FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	UROLOGY SUBCOMMITTEE

	OF THE

	ADVISORY COMMITTEE FOR REPRODUCTIVE HEALTH DRUGS

	9:03 a.m.

	Monday, April 10, 2000

	Versailles Ballroom
	Holiday Inn
	8120 Wisconsin Avenue
	Bethesda, Maryland

	ATTENDEES

SUBCOMMITTEE MEMBERS:

RICARDO AZZIZ, M.D., M.P.H.
Professor of Obstetrics and Gynecology
Department of Obstetrics and Gynecology
University of Alabama at Birmingham
Old Hillman Building, Room 549
618 South 20th Street
Birmingham, Alabama  35233-7333

JAYNE PETERSON, R.Ph., J.D., Executive Secretary
Advisors and Consultants Staff, HFD-21
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

MICHAEL F. GREENE, M.D., Chairman
Associate Professor of Obstetrics,
  Gynecology and Reproductive Biology
Department of Obstetrics and Gynecology 
Massachusetts General Hospital
Boston, Massachusetts  02114

JULIA SCOTT, R.N., Consumer Representative
President
National Black Women's Health Project
600 Pennsylvania Avenue, S.E., Suite 310
Washington, D.C.  20003

VOTING SGE CONSULTANTS:

ROBERT CALIFF, M.D.
Professor of Medicine/Director
Duke Clinical Research Center
Duke University Medical Center
2024 West Main Street, Box 31123
Durham, North Carolina  27707

RALPH D'AGOSTINO, PH.D.
Professor of Math, Statistics and Public Health
Boston University
111 Cummington Street
Boston, Massachusetts  02215

	ATTENDEES  (Continued)

VOTING SGE CONSULTANTS:  (Continued)

CRAIG DONATUCCI, M.D.
Assistant Professor of Urology
Department of Surgery, Division of Urology
Duke University Medical Center
Room 1108A Green
Trent Street, Box 3274
Durham, North Carolina  27710

THOMAS GRABOYS, M.D.
Brigham and Women's Hospital
Harvard University
Director, Lown Cardiovascular Center
21 Longwood Avenue
Brookline, Massachusetts  02146

PHILLIP HANNO, M.D.
Fellow, Disease Management, Managed Care,
  Quality Assurance
Division of Urology
First Floor Rhoads Pavilion
Hospital of the University of Pennsylvania
3400 Spruce Street
Philadelphia, Pennsylvania  19104

STEPHEN C. JACOBS, M.D.
Professor and Chairman
Division of Urology
University of Maryland, School of Medicine
22 South Greene Street
Baltimore, Maryland  21201

PETER KOWEY, M.D.
Chief, Division of Cardiovascular Diseases
The Lankenau Hospital and Medical Research Center
Lankenau Medical Office Building East
100 Lancaster Avenue West of City Line, Suite 556
Wynnewood, Pennsylvania  29096

MARGUERITE LIPPERT, M.D.
Associate Professor of Urology
Department of Urology
University of Virginia Health System
Lee Street, Room 2556A, Box 422
Charlottesville, Virginia  22908

	ATTENDEES  (Continued)

VOTING SGE CONSULTANTS:  (Continued)

MICHAEL P. O'LEARY, M.D., M.P.H.
Associate Professor of Surgery
Harvard Medical School
45 Francis Street
Boston, Massachusetts  02115

LEONORE TIEFER, PH.D.
Associate Clinical Professor of Psychiatry
Department of Psychiatry
Albert Einstein College of Medicine
111 East 210 Street
Bronx, New York  10467

FOOD AND DRUG ADMINISTRATION STAFF:

MARK HIRSCH, M.D.
VENKATESWAR JARUGULA, PH.D.
MARIANNE MANN, M.D.
VICTOR RACZKOWSKI, M.D.
DANIEL SHAMES, M.D.

TAP HOLDINGS, INC. REPRESENTATIVES:

BARBARA BOPP, PH.D.
SUSAN BUTTLER, M.S.
ANTHONY EDMONDS, M.S.
TIMOTHY FAGAN, M.D.
JAMES FRESTON, M.D, PH.D.
JEREMY HEATON, M.D.
DENNIS JENNINGS, PH.D.
RONALD LEWIS, M.D.
JOEL MORGANROTH, M.D.

