standard of care is, and that\'s an easy
study to do.

CHAIRMAN BRASS: But you wouldn\'t know that as a practitioner unless you
did an endoscopy. If the patient felt better on a trial of pump
inhibitor regardless of dose \--

DR. COHEN: But you would know if at that dose that\'s a healing dose and
you can leave the patient on, or you would know at that dose you\'re
getting continued chronic erosive disease with only relief of symptoms,
and you can have a discrepancy or a separation of symptom relief and
healing, and that\'s the issue.

CHAIRMAN BRASS: We saw some data at 20 that showed a healing rate, but
it wasn\'t 100 percent.

DR. COHEN: No, 20 heals and maintains healing, is excellent in that
effect, and it\'s used that way. But the question is does ten heal and
can ten maintain healing or does the physician have to do something
different at the end of the two weeks or four weeks.

CHAIRMAN BRASS: Does sponsor have data from your earlier development
program for healing intent?

DR. LEVINE: Based on the development program, we did not test ten
milligrams in erosive esophagitis.

DR. CASTELL: Dr. Brass, can I give you another perspective on what I
think you were asking?

From my point of view, if, in fact, this were to occur and it brought
the patients to the gastroenterologist, what did you call us, informed
intermediaries or something like that? Thank you very much. I didn\'t
know that.

If it brought the patient to the gastroenterologist and an endoscopy was
performed that ruled out Barrett\'s \-- and, by the way, we\'re very
close to being able to do that with a skinny endoscope through the nose,
a nasogastric endoscope \-- and we ruled out Barrett\'s, then I would be
absolutely comfortable telling the patient if that dose of the drug ws
working for your symptoms, you can stay with it.

CHAIRMAN BRASS: But that seems to imply that the standard of care
requires a physician evaluation to make that decision. Symptom relief is
not adequate to meet the standard of clinical care.

Yes?

DR. ROBINSON: As a person who knows what physicians are doing in the
community because I spend my life teaching them and speaking to them, I
can tell you that although perhaps a lot of gastroenterologists wish
that physicians in the community were sending all of their patients who
don\'t do well or who do well on therapy and then relapse to have
endoscopy, that, in fact, is not the case.

In fact, what doctors do is some of them send their patients for
endoscopy, and I would suspect the great majority do not. The great
majority of doctors continue therapy that is symptomatically effective,
whatever therapy it may be, and never investigate the patients unless
there is some alarm symptom.

So I don\'t think we\'re going to be changing that by adding another
drug which also blocks acid secretion.

DR. COHEN: But, Dr. Robinson, they\'re using a dose of the drug that
heals the mucosa. So they may use it. Empirically it\'s still healing
the tissue.

DR. ROBINSON: Well, far be it from me to tell Dr. Cohen anything about
the esophagus, who, after all, wrote the book, but I would say that I at
least am not so sure I care whether patients are healed or not because I
know of no data that shows that people who have tiny, little erosions
that remain unhealed have any untoward consequences.

That is, they don\'t seem to develop cancer, Barrett\'s or anything
else, and in fact, the data I\'m aware of suggest \-- I think Don could
address this \-- that people who feel well, who are symptomatic over the
long haul as a group do very well, and that people who are not
controlled symptomatically are the ones who do not do well.

CHAIRMAN BRASS: Dr. Gilliam.

DR. GILLIAM: I guess my concern is just adding another class of drugs
for heartburn that\'s going to be available over the counter. You know,
from a primary care standpoint I would hate for somebody that\'s tried
Maalox and then tried another antacid and then has tried an H2 receptor
blocker to have another choice that\'s available over the counter that
might delay them coming in and getting scoped or talking with someone
else about it.

And then to follow up on what Dr. Brass said about having somebody
that\'s on Prilosec and then they go off and then they\'re put back on
it and they get relief, does that necessarily show that they don\'t have
H. pylori or something else that\'s going on that we should be treating?

CHAIRMAN BRASS: Dr. Uden?

DR. UDEN: If you want to finish this discussion, mine is going to be
about rebound hyperacidity.

CHAIRMAN BRASS: Dr. Steinberg.

DR. STEINBERG: Back to your question, I don\'t think there is a standard
of care. It really depends on the referring doc. Some internists and
family physicians are very aggressive about sending to the
gastroenterologist, who is the consultant, and the gastroenterologist
winds up taking a look down, and some are not. And so I don\'t think
there\'s a standard of care, nor should there be a standard of care
because we don\'t have the data to even decide who we should scope, when
we should scope.

We\'re worried about Barrett\'s, but having scoped a lot of people over
many years, I have yet to pick up, except for the initial endoscopy when
they present with dysphasia, somebody who gets into trouble. You have to
read the big studies to show a few cases.

CHAIRMAN BRASS: Well, at an internist, that\'s certainly been my
impression of the literature, that the justification for a screen
endoscopy particularly in young people is just really low.

DR. COHEN: I want to clarify my point. I am not as concerned as Dr.
Gilliam about patients having a ten milligram dose to take. All I would
like to know is if they\'re taking it what the outcome is going to be,
and I think the sponsor \-- if I knew that from the sponsor, it would be
reassuring, and it would be helpful, but I\'m not concerned about giving
somebody that dose to take if I knew what was going on with the mucosa.

CHAIRMAN BRASS: Okay. Dr. Uden.

DR. UDEN: I have a question about the clinical picture of rebound
hyperacidity. Let\'s say somebody takes either ten or 20 milligrams of
omeprazole for 25 days that I saw in the study and they discontinue it.
If they have rebound hyperacidity, does that present then as heartburn,
and is that then a reason for them to use more omeprazole? How does
rebound hyperacidity present clinically?

DR. LEVINE: May I address that? We have data from our studies if I could
share that with you.

If I could please have slide 40. Could I have the mic on, please? Can
you hear me?

Okay. This is my back-up 40. That\'s the wrong slide set.

What I want to be able to present is just what the baseline heartburn
severity was. As part of the studies where patients had the option to
dose on multiple days, what we then did at the end was do a placebo
run-out, if you will, a two-week follow-up to assess what happened to
their symptoms.

The existing literature, just for background, looks exclusively at acid
secretion with no effort to correlate to symptoms. Our studies have the
weakness because we do not have pH data to look at acid hyper secretion,
but we do have the ability to look at that. We may not be able to get
the slide.

But the point that I wanted to make was that at baseline we measured
heartburn on a four grade scale. About 30 percent of the individuals at
baseline before treatment had severe. So there would be no way to assess
them at run-out as to whether or not they got worse.

So about two-thirds of the patients had mild or moderate heartburn, and
what we did evaluate ‑- I think we can just close the slides down,
please \-- what we were able to do is look at across the 20 milligram,
ten milligram, and placebo group, look to see whether or not there was
any evidence within the group for worse heartburn than baseline after
treatment. We could not demonstrate that.

What we also looked at was the number of episodes that they had, again,
following treatment withdrawal versus baseline, and again, across groups
we could not demonstrate any difference.

DR. UDEN: But logically rebound hyperacidity does occur, correct? And
\-- it does not?

CHAIRMAN BRASS: Microphone, microphone.

DR. LEVINE: I can speak to that as well. I won\'t try with another
slide, but the data that we have from the literature is that at doses of
20 milligrams one cannot measure that. So it\'s usually you\'re getting
to at least 40 milligrams for sustained periods of time when you
actually elicit that phenomenon.

DR. UDEN: Thank you.

DR. STEINBERG: How long does it last when you do get rebound? Is that
just a very transient phenomenon lasting a day or two or is that
something that persists?

DR. LEVINE: You know, I think it\'s a field that, first of all, you can
argue whether or not additional work should be done because it\'s of
uncertain clinical relevance, but the available data I would say are
limited. So we don\'t know that.

In one of the studies where we looked at acid hypersecretion following
two years of very, very high doses of omeprazole, 80 milligrams a day
for a year followed by 40 milligrams, there was a follow-up done
approximately three months after the conclusion, and the acid
hypersecretion had normalized, which had been demonstrated within the
first week, but we don\'t know when it stopped.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: As I said, it lasts up to two months, and then a question of
dose. It is a question of degree of acid inhibition and
hypergastrinemia. So if you use a low dose, fewer patients will have
rebound acid hypersecretion, and it\'s a question of duration of the
treatment. The shorter the time the less the rebound hypersecretion.

But if you examine enough patients, you will see it also at the short
periods, I think.

CHAIRMAN BRASS: I\'m going \--

DR. COHEN: I would just comment that a 20 percent acid inhibition for
ten days, you\'re not going to get very much acid rebound. I just think
it\'s a non-event.

