FOOD AND DRUG ADMINISTRATION
	CENTER FOR DRUG EVALUATION AND RESEARCH
	+ + + + +
	JOINT MEETING
	OF THE
	NONPRESCRIPTION DRUGS AND GASTROINTESTINAL DRUGS
	ADVISORY COMMITTEES
	+ + + + +
	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
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, 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, 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 and in vitro 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 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 genotoxicity.  It's stated one place in the briefing book and again in the presentation you say in vivo 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 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 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.  The second one is most bone marrow cell chromosal aberration test in vivo, 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 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 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., in Toxicology, 1998, that omeprazole produces micronuclei in vitro, in in vitro tests of rat and human hepatocyte cell cultures, and in vitro 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.
		(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 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.)