	C O N T E N T S

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
  by Ms. Jayne Peterson	9

TAP HOLDINGS PRESENTATION:
	INTRODUCTION
	  by Dr. James Freston	10

	PHARMACOKINETICS AND METABOLISM
	  by Dr. Barbara Bopp	20

	ERECTILE DYSFUNCTION TREATMENTS AND
	SUMMARY OF EFFICACY
	  by Dr. Jeremy Heaton	27

	SUMMARY OF SAFETY
	  by Dr. James Freston	54
	  by Dr. Timothy Fagan	57

	BENEFIT-RISK ASSESSMENT AND SUMMARY
	  by Dr. James Freston	74

FDA PRESENTATION:
	OVERVIEW
	  by Dr. Daniel Shames	86

	PHARMACOKINETICS AND DRUG-ALCOHOL INTERACTIONS
  	  by Dr. Venkateswar Jarugula	93

	CLINICAL SAFETY AND EFFICACY
	  by Dr. Mark Hirsch	102

	DRUG-ANTIHYPERTENSIVE INTERACTIONS AND SUMMARY
	  by Dr. Marianne Mann	116

OPEN PUBLIC HEARING PRESENTATION
  by Mr. Donald L. Vieth	129

SUBCOMMITTEE DISCUSSION OF QUESTIONS	180

	P R O C E E D I N G S
	(9:03 a.m.)
		DR. AZZIZ:  Good morning.  Let us begin our meeting of the Urology Subcommittee for the Advisory Committee for Reproductive Health Drugs.  The topic today will be the safety and efficacy of Uprima, which is NDA 21‑118, presented by TAP Holdings.
		I would like to introduce a few people or at least discuss how we are going to outline today's meeting.  You may have the agenda.  We will have a little bit of a change in the agenda this morning.  The presentations by TAP Holdings, which will begin at 9:10, will be extended to 11 o'clock, another 30 minutes.  We will have an additional question and answer period in the middle of the presentations, and I will make sure that we don't run over.
		I wanted to make sure that we understood that today we need to stay on time.  I will make sure that we do so by simply interrupting the speaker and asking him to finish.  Hopefully that won't be necessary.
		Before I ask all the FDA staff and committee members to introduce themselves, I wanted to thank Dr. Marianne Mann for very good work in presenting the data, which is quite complex, in a legible fashion, which is something that we committee members really do need.
		Another point is during the comments in the session, I would ask you to please identify yourself before making your comment.  This is obviously being transcribed, and it is very difficult to figure out who is talking if you do not do so. 
		So, without further ado, I would like to have introductions beginning in that corner.
		DR. RACZKOWSKI:  Good morning.  I'm Victor Raczkowski with the FDA.  I'm the Deputy Director in the Office of Drug Evaluation III, and that's the office that oversees the Division of Reproductive and Urological Drugs.
		DR. MANN:  I'm Marianne Mann, and I'm the Deputy Director of the Division of Reproductive and Urologic Drugs.
		DR. SHAMES:  I'm Dan Shames.  I'm the team leader for Urologic Drugs.
		DR. HIRSCH:  Mark Hirsch, medical officer.
		DR. JARUGULA:  Venkateswar Jarugula, pharmacokinetics reviewer.
		DR. AZZIZ:  Dr. Jacobs will be here.
		DR. O'LEARY:  I'm Michael O'Leary.  I'm on the faculty of the Harvard Medical School and a urologist at Brigham and Women's Hospital in Boston.
		DR. DONATUCCI:  Craig Donatucci.  I'm a urologist from Duke University.
		DR. LIPPERT:  Marguerite Lippert.  I'm a urologist at the University of Virginia.
		MS. PETERSON:  I'm Jayne Peterson.  I'm the Executive Secretary of the subcommittee with FDA.
		DR. AZZIZ:  Ricardo Azziz.  I'm a professor of obstetrics and gynecology and medicine at the University of Alabama at Birmingham, and I'm chairing the committee.
		DR. KOWEY:  Peter Kowey.  I'm a professor of medicine at Jefferson Medical College in Philadelphia and a cardiology consultant to the committee.
		DR. GRABOYS:  Tom Graboys.  I'm a cardiologist at the Brigham and Women's Hospital and Director of the Lown Cardiovascular Center.
		DR. D'AGOSTINO:  Ralph D'Agostino, Boston University, biostatistician.
		MS. SCOTT:  Julia Scott, registered nurse, and I'm the consumer representative on the panel.
		DR. TIEFER:  Leonore Tiefer.  I'm a clinical psychologist in the Department of Psychiatry at New York University Medical Center and Albert Einstein College of Medicine and a sex therapist and sex researcher.
		DR. GREENE:  I'm Mike Greene.  I'm an obstetrician/gynecologist at Massachusetts General Hospital and Harvard Medical School.
		DR. HANNO:  Phil Hanno.  I'm a urologist at the University of Pennsylvania in Philadelphia.  
		DR. AZZIZ:  I would like to have Jayne Peterson, Executive Secretary of the committee, present the conflict of interest statement please.
		MS. PETERSON:  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 for the meeting and all financial interests reported by the participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research, which have been reported by the participants, present no potential for a conflict of interest at this meeting with the following exceptions. 
		In accordance with 18 U.S.C. 208, full waivers have been granted to Dr. Lippert, Dr. Jacobs, Dr. D'Agostino, Dr. Kowey, and to Julia Scott.  A copy of these waiver statements may be obtained by submitting a written request to the FDA's Freedom of Information Office, Room 12A-30 of the Parklawn Building. 
		Further, we would like to disclose that Drs. Califf, Kowey, and Donatucci have involvements which do not constitute a financial interest in the particular matter within the meaning of 18 U.S.C. 208, but which may create the appearance of a conflict.  The agency has determined, notwithstanding these interests, that the interest of the government in the participation of Drs. Califf, Kowey, and Donatucci outweighs the appearance of the conflict.  Therefore, they may participate fully in all matters concerning Uprima.
		In the event that the discussions involve any other products or firms not already on the agenda for which a 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 involvement with any firm whose products they may wish to comment upon. 