CHAIRMAN BRASS: I think what I\'d like to do is now call the question,
please.

DR. DOUGLAS: As a non-voting member, I guess my job is to be a devil\'s
advocate, and I\'d just like to be a little devilish if you don\'t mind.

I don\'t think there\'s been enough discussion about the potential for
genotoxicity and tumorigenicity. The question has been raised by the
FDA, and as a genetic toxicologist, I look at the animal toxicology data
that was given in this package from FDA. In fact, it\'s not data. It\'s
just a description of the data, and it raises a number of questions in
my mind.

And I presume this data was presented in support of the original request
for application for prescription use by the sponsor, and I think had it
been today rather than whenever it was, ten or 12 years ago, that there
would be a much better data package and there would be fewer questions
left in my mind.

And I think despite the fact that there has been millions of
prescriptions, it\'s always true that if you\'re not looking for the
right thing, absence of evidence is not evidence of absence.

Now, this chemical causes most bone marrow micronucleus and chromosomal
aberrations, and it\'s been shown through a survey of the literature in
a published paper that chemicals that cause that effect have a 75
percent chance of causing germ cell effects, causing domino lethal
effects, for example.

Now, there was a study, a reproductive toxicity study that was cited
here where male and female rats were treated at 5.6 to 60 times the
human dose. I don\'t know exactly what that \-- whether it\'s 20 or ten
or 40. So these animals are treated prior to conception and then post
conception and on into the next generation.

But there was no effects in the treated animals, but in their offspring
it produced fetal toxicity, postnatal developmental toxicity as
evidenced by dose related increase in post implantation losses,
decreases in the number of viable fetuses, decreases in the number of
viable pups, decreases in survival of pups, and so on, and in a further
study, postnatal behavioral development effects as well.

So the fact that there is limited evidence here of some sort of effect,
you can\'t specify in that type of a study, in a one generation
reproductive toxicity study. You can\'t specify exactly what the effects
were due to, and I didn\'t have the benefit of seeing the data that was
given to Dr. Shapiro. So I can\'t really comment further.

But taken together the fact that we have a bone marrow micronucleus
study which suggests, but only suggests, that there could be germ cell
effects, and there\'s effects in this reproductive study that have been
shown. I would think I would be concerned about unrecognized pregnancy
loss. So not just if you\'re pregnant don\'t take it, but pregnancies
that you don\'t know you\'re pregnant but you lose the conception.

CHAIRMAN BRASS: Dr. Shapiro, would you like to provide some context or
alternative?

DR. SHAPIRO: Yes. The experimental data that have been referred to were
extraordinary high doses in the rat and doses which were many multiples
of the human dose in the rabbit.

The sponsor argued, I think, correctly that there was a mechanistic
explanation for the increased fetal loss, which was that these animals
at these doses became profoundly sick, didn\'t eat properly, and were
unhealthy animals, and unhealthy animals have increased fetal loss.

That explanation struck me as plausible, and they may want to add to it.

The epidemiological evidence, as I\'ve said, is inconclusive, but gives
no evidence of an increase of an increased risk. If one is talking
specifically about fetal loss, the issues are spontaneous abortion,
inhibited development or premature birth or stillbirth.

For spontaneous abortion, at least 50 percent of spontaneous abortions
have major chromosomal anomalies, well over 50 percent, which is
probably why they abort. This means that if one wants to study this
issue, it would call for an ad hoc case control study of women who abort
and the controls, and such a study could be done, but it\'s up to this
panel to decide whether the evidence is persuasive to warrant such a
recommendation.

For the other outcomes, I don\'t think that the animal data provides
sufficient grounds to recommend that studies be done in human beings at
the moment, but others might disagree with me.

On the issue of birth defects and germ cell effects, it would be
necessary to mount case control studies concerning the specific defects
that are alleged to be placed at increased risk by this drug.

CHAIRMAN BRASS: If I could just let the sponsor \-- if there\'s any
information I could provide and then I\'ll come back to that.

DR. LEVINE: Let me introduce Dr. Lewis Kinter, who\'s our preclinical
scientist lead.

DR. KINTER: First, we would completely concur that the results in this
repro. tox. battery that has been conducted, a very extensive repro.
tox. battery at very high multiples of dose and exposure in both rabbits
and rats, there is only evidence of increased abortion, and these
developmental effects that have been alluded to only occur in the
presence of significant and substantial maternal toxicity.

This is a bioassay system, and unfortunately because it\'s a bioassay
system, when you introduce the confounding variables of significant
maternal toxicity, it\'s now simply not possible to separate the two,
and in this particular case we know that these effects of material
toxicity with the loss in body weight and the decrease in food
consumption are independently controlled to produce these effects.

Regarding the genotoxicity issue, again, this is an issue \-- probably
omeprazole is one of the most heavily studied compounds in genotoxicity
tests that exist today, other than some of the positive controls that
are used in Ames tests and things.

And I\'d like to ask Dr. Dave Brusick \--

CHAIRMAN BRASS: I\'d like to not unless you think it\'s absolutely
critical.

DR. KINTER: I\'ll leave it to the committee.

CHAIRMAN BRASS: Would the FDA like to have some additional input?

DR. CHOUDARY: I\'m Jaspi Choudary, supervisory pharmacologist for the
Division of Gastrointestinal and Coagulation Drugs.

Dr. DeGeorge, before he left for another meeting, asked me to clarify on
genotoxicity and as well as repro. toxicity and the reference that is
made by Dr. George Sachs about the high doses in the carcinogenicity
studies.

Let\'s first focus on the genotoxicity data. The genotoxicity data
findings that we referred to in the Advisory Committee FDA package are
referred to the sponsor studies. One is the most micronucleus test [in
vivo]{.underline}. The second one is most bone marrow cell chromosal
aberration test [in vivo]{.underline}, and these data have been
presented in 1989 Advisory Committee meeting, and this is part of the
labeling.

And recent data from the sponsor\'s tests shows [in vitro]{.underline}
human lymphocyte chromosomal aberration tests were also positive. Now,
that is the extent of the data from the sponsor.

Now, there are negative tests conducted by the sponsor. The Ames test is
negative. Most lymphoma cell farbore (phonetic) mutation essay is
negative. [In vivo]{.underline} rat liver DNA damage also is negative.

So the leveling (phonetic) affects that. One doesn\'t cancel the other.
That has to be kept in mind, and one also has to keep in mind the doses
selected for the animal toxicology studies, particularly the Product II
toxicology studies, carcinogenicity studies, they may seemingly be very
high when you compare to the human dose, but you have to realize these
doses are meant to detect certain things. They\'re surrogates for
certain aspects of the drug effects, and those are done not at overtly
toxic doses. That\'s what you have to keep in mind.

You also have to keep in mind what are the exposure ratios when compared
to the exposure in human, and you also have to take into account what
are the dose \-- how do the doses compare When putting it on surface
area basis, which are more closely related to the exposure ratios?

Now, in that context, let me point out something.

CHAIRMAN BRASS: Very quickly, please.

DR. CHOUDARY: Surely. Published information does show \-- published,
Martelli, [et al.]{.underline}, in [Toxicology]{.underline}, 1998, that
omeprazole produces micronuclei [in vitro]{.underline}, in [in
vitro]{.underline} tests of rat and human hepatocyte cell cultures, and
[in vitro]{.underline} human lymphoblastoid TK cell line cultures. This
is published in 1998. It is more recent.

Now, the other information that is available, which Dr. Avigan also
pointed out in the slide, which is not conformed later. That is, the
sister (unintelligible) in human lymphocytes of volunteers who are
treated with the drug, that was not conformed by anybody else. Now,
those are the tests.

As far as the two toxicology studies that are concerned, if there was a
dominant lethal effect, that would have been detected in the assay if
there was an autopsy at the earlier part of the pregnancy, which wasn\'t
the case.

The things we have observed, that is the fetal loss at embryonic loss, a
fetal toxicity in terms of weight loss, fetal weight, retardation of
body weight, these are all detected later on during the gestation.

Now, for specifically diagnosing or detecting any preliminary indication
for dominant level effects, we need to have the autopsy much earlier in
gestation, say, for example, day 13 or day nine or something like that.
That was not done in those cases.

The other thing is leveling indicates, clearly states, and we also
clearly stated the drug did not show any anatomical teratological
effects.

DR. DOUGLAS: That\'s correct.

CHAIRMAN BRASS: Thank you.

DR. CHOUDARY: No (unintelligible) \--

CHAIRMAN BRASS: Right.

DR. CHOUDARY: But, however \--

CHAIRMAN BRASS: I\'m sorry. You have exactly 30 second.

DR. CHOUDARY: Sir, there is one \-- one piece \--

CHAIRMAN BRASS: Thirty seconds.

DR. CHOUDARY: \-- of evidence that (unintelligible) recently. There is
some effect on the behavioral development of the offspring of the
animals treated. This is most recent.

As far as the carcinogenicity \-- oh, okay. Thank you very much for the
opportunity.

(Laughter.)

CHAIRMAN BRASS: Dr. Douglas, one sentence.

DR. DOUGLAS: Thank you.

What particularly raised my concern was the sister common exchange study
on unexposed volunteers because that indicates that there is a form of
genotoxicity in people who are exposed apparently at \-- I don\'t know.
I don\'t know the study \-- at therapeutic doses. So it is a tie-in to
the animal data, although it\'s not the same endpoint. Sister common
exchange is not mutation. It\'s a reciprocal event normally, but it
indicates that there is effects on the DNA.

CHAIRMAN BRASS: Thank you.

And I don\'t want to trivialize this issue, but from our perspective an
important consideration is that it\'s not an OTC specific issue; that
if, in fact, this drug has a major problem, it\'s in all formulations,
and if it\'s identified, if anything, it\'s going to be less of a
concern because of the dose issues in the OTC.

So if it is a concern and these issues need to be addressed, it really
applies independent of its OTC status.

Okay. So I\'d like to call Question E, and without going through the
entire thing again, I want to simply phrase it: are there other safety
concerns that affect the acceptability of the OTC marketing of
omeprazole from the list of things that we discussed and are listed
below?

If the answer is yes, it means you do have safety concerns. If the
answer is no, it means you do not. Yes, no, abstain.

DR. STEINBERG: Can I ask a question? Does that mean that it can be
addressed in the labeling?

CHAIRMAN BRASS: Yes.

DR. STEINBERG: Or it needs to be addressed if you answer yes?

CHAIRMAN BRASS: Yes, and I think several of those points came up in the
discussion. So hopefully the FDA will have captured that information.

All who would like to vote, yes, there are safety concerns, please raise
your hand.

(Show of hands.)

CHAIRMAN BRASS: All those who feel there are not safety concerns, please
raise your hand.

DR. SHAPIRO: Mr. Chairman, could I raise a point of order?

CHAIRMAN BRASS: Let\'s finish the vote and then we\'ll come back to it.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Yes, Dr. Shapiro.

DR. SHAPIRO: Well, this has to do with my point of order. There are too
many items here to answer this. I don\'t feel competent, for example, to
judge on issues such as genotoxicity or rebound hyperacidity. So I would
abstain on that.

But I do feel competent to judge on some of these items.

CHAIRMAN BRASS: And that\'s reflected in the discussion, but we have to
have a yes/no vote.

Now, because there were so many expressions of concern \--

DR. DeLAP: I was a little bit confused about what you were voting on
frankly. I think the last question just before the vote was whether you
could vote yes and still think that there were concerns that could be
managed in labeling, which I think might have been what some of the
people were voting on.

CHAIRMAN BRASS: I\'m sorry. If you think the concerns could be addressed
in the labeling, you should vote no.

PARTICIPANT: Well, that\'s a different question.

CHAIRMAN BRASS: I apologize. I apologize. I apologize. Okay. We will go
again.

A yes vote means that there are substantial safety concerns that affect
the OTC marketing regardless of any labeling that would be put in place.
No means that any concerns you have could be addressed in the label. I
apologize. That\'s what I meant to say.

Okay. Here we go again. Yes, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: No, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstain, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Okay. We have to do it again. Yes, please raise your
hand.

(Show of hands.)

CHAIRMAN BRASS: No, raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstain raise your hand.

(Show of hands.)

DR. TITUS: Okay. There are eight noes, which mean \-- eight noes mean?

CHAIRMAN BRASS: That there are not safety concerns.

DR. TITUS: Five yeses, which mean there are safety concerns, and one
abstention.

CHAIRMAN BRASS: Okay. I propose we skip F as already discussed in the
earlier discussions unless somebody has an urgent point about drug-drug
interactions.

Moving on to G, and I think several of these points have already been
discussed actually, in the actual use studies approximately 65 percent
of the subset of subjects using the product only for the prevention of
heartburn exceeded the ten consecutive day limit for dosing recommended
on the label. Note 19 to 22 percent of consumers using omeprazole for
both symptoms and prevention similarly exceeded the ten consecutive day
limit for dosing recommended on the label.

Do these results suggest that omeprazole will likely be used by
consumers on a chronic basis for conditions other than episodic
heartburn? For example, will they use it for GERD?

Is the treatment of GERD an acceptable OTC indication?

I would submit we\'ve discussed this a great deal directly and
indirectly, and I would put on the table that it is extremely likely
that there will be chronic use of this product, and that the issue of
whether GERD is an acceptable OTC indication, I think we have to address
specifically in the context of, as I\'ve already indicated my bias is,
it\'s a standard of care issue, and that if a patient with GERD got
symptomatic relief and continued taking this product chronically, would
there be any down side in terms of their health?

Dr. Shuster?

DR. SHUSTER: One of the things that I take great pleasure in teaching
house staff and Fellows is that the patient is not always wrong, and I
think in this instance the patient was right, always right because to me
it\'s a nonissue.

You cannot prevent chronic problems by giving ten days or two weeks of
treatment. The only thing you prevent is the symptoms during that ten
days or two weeks that you\'re treating. So that\'s not prevention.
That\'s treatment, and it seems to me that prevention requires long-term
treatment, and that we should not criticize patients for doing that. We
should applaud them. They\'re doing the right thing, and we would do the
same thing.

And so it seems to me it should be of absolutely no concern if patients
do treat themselves for longer periods than the indicated ten days or
two weeks.

CHAIRMAN BRASS: Ms. Cohen.

MS. COHEN: How do you know it doesn\'t have something else wrong with
them? I mean I go to a doctor because I don\'t know, and we have 50
million Americans who don\'t. So if I continue to treat myself, how do I
know I\'m not masking something more serious?

DR. SHUSTER: Well, the labeling states that they are, first of all, to
see a doctor if they are not treated successfully. If they\'re treating
cancer, they\'re not going to get relief of their symptoms.

MS. COHEN: But the real world is what consumers actually do, and that\'s
what we have to deal with.

CHAIRMAN BRASS: I think Dr. Shuster is completing his \-- I mean,
continue because I think your point is the critical one.

DR. SHUSTER: Well, I think that there\'s no way we can control what
people do with antacids and with H2 receptor blockers, and so forth.
People are going to do what they feel is appropriate, and I think that
treating the symptoms successfully requires further treatment, and in
essence that\'s what the doctor does, too.

MS. COHEN: You know what worries me is direct advertising to consumers
because consumers all of a sudden don\'t think it through anymore. They
see the advertising, and that\'s good enough for them, and they\'ve
given up thinking.

We have to get consumers to think again about what they\'re taking and
what they\'re doing. We have to do better education than that.

DR. SHUSTER: We have to educate patients as to \-- and incidently, I
would take issue with the term \"consumers.\" I\'ve always objected to
this. I think it\'s a pernicious term. They are patients. We are not
providers. We are doctors. The relationship is a doctor-patient
relationship. It\'s not a supermarket relationship.

DR. SCHACHTEL: Just one quick remark that might help amplify this. In
the 488 patients who were in the actual use study, approximately half of
them, in fact, had been seeing a physician for over the past year with
whom they had discussed their heartburn.

Those people who had been seeing a doctor for their heartburn, 67
percent of them went beyond ten days. On the other hand, the other half,
over 240 patients who had never seen a doctor for their heartburn, the
compliance was 88 percent.

So the people, in fact, who are going beyond the ten days are already
under the care of a physician, and half of those have been prescribed
Prilosec.

CHAIRMAN BRASS: Dr. Blewitt? Microphone.

DR. BLEWITT: I\'m sorry. One has to do with current patterns of use. In
other words, what\'s happening today in the OTC marketplace? How are
people treating themselves? How much chronic treatment is going on?

And related to that, which I really think ought to come out of this
discussion, is how one defines GERD, you know, and I think what I\'ve
heard is it sounds like it depends upon whether you\'re a lumper or a
splitter.

I\'ve heard that GERD is a spectrum that goes from symptomatic up to
significant disease, and then I\'ve heard that there\'s a stigma of GERD
that this is a serious disease problem.

Now, if it\'s a spectrum of disease, you know, symptoms or is it
something that\'s \--

CHAIRMAN BRASS: Well, here\'s how I\'ve thought about it in the context
of today\'s discussion: that what will happen is patients with chronic
heartburn will undergo chronic treatment, self-medication. A subset of
those will meet somebody\'s definition of GERD, and depending on whose
definition it is, a different percentage of them will meeting it.