		DR. AZZIZ:  Without further ado, to stay on time -- it is 9:10 -- I would like to have TAP begin their presentation, if you would please.  As I noted before, we have extended the time allotted to them by 30 minutes, till 11 o'clock.  After the presentation by Dr. Heaton on erectile dysfunction treatments and summary of efficacy, we will take 10 minutes for questions and answers, and then we will proceed. 
		Thank you.
		DR. FRESTON:  Mr. Chairman, ladies and gentlemen, good morning.  I'm Dr. Jim Freston from the University of Connecticut Health Center.  I serve as a scientific advisor to TAP in the development of Uprima and for other drugs in their pipeline, and I am pleased to be able to moderate their presentations today and to present some of the data.
		Others who will join me in presenting are shown on this slide.  They include Dr. Barbara Bopp of the Drug Metabolism and Pharmacology Division, Dr. Jeremy Heaton, Professor of Urology at Queens in Kingston, Ontario; and Dr. Timothy Fagan, Professor of Medicine and Associate Professor of Pharmacology at the University of Arizona.  Dr. Heaton is an expert in erectile dysfunction, and Dr. Fagan is a specialist in cardiovascular clinical pharmacology.
		A number of TAP officials and scientists are here to support this presentation and can be called upon if needed, and they are listed here.  We will introduce them, as needed, along the way. 
		We also have some other ED experts who are serving as consultants and have done so over the course of time in developing this compound.  They are shown here.  It includes Drs. Carson, Dula, Lewis, and Melman, as well as Dr. Ray Rosen in the Department of Psychiatry at Robert Wood Johnson.  His presence is important to us because he helped developed the IIEF, a survey instrument for sexual function, which we'll be referring to today.  Dr. Addison Taylor is another professor of medicine, a specialist in cardiovascular and clinical pharmacology from Baylor, and Dr. Joel Morganroth from Philadelphia is a cardiologist and a specialist in electrophysiology and the interpretation of EKGs and something called Holter monitors that we will be discussing today.  And finally, Dr. Gary Koch is a senior statistician from Chapel Hill.
		Our proposed agenda is set out here.  After my introductory remarks, we will turn to the pharmacokinetics and metabolism of the compound, and then we'll get right into the state of the art of ED treatments and the efficacy data.  As Dr. Azziz mentioned, we'll take a 10-minute break there and then pursue the safety assessment, and then I'll try to summarize on time. 
		The FDA briefing document highlighted a number of areas for your focus and concentration, and we have tried to list them here.  Some comparisons were drawn in the FDA briefing document to other approved ED therapies, and we found that that worked very well.  It does provide a context for Uprima on both the safety and efficacy side and a point of reference as well.  So, we'll be bringing in some of those comparisons too to assist in your deliberations.
		You were asked to answer the question are the Uprima ED patients representative of those with ED in the general population, and we will address that comprehensively along the way. 
		The question was raised about the extent of pharmacokinetic variability.  We will deal with that as well as the clinical relevance of the 2 milligram dose.
		The efficacy in diabetes is of interest to all of us and we'll address that head on.
		Also, a question was raised about why the patients dropped out of the long-term safety despite continuation of efficacy in most instances, a very important question.  We'll deal with that. 
		But the main event today, if you will, obviously is in the area of hemodynamics.  We're all aware that in recent years there has been quite a lot of interest in cardiovascular events, including deaths in patients with erectile dysfunction who have had increased sexual activity in the context of using ED drugs.  So, we'll be spending a lot of time discussing that and its relationship to nitrate usage in this population and specifically in those who take Uprima.  
		And we will round out by discussing the nature of the experience when patients take Uprima at the same time as they consume alcohol.
		Let us begin with the definition of erectile dysfunction.  This is the one that we have used.  It is the NIH definition and it highlights that ED is the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance.  In recent years, WHO has also incorporated these features and added the concept of chronicity up to 3 months and variability.  ED can come and go.
		A bit about the epidemiology and demographics of ED.  We have two major surveys that we can draw on for help in this regard.  One is the U.S. National Health and Social Life Survey which was conducted in 1992 in 1,410 men and women between ages 18 and 49.  I'm sorry.  It's 1,410 men in this study of men and women, and they correlated ED to other diagnoses -- I will come to that in a moment -- and projected that ED was probably present in about 10 percent of men in this age bracket. 
		The other major study was the so-called Massachusetts Male Aging Study, MMAS, which actually antedated the previous study but was recently updated as well.  This was a cross-sectional study of 1,300 men, a slightly older group.  They found an ED rate of 52 percent.  10 percent of ED was complete, but most of it was moderate, with some minimal.  They extrapolated to the U.S. population and concluded that probably 30 million men in the U.S. suffer from ED, and they correlated ED with age, health status, and emotional status as well.
		This shows the relationship of ED to age from the MMAS, and you can see that the incidence certainly does march up into the elder years.  The increase is mostly in the moderate severity and the complete severity, with minimal remaining stable.  