And my only concern is that if those patients, whatever the definition,
continue to self-medicate and get symptomatic relief, are they exposing
themselves to any risk or harm from not being further diagnosed?

Dr. Johnson.

DR. JOHNSON: I guess I\'m getting the sense from the gastroenterologist
that you don\'t really have concerns, and that means a lot to me because
I\'m not a gastroenterologist, and so I guess I\'d like to make sure
that the sense I\'m getting is accurate and hear if there are any people
that have major concerns about basically out-patient self-care of GERD.

CHAIRMAN BRASS: Dr. Waldum.

DR. WALDUM: I\'m a gastroenterologist, and we, too, normally do
endoscopy of all patients. We never treat patients for a long time
without endoscopy.

CHAIRMAN BRASS: Could you quote data to support that practice?

DR. WALDUM: What?

CHAIRMAN BRASS: Could you quote outcomes data to support that practice?

DR. WALDUM: We feel that if you are going to use a drug for a long time,
it\'s important for the doctor and for the patient to know what you are
treating.

CHAIRMAN BRASS: Dr. Cohen.

DR. COHEN: My feeling is I don\'t think you\'re going to mask any
serious underlying disease like gastric cancer, esophageal cancer,
duodenal ulcer. I just don\'t think it\'s going to happen. Although I
think in the United States we try to endoscope everybody, we have not
been as successful as you have been.

CHAIRMAN BRASS: Dr. Steinberg.

DR. STEINBERG: The answer is there probably are some concerns here.
They\'re probably very small concerns. There\'s only a very small
percentage of patients \-- for instance, Barrett\'s would be my concern
\-- that we\'re going to miss some dysplasia on that small percentage
who don\'t go to see a doctor, who continue to take the medicine.

But we have no data. I know what\'s being done in practice. What\'s
being done is some internist or family doctor referring for endoscopies,
and the gastroenterologist does it, and I, as one who does do it, see
very little problems to be concerned about in the patients that I\'m
seeing, but there is a small concern.

CHAIRMAN BRASS: Dr. Robinson.

DR. ROBINSON: As far as I know, there\'s no demonstrable risk in
patients self-treating for heartburn, and although we as
gastroenterologists do, indeed, love to see these patients and would
like to continue our studies of an actual history of heartburn and
Barrett\'s esophagus, as yet we can\'t prove that doing so is of great
benefit to the patients who are so treated.

CHAIRMAN BRASS: Really, really quick, please.

DR. CASTELL: I promise it will be very quick.

Just to make everybody comfortable on the committee here, there are
already many patients with GERD that are being treated over the counter
with antacids and H2 receptor antagonists. So if that\'s a burning
question, don\'t let it be. This is not a new change. All you\'re doing
is talking about moving it to maybe another level, but it\'s already
happening.

CHAIRMAN BRASS: That doesn\'t make it right.

Dr. Gilliam.

DR. GILLIAM: Well, I want to go \-- I\'m referring to page 143, and I
think it\'s the sponsor\'s material, and they talk about the guidelines
for the American Society for Endoscopy, and \--

CHAIRMAN BRASS: An unbiased group.

(Laughter.)

DR. GILLIAM: Well, okay. But the reason I\'m bringing up is that I think
when things are published like that, it becomes the standard of care,
and you know, if a lawsuit is brought, people do literature searches and
seeing, okay, what do the experts in that field recommend, and you know,
it says here if drug therapy \-- and I\'m assuming that means what\'s
currently over the counter being antacids and H2 receptor blockers and
lifestyle modifications are unsuccessful, which I don\'t think most
people follow anyway.

The endoscopy, you know, other diagnostic tests are recommended, and
I\'m just worried that we\'re going beyond what are kind of the standard
of treatment.

CHAIRMAN BRASS: But, again, maybe somebody can correct me. I had
interpreted that drug failure to include a pump inhibitor failure.

PARTICIPANTS: Yes.

CHAIRMAN BRASS: And so that, again, that\'s part of the reason why a
patient over the counter who is being symptomatically relieved of
symptoms would, in fact, meet those guidelines, and to me the critical
warning on the label is that if symptoms persist, that that be a red
flag, and we can argue whether it will be a bigger red flag than if they
didn\'t have to take the drug and see the red flag. That doesn\'t
matter.

What matters to me is that that warning must be communicated very
effectively.

Yes.

DR. HARI SACHS: Forgive my naivete in this regard, but let\'s say a
patient takes this PPI over the counter. Symptoms are relieved. They
stop. The symptoms recur so they start it again. Symptoms are relieved.
They stop it again and symptoms recur. So they take it.

Now they\'ve been taking it for a year. They stop it. Symptoms recur. At
that point would patients be asked, \"Hey, you know, you need to consult
somebody\"?

You know, I don\'t know. Okay? And from you guys from what you see, if
you have a patient thing you\'ve been following that you treat with a
PPI for, say, a year, you know, they get a trial off medicine to see if
symptoms recur or, you know, they stay on this indefinitely.

DR. STEINBERG: Well, we see patients referred to us that have been on
all sorts of durations of therapy, and we wind up endoscoping them.
There are no guidelines as to a year or six months or anything like
that, and very few of these people wind up having lesions in there that
are clinically significant or worrisome, but we really don\'t have the
data upon which to make judgments as to who should be scoped, who
isn\'t.

I know what the guidelines are, but the guidelines I don\'t think are
based on good data. There\'s impressions. There\'s this, that and the
other, and I think as long as the labeling says that if your symptoms
recur after a ten-day use you should see your physician, I would be
happy with that kind of labeling.

CHAIRMAN BRASS: Quickly, please.

DR. SHUSTER: To reassure Dr. Gilliam, the guidelines that are put out by
the four gastrointestinal societies are usually passed through the
boards of each of the four, and it\'s emphasized by a preamble that is
uniform for every article that comes out, and that simply states that
this is a guideline and not a standard of care, and it\'s not to be used
as such. It is based on a judgment, which in turn is based on an
evaluation of the literature.

CHAIRMAN BRASS: Okay. I would like to call these questions, and does
anybody object to just acclamation that it\'s going to be used
chronically?

Okay. Then I\'d like to go on to the second part of the question, and
I\'m going to just change it if the committee will accept it to: is the
treatment of chronic heartburn, comma, including patients who may have
GERD, comma, an acceptable OTC indication?

In other words, I don\'t think the label is going to say GERD. I think
it\'s going to say chronic heartburn, and we need to understand that
will include patients who have GERD.

Is that acceptable to everybody as a rephrasing of the question?

All those who feel that this is an acceptable OTC indication, please
raise your hand.

(Show of hands.)

CHAIRMAN BRASS: All those you feel it is not an acceptable indication,
please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Do those who have voted no wish to make any points that
they don\'t feel were brought out in the discussion that are critical to
their decision?

Oh, I\'m sorry. What was the vote?

DR. TITUS: The vote was seven yeses, it was acceptable; six noes, not
acceptable; and one abstention.

CHAIRMAN BRASS: Yes, Dr. Neill.

DR. NEILL: I\'m probably being overly semantic, but I think that goes
into what we\'ve demonstrated today, which is that working for the
government, Talmudic scholars, and Jesuit priests have nothing on us
when we look at FDA dockets in the [Federal Register]{.underline}.

(Laughter.)

DR. NEILL: My only concern about having GERD as a chronic maintenance or
prevention of GERD as an OTC indication revolves around our ability to
appropriately refer patients into physicians.

Having said that, I\'m not aware that having been referred to me, since
I\'m the one who is able to talk a quarter of my patients into coming to
you gastroenterologists, the other three-quarters continue to come to me
for another few years and whine about it. I don\'t know that I do them
any good.

Having said that, I agree that the numbers are very small, and I\'m
thrilled to hear a group of esteemed gastroenterologists confirm for me
what I\'ve been doing silently and guiltily, and I\'m not going to feel
guilty about it anymore.

So I\'ve abstained in order so as not to imply that this is an
inappropriate indication, the caveat, again, being that the labeling for
this needs to be clear.

CHAIRMAN BRASS: Again, any of the no votes want to register specific
concerns that were instrumental in their decision making?

Dr. Blewitt, you had a comment?

DR. BLEWITT: I would simply add that this would seem like an appropriate
\-- that perhaps it\'s not appropriate to sort of accept that chronic
use, you know, has to be maintained at its current levels. It seems to
me that with appropriate labeling, but even moreover with an opportunity
for a good, effective consumer education program you might be able to
reduce the amount of chronic use, you know, and increase the amount of
appropriate referral.

CHAIRMAN BRASS: But I think if that becomes a caveat then we play \-- if
that caveat becomes essential to a yes vote, then we\'ve placed a burden
of proof which I\'m not sure is necessary.

DR. BLEWITT: Well, this was a post hoc statement.

CHAIRMAN BRASS: Yes, Dr. Steinberg.

DR. STEINBERG: I guess I\'m a little confused. The current labeling is
projected to say ten days of use. Are you suggesting that the labeling
should be changed?

CHAIRMAN BRASS: We\'re talking generically now, not about their specific
label. So that we\'ve accepted that it\'s going to be used chronically.
So as a general question, is that an appropriate thing to do?

The next question is: based on the results of the actual use in label
comprehension studies, has the sponsor presented adequate data to
substantiate that consumers will be able to use omeprazole appropriately
in the OTC setting for acute symptomatic treatment, prevention up to ten
days?

By, I think, our previous vote, I think the answer to that is no, that
we have not seen that consumers will reliably use that, in my opinion,
for a short period of time.

I think we can discuss these issues further, and again, when I say it
has not been shown, it\'s in the context of the chronicity of use, the
concern about the ten-day use, and we talked about interacting drugs and
some other things. So I don\'t know what other people would like to
comment about conclusions from the actual use studies.

Yes, Dr. Geller.

DR. GELLER: I will say that the reported compliance is very optimistic
because if you look carefully at the denominators as you go through
these studies, I mean, in randomized trials, I know who I want to
analyze: everyone who\'s randomized. But in use studies, I have this
problem of disappearing denominators. You have the number who consent
and meet the entry criteria, and the number who complete, and then the
number who are evaluated, and these numbers decrease quite a bit.

And when compliance was reported, it was reported based on the number
which the company or the people conducting these studies considered
evaluable. So the numbers are very optimistic.

CHAIRMAN BRASS: Yes, Dr. Shuster.

DR. SHUSTER: Again, I\'d like to point out that we are looking at
noncompliance as if it were a sin, and it isn\'t. What I\'m saying is
that it\'s a blessing, that these are people who are doing the right
thing. If they\'re using chronic therapy for a chronic problem, that ten
days of treatment does not solve a chronic problem.

CHAIRMAN BRASS: I just want to emphasize the answer to this question is
not implied to be judgmental. The question is simply put that the
original intent was organized to tell consumers to use it this way.
Whether that was a correct strategy or not, I think our previous
discussion has shed some light on.

But we\'ve been asked to address specifically whether or not the actual
use studies addressed these factors appropriately in terms of what the
intent of those actual use studies were. To the degree they identify
concerns that we need not be concerned about in the future or can be
modified by changes in the label, that may be good.

So I don\'t think this should be interpreted as a good or bad. I think
it\'s a yes or no.

Yes, Dr. Shapiro.

DR. SHAPIRO: I feel somewhat schizoid with apologies to where we\'ve
been convinced that chronic treatment might be \-- or I\'ve been
convinced ‑- that chronic treatment might be preferable to short-term
treatment to now have to respond to this question.

CHAIRMAN BRASS: Well, we can ask him if he would like to withdraw the
question given your previous discussion, but I think we would still like
to get some insight into the actual use studies and behaviors, but I
will leave it to the \--

DR. DeLAP: I think our biggest interest is just in knowing what you
think is the appropriate use, and you know, we structured it this way
kind of because this was the way the data were structured coming into
us, but if you \--

CHAIRMAN BRASS: I actually thought we\'d get to that in I because I
talks about the appropriate indication, and H was focused specifically
on the actual use data, and I don\'t disagree that I think many of the
points of the actual use study that are the most pertinent have already
come out in the discussion and a judgmental or inferred judgmental
discussion of it may not add very much.

DR. KATZ: I was going to say given the discussion that\'s gone forward
so far, you can go ahead and skip H and go on to I because that will
come into part of the decision making process for I.

CHAIRMAN BRASS: Thank you.

So without objection, I will so do, and I is: has the sponsor provided
sufficient evidence to support the approval of omeprazole ten milligrams
and/or 20 milligrams for use in the OTC setting?

And I\'ll put it as an \"or\" so that if you think either dose has been
shown you would vote yes, and I want to emphasize that this is really
the critical demonstration of efficacy question. So that unless the
sponsor for this particular question has shown evidence in their data
presented, then your vote would be no. If you feel the sponsor has shown
evidence to support the approval, then one would vote yes. So it\'s not
an extrapolation. It\'s not what you think would have happened, should
have happened, could have happened. Okay?

Yes, Dr. Elashoff.

DR. ELASHOFF: Is this irrespective \-- let\'s see. Is this to refer only
to efficacy issues, and that even though you might think that safety
issues precluded approval?

CHAIRMAN BRASS: No.

DR. ELASHOFF: So that this is only efficacy or is this the combination
of the two?

CHAIRMAN BRASS: It is the combination of the two so that it clearly says
to support the approval of, and that involves both the safety and
efficacy databases.

Dr. D\'Agostino.

DR. D\'AGOSTINO: I just want to make sure for myself that now we\'re
going back to the six studies we looked at, and in those six studies we
have some convincing evidence on the ten-day.

CHAIRMAN BRASS: That is absolutely correct. So this is based on the data
that has been presented to us today, yes.

DR. D\'AGOSTINO: And if we say yes and so forth, all of this discussion
about GERD and chronic use and what have you, we\'re not saying that
these studies allow us to give a blessing to chronic use since, again,
within that ten days and the type of labeling that would follow from the
\--

CHAIRMAN BRASS: That is correct.

Yes, Ms. Cohen.

MS. COHEN: Are you going to separate out the ten milligrams from the 20
milligrams?

CHAIRMAN BRASS: I proposed not doing that. I proposed doing it as an
\"or.\" So if you thought either was, you would vote yes, and then if
asked to I would separate after the initial vote.

Dr. Geller.

DR. GELLER: I\'m having a little problem because the labeling is saying
for no more than ten days, but we\'ve all agreed that people are going
to not obey that, and given that they\'re not going to obey that, some
of us believe those people should go to doctors after a certain point,
which I\'d rather not try to define.

So this is not a black-white issue for me here. So this overall
assessment for over the counter is different from this efficacy
question.

CHAIRMAN BRASS: Well, you are correct. We\'re talking specific \--
we\'re going to talk about two specific populations, and we\'re going to
separate those by the vote, and if you feel that either there are safety
concerns that preclude approvability or the absence of data to support
efficacy, then you would not be able to recommend approval.

DR. GELLER: I think you should say that again to make sure everybody
gets the question right this time and we can vote once instead of twice.

(Laughter.)

CHAIRMAN BRASS: Okay. The vote is on \-- will be on approvability. By
definition approvability is based on the evidence presented to us and
requires both demonstration of safety and efficacy in the OT setting for
the indication that would be proposed.

DR. STEINBERG: Dr. Brass, can I comment?

CHAIRMAN BRASS: Please.

DR. STEINBERG: I think the ten milligram and 20 milligram are very
different. I think the ten milligrams is the dosage, and the 20 is
really very different. My feeling is you should vote just on the ten,
which would be a vote separately, but it\'s the ten milligram that I
think the discussion has revolved around.

CHAIRMAN BRASS: Okay. We will vote each indication separately for each
dose. We\'ll do a ten milligram dose because what I\'m trying, unless
there\'s objection, what I\'m trying to do is we\'ve been presented
data, and our reaction to that data will be very helpful to both the
sponsor and the agency in their future deliberations and to only vote on
a subset of the data, I think, minimizes our impact on the overall
process, but I will accept the point, and we will separate the ten and
20 in the voting.

Yes.

DR. GELLER: I do have one question for the company. Based on the
discussions here where the efficacy is clearly greater for 20, yet so
are the risks, are you going for the ten? Is that what you want to do,
or are you going for anything? What\'s going on here?

(Laughter.)

DR. LEVINE: We do not think that there\'s a risk issue between ten and
20. I\'ve been trying to explain we\'ve been talking about risk
potential, given some of the theoretical issues, but we don\'t believe
there\'s any risk difference between ten and 20 milligrams.

DR. GELLER: So you\'re going for any, anything?

DR. LEVINE: We will let you vote.

CHAIRMAN BRASS: Thank you.

Okay. Has the sponsor provided sufficient evidence to support the
approval of omeprazole ten milligrams for use in the OTC setting for
acute, symptomatic heartburn?

All who would like to vote yes on that question, please raise your hand.

(Show of hands.)

DR. TITUS: Higher. Thank you.