		Now, although we all associate ED with age, it's important to point out that the incidence starts to tick up additionally because of the co-morbidities that creep in in the elder years.  And the other point to be made is that, yes, even though it is more common in elders, there is plenty of it in middle age.
		These are the associated diseases:  hypertension, diabetes, heart disease, concomitant use of medications, depression, and psychological factors.
		This shows the distribution of patients in some of these subgroups in the Uprima studies.  The duration of ED was 4.5 years.  We'll come back to that important duration.
		Hypertension.  31 percent of our patients were hypertensives versus 33 percent in MMAS.
		Coronary artery disease, 16 and 16.  We defined coronary artery disease as patients who had previous angina, previous myocardial infarction, or a revascularization procedure in the past, either angioplasty, placement of a stint, or bypass surgery.
		So, you can see that our populations are looking very much like the general population in MMAS with ED.
		Turning now to apomorphine itself.  This is a drug, a USP drug.  It has been around for quite a while.  In fact, it was first used as a pharmacologic agent in 1869, and there are now over 1,100 literature citations using doses all the way from 0.2 milligrams to 1,500 milligrams, and approximately 8,000 patients have been studied in clinical trials around the world, in addition to the 3,000 in the Uprima trials.
		It's approved in 12 countries for various indications, but mostly for Parkinson's disease which requires daily administration.  The usual doses are 3 to 30 milligrams subcutaneously.  Why Parkinson's disease?  Because apomorphine has dopaminergic properties and they were recognized as long ago as 1967.  In fact, the mechanism of its erectogenic effect is directly related to this property.  Specifically, apomorphine activates dopamine receptors in the hypothalamus and limbic neural pathways, and that's how it works in erections.
		Now, what about Uprima itself?  It's reformulated apomorphine.  It has been put into a sublingual preparation.  It, of course, has a unique central mechanism of action and, because of its sublingual formulation, a rapid and quite predictable onset of action.  And we'll show you data to support the fact that it's effective for ED in a wide spectrum of organic and nonorganic etiologies and severities. 
		There's good news on the safety side.  Again, we are all aware of the heightened interest in cardiovascular events in this population of patients.  We're pleased to report that in extensive Uprima trials, there have been no deaths, nor have there been any myocardial infarctions or cerebrovascular accidents related to the drug, and no priapisms.  Nausea was the most frequent adverse event, and syncope was the most significant.  And we'll spend time on both of these. 
		The proposed indication for Uprima is for the treatment of erectile dysfunction in these doses, 2, 3 and 4 milligrams.  The agency has asked us to present data at higher doses above the recommended dose, and we're pleased to do so today. 
		Above 4 milligrams, there's very little gain in efficacy, but there are more side effects.  Therefore, we're recommending the doses 2 to 4.
		Now, what's the rationale for proposing approval of Uprima at this time?  That is set out on this and the following slide.  As I pointed out, ED is associated with a number of diseases and conditions.  Drugs with different mechanisms of action are particularly useful in diseases that have multiple pathogenic pathways.  Think of hypertension, think of depression,  Hypertension is a particularly good example.  Multiple pathogenic mechanisms. In the beginning we had reserpine, hydrochlorothiazide.  Then we got methyldopa.  Then we added alpha-1 antagonists and beta blockers, and then calcium channel blockers, ACE inhibitors, and more recently the AT-2 inhibitors.  Each class of drugs in its time advanced the field and more patients were able to have their hypertension controlled.  Today, as you know, we can treat effectively hypertension in any patient, and in fact, with this array of different drugs, we can even tease out the etiologies of hypertension in some patients. 
		In contrast, the field of ED therapy is in its infancy.  We've only got three drugs that are approved.  One requires injections into the penis.  One requires insertion of a pellet into the urethra.  There's only one that's available orally.  All of them work by a peripheral mechanism, and all have a unique set of adverse events.  And there's no one drug that's effective for all patients.  Treatment, moreover, is strongly influenced by couple and physician choice.  So, a new drug with a different mechanism of action ought to have considerable potential in this setting. 
		Uprima has a unique central mechanism of action, a novel delivery system, and a rapid onset.  And we've studied it in 27 clinical trials, and we'll show you data to support our contention and conclusion that it's safe and effective treatment for ED in patients with and without organic disease.  
		This shows the scope of the 27 trials divided by classical FDA development phases, I, II, and III, and we've lumped I, II, and III down here.  We've looked at the pharmacokinetics and metabolic rate, including in elders and those with renal and hepatic impairment.  We've also looked at interactions with two antiemetics.  We have done careful prospective studies in populations with these conditions:  patients taking anti-hypertensives, five different classes, as well as short and long-acting nitrates.  
		We have looked prospectively in diabetics, in those who have consumed substantial amounts of alcohol quickly in conjunction with larger than recommended doses of Uprima, and we have a small group of patients with prostatectomy and spinal cord injury in whom we have just addressed safety issues, not efficacy issues.