CHAIRMAN BRASS: All those who would like to vote no on that question,
please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: All those who would like to abstain, please raise your
hand.

(No response.)

DR. TITUS: There are two yeses, 11 noes, and zero abstentions.

CHAIRMAN BRASS: Next question: has the sponsor provided sufficient
evidence to support the approval of omeprazole 20 milligrams for use in
the OTC setting for acute, symptomatic heartburn?

All in favor, please vote yes at this time.

(Show of hands.)

CHAIRMAN BRASS: There were two.

All those voting no, please raise your hand.

(Show of hands.)

DR. STEINBERG: Dr. Brass, can I ask you is this vote based on the two
prevention studies or the six studies?

CHAIRMAN BRASS: It is in total all the data that has been presented to
us today.

Next question \-- oh, I\'m sorry.

DR. TITUS: There are two yeses for 20 milligrams and 11 noes.

CHAIRMAN BRASS: Next question: has the sponsor provided sufficient
evidence to support the approval of omeprazole ten milligrams for use in
the OTC setting for prevention of episodic or chronic heartburn?

All those \--

DR. GANLEY: We need to probably \--

CHAIRMAN BRASS: Separate those two?

DR. GANLEY: Yeah, and I think the other thing that\'s important here is
the way the follow up is.

CHAIRMAN BRASS: I understand.

DR. GANLEY: If you vote yes, then you\'re essentially saying that
there\'s no more information needed from them, such as an actual use
study or a labeling comprehension study.

If you vote no, then you can qualify it and say we think it is
acceptable for chronic therapy, for example, but you have to do these
and these studies.

CHAIRMAN BRASS: Correct. Okay. So we have four votes left on Question I.

Has the sponsor provided sufficient evidence to support the approval of
omeprazole ten milligrams for use in the OTC setting for prevention of
episodic heartburn?

PARTICIPANT: If you\'re separating episodic from \--

CHAIRMAN BRASS: All in favor, please raise your hand yes.

(Show of hands.)

CHAIRMAN BRASS: All opposed, please raise your hand no.

(Show of hands.)

DR. STEINBERG: Perhaps I don\'t understand the question. Episodic
heartburn over a chronic period of time and chronic heartburn are the
same.

CHAIRMAN BRASS: We are talking about based on the evidence presented to
\-- well, based on the evidence presented to us in totality.

DR. STEINBERG: But heartburn is an episodic issue, and I don\'t see how
when you\'re talking about prevention there\'s a difference between
prevention of episodic heartburn and prevention of chronic heartburn.
They\'re both episodic and they\'re chronic.

CHAIRMAN BRASS: I think the implication was from the discussion, and
again, I was happy to lump them, but I think the supposition was that a
patient \-- that there\'s an implication as to frequency and severity
that would differentiate.

So, for example, prevention of episodic heartburn might be a person who
has it once a month with a specifically provocative meal as opposed to
the person who has three episodes a week and is taking it on a chronic
basis for that purpose.

Abstentions on that question?

(Show of hands.)

CHAIRMAN BRASS: Okay. We have to do it again because we didn\'t get
everybody\'s vote.

Has the sponsor provided sufficient evidence to support the approval of
omeprazole ten milligrams for prevention of episodic heartburn?

Yes, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: No, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: For ten milligrams for prevention of episodic, there are
two yeses, ten noes, and one abstention.

CHAIRMAN BRASS: Has the sponsor provided sufficient evidence to support
the approval of omeprazole 20 milligrams for use in the OTC setting for
prevention of episodic heartburn?

Yeses, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Noes, please raise your hand.

(Show of hands.)

PARTICIPANT: I think someone\'s confused. I see the gastroenterologists
on the other side of the table.

CHAIRMAN BRASS: Abstentions, please raise your hand.

(Show of hands.)

DR. TITUS: There are two yeses, ten noes, and one abstention, but I
don\'t know what we voted on.

CHAIRMAN BRASS: That was 20 milligrams for episodic.

Has the sponsor provided sufficient evidence to support the approval of
omeprazole ten milligrams for prevention of chronic heartburn?

Yeses, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Noes, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Has the sponsor provided sufficient evidence to support
the approval of omeprazole 20 milligrams for use in the OTC setting for
prevention of chronic heartburn?

All in favor, please raise your hand yes.

(Show of hands.)

CHAIRMAN BRASS: Noes, please raise your hand.

(Show of hands.)

CHAIRMAN BRASS: Abstentions, please raise your hand.

DR. TITUS: For the last two votes they were the same for ten and 20
milligrams for chronic. it was three yeses, nine noes, and one
abstention.

CHAIRMAN BRASS: Now, as one of the noes, I would like to expand upon my
vote and try to explain my rationale. I think that the evidence provided
by the sponsor gives every assurance that this drug would have efficacy
in the prevention of chronic heartburn. I am convinced of that. I tend
to believe that 20 milligrams would be better than ten milligrams, and
that the efficacy will be there.

I also have only very limited questions about safety, and they have to
do with developing a label that can be shown to convey to consumers how
to use this drug appropriately in the setting of chronic heartburn that
conveys key elements of proper use, any warnings that need to be
considered, and when to see a physician; that whether or not that label
ends up being congruent with the efficacy data that has already been
developed or requires additional support of studies will be up to what
that actual indication looks like.

My point here is that we do not have an indication, a label, an
indication and studies of that label which reflect how we expect this
drug to be used, nor do we have data that without knowing that it\'s
hard to say we have efficacy data that is congruent with that labeling.

I don\'t know if that\'s clear, but that was why I ended up voting no,
even though I have great confidence that this drug will be, based on the
data we\'ve been presented, be able to meet that kind of standard.

Dr. Geller.

DR. GELLER: I would like to address further the issue of the ten-day
limitation. This group was unanimous in believing that would not be
adhered to, and so I wonder if that should be included in the label, and
if not, I think that the implication is that longer term studies are
necessary.

I guess I would just like this group to discuss this to advise the
company on how to proceed.

CHAIRMAN BRASS: Well, again, from my perspective if the label is for
ten-day use, and that\'s felt to be critical for the proper use of the
drug, then the sponsor has failed to meet a standard because, in fact,
the drug is going to be used by more than ten days.

If the ten-day window is not an absolute window, then that needs to be
better defined, communicated to a consumer and then an assessment made
to see whether the existing database is adequate for that new \--

DR. GELLER: Yeah, my concern is that the studies conducted don\'t test
longer term use according to directions. So are you saying you think
such studies would have to be done then?

CHAIRMAN BRASS: I\'m not prejudging what a modified label would look
like. So I\'m not prejudging whether additional studies would need to be
done.

Dr. D\'Agostino.

DR. D\'AGOSTINO: I have very much the same feeling in response to this
question. I think that the efficacy studies for the ten days are quite
good studies and quite clear in their results.

I\'m concerned as we started doing more of the talking about the chronic
use of it and so forth, and it\'s very much what Nancy is saying, that
the unfolding of actual use studies and labeling and so forth may say
that you want to go beyond the ten days, and if you do, then I think you
need to \-- there\'s a point where you have to ask for more studies, and
again, I think the studies are convincing, but there are so many issues
left unsettled and undone that I think the discussion between the drug
company and the FDA now hears our concerns and really has to be done
very seriously.

CHAIRMAN BRASS: Dr. Sachs.

DR. HARI SACHS: What I think I would need to see, for example, to turn
my no vote to a yes because I agree short term efficacy for prevention
was shown. My concerns is the likelihood that much longer term chronic
use would be done. I would want to see some of the longer term studies,
and there may be data based on the prescription use which would
certainly reassure me as to safety.

I think, number two, if you\'re putting it into the OTC market, there\'s
going to be a lot more exposure of pregnant women who may take it for GI
symptoms, not realizing they\'re pregnant, and you know, that needs to
be addressed a little bit. I know it has been addressed slightly, but
there wasn\'t consensus, and I think you need to have that.

I also think there\'s going to be a lot of self-selection that I\'m not
sure was demonstrated, especially if people are going to be using it
over a long term.

CHAIRMAN BRASS: Dr. Uden.

DR. UDEN: Well, first of all the acute, symptomatic heartburn, I think
for both doses it was very clearly shown in the studies that how they
ran them it didn\'t work. But in the episodic where there was mixed
results and even the sponsors themselves admitted it, for the episodic
they were directed to take it an hour before their challenge.

Clearly, if it\'s taken \-- well, intuitively, if it\'s taken, you know,
two, three or four hours before the insult, then it might work better,
but that was not what was presented to us. And so that\'s how the
decision was made.

CHAIRMAN BRASS: Dr. Cohen.

DR. COHEN: I think that some of the panelists are trying to recreate the
prescription dosage of the drug. Twenty milligram for long term use,
those data are available. That\'s the way we\'ve used it for the past
ten years. It\'s really the lower dose for short term use for the
prevention of heartburn, and I can\'t see reinventing now the
prescription dose and redoing the studies. It\'s clear that it works on
the prescription dose 20 milligrams daily for four, eight weeks, or
prolonged treatment. That was done.

Short term it works in this very limited sphere for prevention, but I
think you\'re talking about something completely out of the context of
OTC usage.

CHAIRMAN BRASS: Well, that\'s again why I said that it wasn\'t
necessarily clear to me that additional efficacy would, in fact, be
presented. What we have now is a complete disconnect between the
efficacy data, the actual use data and the label comprehension as far as
I\'m concerned and what any label might look like.

Those need to be made congruent, and there are a variety of strategies
that one might employ, given the expectation of efficacy and the
experience with this drug that would convince people that consumers
would be able to use the drug safely and with clear expectations.

I think it does no good to say we\'re going to fool everybody and, say,
put ten days on it or ten milligrams and who in the hell cares how they
actually use it. I think that if we believe that a more chronic use is
appropriate and that there needs to be specific warnings, under what
circumstances that\'s inappropriate, that needs to be demonstrably
conveyed, and it may or may not require additional efficacy data to
accomplish that end.

Yes, Dr. Shapiro.

DR. SHAPIRO: Mr. Chairman, just as a matter of logic, it seems to me
that what has been demonstrated is that ten days of use works. We know
from countless studies of prescription use that 20 milligrams of use for
longer term also works.

The recommendation is ill conceived. The ten-day limit is ill conceived.
If the over-the-counter use were to use it for chronic heartburn and use
it as long as you like, that would make sense to me, and it seems to me
logically that we already know that.

CHAIRMAN BRASS: Again, this is part of the difference between an
over-the-counter consideration and a prescription. If we did not need to
have some sense that a consumer would be able to translate your and my
understanding into an appropriate use in the out-patient setting, there
would be no deliberation about any prescription to OTC switch because we
already know they work.

And so the issue is being able to convey the key messages in an
over-the-counter setting, and if there were any safety or efficacy
concerns, be able to demonstrate that the label adequately addresses
them.

So I don\'t disagree with your logic. I think it\'s an issue of where
the bar is placed in an over-the-counter setting.

Dr. Blewitt.

DR. BLEWITT: Just for the record, these studies were carried out over 14
days.

CHAIRMAN BRASS: I appreciate the clarity. Thank you.

Yes, Dr. Ganley.

DR. GANLEY: Yeah, I just have some or one main question, and I\'m
getting a little mixed signals here from Dr. Cohen and Dr. Shapiro. On
the one hand, Dr. Shapiro and I can understand your rationale that if
people were going to take it, they should take it all the time and we
can label it very easily like that, and, Dr. Cohen, I got the sense that
you would want a limitation possibly of four to eight weeks or am I
wrong in understanding some of your previous comments?

DR. COHEN: My feeling is that the data that were just presented would
justify approval for OTC usage at ten milligrams for short-term use, and
I think most patients would use it like that.

I think if you\'re going for long term use, at ten milligrams you really
have to present more data on what the healing rates are going to be,
what the effects on the esophagus are going to be. I think that we
should stick to the studies that were presented.

DR. GANLEY: Well, you had a prevention study that showed 20 milligrams
was effective. Why not give 20 milligrams if there\'s no safety issue?

And please define what you mean by short term.

DR. COHEN: I think the short term is just the length of the study, and
that\'s how we evaluate it today. We show that over short term you had
prevention of symptoms at the lower dose, which I think is a more
appropriate OTC dosage. I think that would be more embraced by the
medical community, by the patient community, and that\'s traditional
that you go, and that\'s what we did with the H2s. We went to a half
dosage.

It\'s been used. It\'s not been abused. It\'s been used appropriately,
and it\'s had wide physician and patient acceptance, and that\'s what I
always thought was appropriate for this drug approval: ten milligrams
with the appropriate wording as presented for ten or 14 days for the
prevention of heartburn.

DR. GANLEY: I think as we had thought about this internally, I think the
question that came up when you connect the prevention data with the
actual use data, we came to the realization that people were going to
use this longer than ten days or 14 days, and our view was, well, if
we\'re going to do that and that\'s an appropriate OTC indication, we
ought to label it appropriately.

And I\'m not sure that labeling it for 14 days as opposed to ten days
really addresses the issue that we have at hand, that people are
actually going to use it longer, and if they are going to use it longer,
how long should they use it and should they stop and see what happens.

I mean those are the issues that we need to grapple with here, I think.

CHAIRMAN BRASS: And I think that from my perspective Dr. Cohen\'s logic
I don\'t disagree with, except for the fact we know that\'s not what
happens. A high percentage of the population won\'t stop at that. They
use the drug for more than the intended period of time, and that the
ability to be able to say whether that\'s correct or not or guide them
in proper use.

From my perspective, I think a period of time and then a discontinuation
with an instruction that it is okay to then restart the therapy or an
instruction to seek medical advice or something like that, but I think,
again, there has to be a match between what\'s actually going to happen
in the OTC setting and the education of the consumer.

Dr. Robinson.

DR. ROBINSON: Perhaps I just don\'t read what I\'m supposed to, but if
I\'m not mistaken, there are, of course, already OTC acid suppressing
drugs on the market. I don\'t believe any of them are approved or have
labels for long-term use. Yet we all know that all of the patients who
take them take them as long as they feel they need them, and nobody has
felt any need to fix that.

And so I\'m not sure why you need to fix it for this drug at this time.

CHAIRMAN BRASS: Dr. Katz.

DR. KATZ: The one difference is that the products that are out there are
actually indicated for acute symptom treatment. This is not acute
symptomatic relief. So there\'s a disconnect in one sense.

The products that people are currently taking they\'re taking to relieve
their current symptoms of heartburn. They\'re taking to prevent a meal
induced heartburn.

Here we\'re talking about, and we\'ve been addressing the issue of
chronicity of therapy so that right away you\'re talking about a
different treatment. This acutely, as you even said earlier, would not
work if someone takes it to relieve their acute heartburn symptoms.

So that we have a different drug with a different label and a different
population of people who may be using it long term. That\'s actually
what we\'re asking you to deal with to help us look at how would we
convey the information that needs to be conveyed to a consumer so that
they can understand how to use this product appropriately.

CHAIRMAN BRASS: Dr. DeLap.

DR. DeLAP: Yeah, if I can just expand a little more on that, I think one
of the things that\'s near and dear to my heart is the notion that we
should label these products so that consumers can use them to best
advantage, and we shouldn\'t have something on the labeling of a product
that we know is suboptimal or that we strongly believe may be
suboptimal.

In that regard, I think one of the concerns that I had as I was
listening to some of the discussion is that people are talking to their
physician over the course of this research took the medicine differently
than people that weren\'t. People that weren\'t talking to their
physician might have been more compliant in obeying the ten-day limit,
but people that actually had the advice of the health care professional
were ignoring the labeling.

So that says something to me about, you know, what\'s the standard of
care here and what should people really be doing, and then it comes back
to, well, if it\'s the standard of care that people take these medicines
longer for these kinds of situations, why can\'t we label it that way.

And then it comes back to, well, what else do we need to know to be able
to go in that direction.

I agree, I think, with some of the sentiment about the long history of
effectiveness of this medicine for, you know, heartburn and various
manifestations. So I don\'t have too many reservations about that, but I
think we do need to have more work, and I think I\'m reflecting what
I\'ve heard from the community. We need to have more work on how you
label it.

CHAIRMAN BRASS: Dr. Neill.

DR. NEILL: There are also some clear implications for how many tablets
go in the box, my experience being patients are going to take this. If
it works, it will be a few days before they go back to their drugstore,
pick up another box of 24 to take. When it doesn\'t work, they\'re going
to call me and come in and ask for the different proton pump inhibitor
that is not approved for OTC.

CHAIRMAN BRASS: Do you want to put your phone number on the \--

DR. NEILL: No.

(Laughter.)

DR. NEILL: The implication being that because it\'s prescription, of
course, it must work better. Otherwise why would Prilosec have gone over
the counter? It can\'t possibly work as well.

I feel I\'m the one person who voted no for episodic and yes for chronic
because I feel comfortable with the efficacy data, and while I would
like to see actual use data in a 20 milligram dose or in a ten milligram
dose for that indication, my level of discomfort in prevention of
chronic is not so great as to feel that that requires a no vote.

CHAIRMAN BRASS: Dr. D\'Agostino.