		The efficacy conclusions are based primarily on three well-controlled cross-over studies that are unique in that they allow the patient to serve as his own control.  In addition, there's a dose optimization parallel study in which patients participate in two phases.  They adjusted the dose until they found the dose that was effective for them, and then they continued for the second phase, the so-called maintenance phase, at that dose, and we've drawn valuable information from that trial.  
		In addition, there are five long-term open-label studies and there are two first dose administered at home studies:  one we'll be discussing today; the other, a larger study has just only recently been filed with the agency.  We'll not be discussing that today because the agency has not had the opportunity to review those data.
		I'd now like to turn the podium over to my colleague, Dr. Barbara Bopp, to go over the pharmacokinetics and metabolism.
		DR. BOPP:  Although apomorphine is synthesized from morphine by an acid catalyzed rearrangement process, the final chemical structure of apomorphine bears little resemblance to that of its precursor morphine.  Apomorphine is not scheduled by the DEA.  It was, indeed, specifically excluded from the list of opiate substances in the schedule 2.
		Apomorphine is a relatively plainer molecule, and if you examine its structure, it contains the dihydroxyphenethyl amine moiety that is common to dopamine and the other catecholamines. 
		Apomorphine was formulated as a sublingual tablet for use in the treatment of erectile dysfunction.  This formulation was selected because it provided a means to obtain rapid absorption of the compound into the systemic circulation, thereby avoiding the first pass metabolism that had limited the usefulness of orally administered apomorphine for many, many years.  Another potential advantage of the sublingual formulation is that it would minimize any possible effect of food on the absorption of apomorphine.
		Depicted on this slide are the mean plasma concentration time profiles from the 2, 4, 5, and 6 milligram Uprima tablets that were administered to a group of 24 healthy young males in a crossover study, and you can see that the goal of rapid absorption of the compound into the systemic circulation was indeed achieved.  Initially there is a very short lag time of about 5 to 7 minutes, which corresponds to the time necessary for the tablet to disintegrate and dissolve in the subject's mouth.  Thereafter the plasma concentrations increase very rapidly and after Tmax, the apomorphine concentrations in the plasma also decrease very rapidly and fall to approximately 10 to 20 percent of their maximal levels by 4 to 6 hours after dosing.  Thereafter, there is a somewhat slower terminal elimination phase which only occurs at very low apomorphine concentrations. 
		This slide summarizes the pharmacokinetic parameters obtained in the study I was just describing and also include those from a 1 milligram subcutaneous dose, which was included as a reference.  Tmax, the time of peak plasma concentrations, averaged about 40 to 45 minutes with all of the sublingual doses compared to 20 minutes with the subcutaneous dose.  
		The peak plasma concentration, Cmax, averaged .7 nanogram per ml in the 2 milligram dose and increased to 1.9 nanograms per ml in the 6 milligram dose.  Coefficients of variation, inter-subject variation for Cmax ranged from about 50 to 80 percent.  
		AUC also increased with the dose, with somewhat smaller coefficients of variation, about 40 to 50 percent.
		Half-life was about 2 to 3 hours and was 2 to 3 hours and was similar with both routes of administration.
		The next slide further illustrates the dose proportionality in the pharmacokinetics of Uprima.  You can see that both Cmax and AUC increase in a linear and dose proportional manner.  Compared to the subcutaneous dose, the bioavailability of apomorphine from Uprima was estimated to be 16 to 18 percent across all doses.  The 3 milligram dose, which is proposed for marketing, was not included in this study but does fall within the range for which dose proportionality has been established.
		Some concern has been expressed about the variability in the pharmacokinetics of apomorphine.  This slide attempts to give a little different perspective on that variability and presents a frequency distribution of the log normalized Cmax values from almost 250 subjects who received the 6 milligram dose of Uprima in our phase I studies.  The higher dose is used in this presentation because that was the dose used in many of the phase I studies which were conducted early in the development of Uprima when we were evaluating the higher doses.  A similar picture of variability could be found for the lower doses as well.
		Mean Cmax in this population was 1.6 nanograms per ml.  The median was 1.5 nanograms per ml.  Approximately 65 percent of the subjects in this group had Cmax falling in these two bars between 1 and 2.7 nanograms per ml.  You can also see that more of the variability in the Cmax values was associated with the low concentrations rather than the high concentrations.
		Since the elderly are an important subgroup of patients with erectile dysfunction, we compared the pharmacokinetics of Uprima in a group of 48 healthy elderly subjects, 64 to 82 years of age, compared to a group of younger male subjects 19 to 40 years of age.  As you can see, the mean plasma concentration time curves in the two groups were reasonably similar.  However, there were some minor changes. 
		Tmax was increased from about 45 minutes in the young subjects to 60 minutes in the elderly subjects, and Cmax was decreased by about 20 percent.  Both of those changes were statistically significant.  AUC, the area under the plasma concentration time curve, was increased about 10 percent in the elderly.  That difference was not statistically significant.  The upper bound of the 95 percent confidence intervals for the relative bioavailability suggested that a 30 percent increase in AUC was possible in the elderly.  Half-lives were not different in the two groups.  Since all of these changes in the pharmacokinetics of apomorphine are relatively small, no dosage adjustment should be needed for Uprima in elderly subjects. 
		The next slide summarizes some of the other aspects of the pharmacokinetics of apomorphine.  It has a relatively large volume of distribution, suggesting extensive distribution into the tissues.  This is consistent with its physical chemical properties as a lipophilic basic compound.  
		Apomorphine is approximately 85 to 90 percent bound to the plasma proteins.  This is true over a wide concentration range, far exceeding the therapeutic concentrations.  It is primarily bound to albumin, with relatively little binding to alpha-1 acid glycoprotein.
		There is minimal renal excretion of the parent drug and the compound is rapidly cleared by hepatic metabolism. 
		This slide illustrates the metabolic pathways for apomorphine.  The compound, after sublingual administration, is predominantly metabolized by conjugation with either glucuronic acid or sulfate.  Together these two pathways account for approximately 75 percent of the dose.  Sulfation appears to predominate over glucuronidation, and apomorphine sulfate is the major metabolite found in the plasma and in the urine.  It is not expected that either of these conjugates would have any pharmacological activity.
		Apomorphine can also undergo N-demethylation, leading to the formation of norapomorphine which can then be conjugated with glucuronic acid or sulfation in a manner analogous to apomorphine.  In vitro binding studies have suggested that norapomorphine has much lower affinity at the dopamine receptors than apomorphine itself.  Unlike the catecholamines, methylation at the hydroxy groups is not a significant pathway for apomorphine.
		As you would expect, the formation of norapomorphine is mediated by the cytochrome P450 system.  However, we must keep in mind that this is a relatively minor metabolic pathway and accounts for only about 20 percent of the dose.  
		We did a series of in vitro studies to characterize which of the cytochrome P450 isoforms were involved in the metabolism of apomorphine.  Several isoforms can N-demethylate apomorphine, and the in vitro studies suggested that 1A2, 3A, and 2C19 were probably the principal isoforms involved in the N-demethylation of apomorphine.
		We also did studies to evaluate the potential of apomorphine to inhibit the cytochrome P450 system, and indeed apomorphine can inhibit 1A2, 3A, and 2D6, but this inhibition was only seen at concentrations that were 1,000-fold higher than the Cmax from Uprima.  Overall, the results of these in vitro studies combined with the extensive conjugation of apomorphine would suggest that it would be a very low potential for interactions of apomorphine with the cytochrome P450 enzyme system.
		We also did a couple of specific drug interaction studies that Dr. Freston mentioned.  Neither of the two antiemetics studied, Zofran or Compazine, had any effect on the pharmacokinetics of apomorphine.  The ethanol interaction studies will be discussed later by Dr. Fagan.
		Finally, a very brief conclusion.  After the administration of Uprima, apomorphine is rapidly absorbed and is also rapidly cleared from the plasma.  
		There is variability in the pharmacokinetics of apomorphine, but the clinical relevance of that variability can only be assessed through the safety and efficacy studies, which will be discussed later in this presentation.  
		No dosage adjustment is needed for the administration of apomorphine in the elderly.
		Apomorphine is primarily metabolized by conjugation and has a relatively low potential for any interactions with the cytochrome P450 system.
		Thank you.  Dr. Heaton will now continue our discussion
		DR. HEATON:  Thank you.  Good morning. 
		The current basis of management of erectile dysfunction stresses the importance of individualization in diagnosis and treatment.  There is a significant imperative to make consideration of the partner and the environment in which the sexual interaction takes place.  Management includes, first of all, the importance of lifestyle modification and education, and current treatment emphasizes non-invasive therapies first -- and there is only one oral agent available -- and also the importance of patient and partner choice of therapy.
		Uprima works by a central mechanism.  It works through known pathways.  It is a dopaminergic agent affecting serotonin and oxytocin, as well as nitric oxide pathways, starting in the hypothalamus and, importantly, progressing down the spinal cord where it induces normal response in the peripheral mechanisms.
		In a summary of efficacy, the major issue is clinical considerations, and this extends further than mere rigidity and erection.  It extends to the necessity to enable intercourse, to have a reasonable timing and onset of action, and to comply with the requirement that this must suit the choice of the couple and the physician.
		Measurement of erectile dysfunction in clinical trials is difficult because there is no standard physical measurement.  There is no accepted means of determining etiology in most cases of patients.  In the past we have had the use of duplex ultrasound, pharmacotesting, and Nocturnal Penile Tumescence, but these are not used currently and routinely in clinical practice.  We have, however, in this series of studies made good use of Nocturnal Penile Tumescence on recommendation of the agency.
		In the later studies here, we have employed the International Index of Erectile Function, which you will see as an acronym IIEF several times, and the Brief Sexual Function Inventory, BSFI, which are validated clinical trial instruments that were introduced after the beginning of the Uprima program.