DR. D\'AGOSTINO: It\'s been said around the table already, but I think
it should be reiterated. When this committee gave its blessing to the H2
antagonist, the types of studies that were before us were relief from a
meal and prevention for a meal. There was no long-term involvement
involved in it. There were with the relief studies that they were spread
over a couple of weeks, but it was just basically if you got an upset
stomach, a heartburn, take the pill, and then we did the analysis where
we actually were separating. If you took it day after day, we separated
the episodes where you have to have two or three days of no drug so that
we could see what was happening basically on a particular episode where
there was a build-up and so forth.

These studies that we see before us are really playing on \-- and the
way you\'re describing the prescriptions \-- are really playing on the
build-up as a part of the feature, and it\'s a new world for us, and I
think that we\'ve made the right decisions.

CHAIRMAN BRASS: Dr. Shuster.

DR. SHUSTER: I\'m confused. I don\'t know how the FDA operates here. My
impression had been that the labeling is based on and the indication is
based on proven efficacy. For example, when cimetidine came out, it was
approved for six weeks of treatment and very specific indications. A
study in the [New England Journal]{.underline} by Fortran showed that it
was much more often used for off-label indications than for the labeled
indications, appropriately so as events showed.

So my first question is: is the approval based on what we project as the
appropriate use or is it based on data, evidence proven studies?

CHAIRMAN BRASS: I will try to answer that. It is based on the data
that\'s presented in studies. In the case of OTC use, part of that
database is the expectation of how consumers will actually use the
product, and to the degree that there are either concerns about
misleading information, use that will substantially differ from the
efficacy studies that make them noncomparable, efforts have to be made
to bring those two into congruence so that we can make a judgment about
the safety and efficacy in the OTC setting.

DR. SHUSTER: So what you\'re suggesting is that the standards for
consumers is more strict than the standards for physicians, and that may
have an element of veracity to it. It\'s probably right.

What I would wonder though is whether experts, physicians, health care
professionals, physiologists, pharmacologists and so forth cannot make
the decision that this is a safe drug even for use beyond the proven
studies and to say that we will put it out there. I mean what you\'re
suggesting is you shouldn\'t put it out there if it\'s going to be
misused, and I think that\'s inappropriate.

DR. COHEN: Yeah, I would just comment that the 20 milligram dose clearly
has efficacy long term. We didn\'t see any data that ten milligram has
efficacy at 12, 16 weeks. So you\'re talking about long-term use, and
there was no presentation of data.

CHAIRMAN BRASS: That\'s why I voted no.

DR. GANLEY: I think you bring up valid points, and that\'s why I tried
to pin you down on short-term use, because generally, you know, labels
say use for four to six weeks in the treatment of GERD, and then \-- but
that\'s a physician monitoring it.

And so if you can envision here that it may say on the label for an OTC
product to use it for four to six weeks and stop and don\'t restart it,
and if your symptoms recur, you see your physician. Okay?

If you want to be very empirical about what data we have for long-term
relief, but from my sense in listening to you folks today is that if you
take people off this therapy and the symptoms come back, you just put
them back on it. There\'s no empirical data in the database that
suggests that\'s beneficial. It\'s based on your experience.

DR. RACZKOWSKI: Yes, I think I was thinking along somewhat similar lines
to Dr. Ganley. What I\'m concerned about is the potential discrepancy
between the prescription labeling, which has for the treatment of GERD
you need to take it for a minimum of eight weeks or so, and what we\'ve
talked about so far is the 20 milligram dose for only a 14-day course,
and I\'d like some advice from the committee on whether you\'re
recommending then that if a 20 milligram dose would be approved for OTC
use, would the paradigm then be for longer term, and by that I mean not
just 14 days, but eight weeks, et cetera, where we do have data from the
prescription use of the drug.

CHAIRMAN BRASS: Again, I think this could be handled in different ways.
Again, from my perspective the indication is not GERD. It\'s chronic
heartburn. Some patients will have GERD, and we understand that, and
what I expect will happen is they will self-select out to longer therapy
as long as we help guide that and have confidence that can be done
safely, and that that really is kind of the critical transition.

There are some patients in this cohort who can take a 14-day course,
stop, and be drug free for an extended period of time. There are others
who after three days will go right back on it, and I don\'t think
that\'s a bad thing either.

The challenge is how to convey that in an appropriate way to the
consumer.

Yes, Dr. Steinberg.

DR. STEINBERG: First of all, I want to get back to this word \"GERD.\"
In my mind there is no difference between GERD and chronic heartburn. So
I think that terminology is very confusing. I don\'t think it should be
differentiated.

But getting back to the whole issue of the reason you voted against this
being the studies are not long enough, that\'s one of the main things
you said.

CHAIRMAN BRASS: Again, there\'s a lack of congruence between the
efficacy studies, the label and the actual use studies.

DR. STEINBERG: Well, the actual use we all agree is going to be long
term, but long term will mean different things to different patients. So
how is the sponsor to know how long term a long term study should be
even if they were doing one? Should it be four weeks, eight weeks or a
year? Because this drug, in effect, will be used long term for years by
some people, and that\'s not a reasonable thing to ask.

CHAIRMAN BRASS: Well, again, there is precedent, and correct me if I\'m
wrong, for much of the efficacy data to come from the prescription NDA,
and those studies may be used in conjunction with additional data to
help support such an indication.

So, again, I don\'t view it as my job to explain how those standards
could be met, but I\'m not prejudging it the other way either. I can
imagine ways to do this without additional studies, and my standard is
congruence between the safety and efficacy assessment for the database,
the label, and expectation of actual use, and I think there are a
variety of ways to get to that endpoint.

Dr. Sachs.

DR. HARI SACHS: The other question I have, which is really additional
information, is how does a patient decide whether to put themselves on
an antacid and H2 blocker or a PP \-- if this is OTC \-- or a PPA.

You know, I think there has to be some consideration for the rather
naive consumer.

CHAIRMAN BRASS: Well, I think that\'s the marketplace, and again, I
don\'t think that\'s an issue where we, unless there\'s a clear health
benefit distinction or risk distinction, need to guide people in doing
that. I think that\'s a marketplace decision.

I don\'t \-- very quickly please.

DR. ROBINSON: The only other thing I would say is that of course, I
think the data that you want or need really all do exist already, and
they exist in the \-- and I think you\'re probably not looking at the
data that were actually presented today totally correctly because, in
fact, most patients do, in fact, take \-- most of these subjects did, in
fact, take their medicine according to labeling. It wasn\'t that most of
them didn\'t, and the ones that didn\'t, you have no idea what they\'re
going to do next, but you have no data to suggest that they\'ll take the
medicine for a year.

And people who have heartburn do use on demand therapy now with all of
the products and will with this one as well, and if you have a bad week,
you\'ll take it for a week, and if you don\'t ever have anymore trouble,
you\'ll stop.

So the fact is putting this medicine on the market is not going to
guarantee that every person that ever takes it will take it forever.

CHAIRMAN BRASS: I think I\'d like to sum up briefly on a positive note
because I think we\'re losing sight of some of the bottom line messages,
and that from the perspective of NDAGC, I think we have really moved
things very substantially, and that for the first time the committee has
agreed that a non-acute, nonsymptomatic symptom, i.e., chronic use or
prevention, may, in fact, be under appropriate circumstances an
approvable OTC indication.

I think that is very significant if that can be handled right.

Additionally, I think that the concept that this product is very likely
to be able to meet such a standard and there is confidence that the
efficacy and safety database are appropriate for OTC if done properly is
also a nontrivial, significant conclusion.

DR. NEILL: This is not a nonsymptomatic symptom.

CHAIRMAN BRASS: Well, I\'m sorry, but the patient will continue to take
it while they\'re nonsymptomatic.

DR. NEILL: Right, but there are clear \--

CHAIRMAN BRASS: So that, again, \--

DR. NEILL: Unlike cholesterol, there are clearly patient identifiable
symptoms that they can use to guide \--

CHAIRMAN BRASS: I agree completely, but again, it is a step in a
direction that allows a more chronic use during a period with an
objective of prevention.

Unless there are really burning issues, I would like to adjourn the
meeting and thank everybody very much for their contribution.

Oh, Dr. DeLap.

DR. DeLAP: I\'d like just to add my thanks for all the hard work by the
people around the table and also the sponsor and our FDA staff, of
course, and I\'m sure we will be having further conversations with the
company, and we will probably invite a number of the Advisory Committee
staff to help us in those discussions as well.

CHAIRMAN BRASS: Thank you all.

(Whereupon, at 5:13 p.m., the meeting was concluded.)