		It's important to recognize that Uprima endpoints were determined after each dose administration, in other words, on every attempt, and these were evaluated from the home-use questionnaires.  Primarily the data points looked at were the erection firm enough for intercourse based on the patient response, the erection firm enough for intercourse based on the partner response, and the intercourse rate based on patient and/or partner responses.
		There's a significant advantage in using home-use questionnaires versus a retrospective questionnaire, in that this makes a direct assessment of efficacy at each dosing attempt.  It does not require the patient to recall attempts after a 4-week period.  It also does not involve averaging the function over a 4-week period.
		The issue of how representative this patient population is can be examined by means of looking at the inclusion criteria into the studies.  Heterosexual males aged 18 to 70 were admitted.  An essential ingredient was the patient's partner consent and agreement to go through with the study, and the partner herself was studied in addition.
		The presence of erectile dysfunction was confirmed by the principal investigator and also was pinned by the ability to attain and maintain an erection firm enough for intercourse in more than 50 percent of attempts in the 3 months prior to study.  
		There should be some documentation that a patient was physically capable of attaining some sort of erection, as documented by an ability to attain an erection sufficient for intercourse on some occasion during 3 months whether by masturbation, morning erection, or nocturnal erection. 
		Nocturnal erections were tested with NPT testing, Nocturnal Penile Tumescence testing, having a threshold of only 55 percent rigidity on 1 of 2 nights for 10 minutes, which is significantly below that required for normal NPT performance. 
		Patients were excluded if they had uncontrolled diseases.  
		They should have clinically acceptable pre-study laboratory values, including hormonal values.  
		Diabetic patients were explicitly included, but they should not have had diabetic instability as evidenced by serum glucoses above 250 or recent episodes of ketoacidosis.
		Similarly, hypertensive patients explicitly were included, as long as they had not had blood pressures over 180 or diastolics over 100.
		Smokers were included but only at a low rate of smoking because of the potential for smoking to mask the nausea adverse event.
		Patients were excluded with a history of allergic reaction to morphine, and they were also excluded if they had any history of pharmacotherapy concurrently or within 3 months prior to the study.
		The term "no major organic component" may be confusing, but this is what was used in the mid-1990's. We're more knowledgeable now, but explicitly this term was coined to exclude prostatectomies, spinal cord injury, Parkinson's disease, multiple sclerosis, where you know there's no chance of pharmacotherapy having a reasonable effect.  And penile prothesis and penile deformity for the same reason.  Also, it is logical not to treat patients with end-stage and unstable disease, so these two were excluded from the trials. 
		So, what kind of patient was admitted with these inclusion criteria?  The patients were 55 years old.  They had a weight of about 200 pounds, and they had had a duration of erectile dysfunction of an average of 4.8 years.  The racial split is shown for you there.
		This is a representative patient population, and we'll demonstrate, by looking at subgroups with organic disease, baseline erectile dysfunction severity, RigiScan values, and the duration of ED.
		The major subgroups represented within these trial patients included hypertension in 31 percent; coronary artery disease, 16 percent; and diabetes and the other listed organic diseases that were found to be coexistent with the patient's erectile dysfunction.
		If we look at the baseline severity based on a psychometric scale, the IIEF, and look at all the phase III studies and classify them according to a classification system that has been published, patients were found to have severe grades of ED in 39.3 percent, moderate in 35.4 percent, with a small minority having mild degrees of erectile dysfunction.
		How does this population admitted to the studies compare with other studies both of drugs and in the general population?  In fact, we see that the duration of erectile dysfunction is comparable to what has been seen in other clinical studies.  We see that the medical conditions represented are almost exactly overlapping, whether you look at a population study, the MMAS, or previous well-conducted clinical studies, the Viagra studies.
		This is a bar graph of the NPT data on admission to the study.  The RAU units is a measure of how much erectile activity occurred, and we're looking at tip rigidity units here.  In the light blue, normal subjects are shown with their average degrees of RAUs, and in the yellow, the Uprima subjects are shown.  The Uprima subjects never achieved the same degree of RAUs as the average patients in the normal population, and if we look at a second cut of the similar data from the RigiScans, we find again that the Uprima patients have a significantly different profile of their rigidities at the time they're admitted to these studies.  These are two different populations, in other words.  The Uprima patients have significantly less rigidity than the normal populations.
		We would conclude, therefore, from looking at the patients admitted to these studies, that this is a representative population because it is reflective of the ED population as a whole.  It includes both organic and non-organic co-morbidities.  It's clearly defined and is relevant to clinical practice.  It's consistent with well-conducted previous clinical studies.  It's consistent with the MMAS.  It included patients with varying degrees of severity.  The RigiScans were clearly abnormal, and the patient population studied does support the proposed indication. 
		Let's look at some of the efficacy endpoints.  Remember, this is applied on every attempt.  The primary endpoint is the answer to the question, did you attain and maintain an erection firm enough for intercourse?  The major secondary endpoints include the percentage of partners who answered yes to the same question, the percent of patients and partners who respond yes to the question about whether they were able to achieve intercourse, and time to erection.  Additional psychometric data is available from the patient Brief Sexual Function Inventory and the partner Brief Sexual Function Inventory, as well as the patient IIEF.
		These endpoints, therefore, are consistently stated.  They are clear, they are relevant to clinical practice and human use, and they are rigorously applied.
		We'll first look at the crossover studies in regard to efficacy looking at the primary endpoint.  Then we'll look at some subgroup analyses and the validated questionnaires. 
		This is a complex diagram, but it represents a schematic of the crossover studies that were utilized in the phase III Uprima studies.  Patients were admitted at baseline.  They were randomized to one of assigned doses.  Within those assigned dose streams, halfway along they would crossover and take placebo or conversely take the drug.  Every patient, therefore, was exposed to drug.  Every patient was exposed to placebo.  And each line of drug has its own placebo for direct comparison.
		This crossover design is important.  It's a very rigorous design.  It was suggested by the FDA and provides a very powerful tool.  It allows patients to be their own control.  All patients are exposed to study drug, and it's an appropriate design for stable chronic diseases.
		This is the first of a series of equivalent bar graphs that you're going to see, and I'll walk you through this slowly.  This is the combined data from the phase III crossover studies.  The percentage of yes responses to the question, is the erection firm enough for intercourse, is found in the y axis.  The yellow bars are baseline scores at around 25 to 27 percent.  The white bars are placebo scores at around 33, 32 percent, and with statistical significance at the p .001 level at both 2 milligrams and 4 milligrams, 45.6 percent respond yes and 54.4 percent respond yes at 4 milligrams.
		If we look at perhaps the most important outcome for a patient, did the attempt actually result in intercourse, the numbers are equivalent.  The baseline levels are there for you to see.  A small increase in placebo and the Uprima effect is visible with clinical and statistical significance.  We've not broken down these data into individual trials because the data are exactly representative across all the trials and correspond to the combined data. 
		If we compare what this means in terms of intercourse rates with available published data in the oral field, we find that the levels of placebo response in the Uprima trials compare very equivalently with that seen in the Viagra trials.  We see at 2 milligrams, the lowest dose of Uprima, we have a very comparable figure with what has been seen in the phase III studies published with Viagra.  Similarly, at the higher applied-for dose, 51 percent of patients were able to achieve intercourse on a per-attempt basis.  That's 51 percent of attempts would result in successful intercourse.
		What about the partner responses which were an essential and integral part of the Uprima studies from the very first?  They are unique to the series of studies that have been done on Uprima.  A particular scale was developed, the partner BSFI.  This was utilized and validated within these studies.  Obviously, partner consent and participation were required, and I've alluded to that.  It stresses the point that all along this has been recognized as a couple's issue.
		The partner responded to the first data point exactly similarly to the patients themselves, with a baseline level that's flat across doses, a small increase for placebo, and a statistically and clinically significant improvement for both 2 and 4 milligrams.
		If you ask about whether this attempt resulted in intercourse, the patients respond in exactly the same way.  In fact, it is very important to note that there was 98 percent concordance between the patient's response and the partner's response.  They all agreed about what was going on.  Men did not lie about their response rates.
		We can do many primary endpoint subgroup analyses and we have some analyses available comparing patients with substantial organic diseases as co-morbidities and non-organic co-morbidities, hypertensive patients, diabetic patients, patients with coronary artery disease, patients who had also got benign prostatic hyperplasia, patients who used alcohol, smokers, the older groups, and with all degrees of ED severity.  I'll show you only a few of these because these data are substantially overlapping.
		This is the documented organic disease subgroup, and if you will recall the numbers that I showed you on a previous bar graph -- and recognize that the baseline level is exactly equivalent -- the Uprima result is just slightly reduced numerically but still has full statistical and clinical significance.
		Similarly in the subgroup of the older patients, those over the age of 65 with a slightly reduced n, they come in with an equivalent baseline level and they are able to have significant improvement in erections firm enough for intercourse.
		The severity of erectile dysfunction is an important issue, and analyses were performed in a number of ways to identify that Uprima does have good activity in all levels of severity.  We studied severity cuts by IIEF criteria.  We looked at patients who had had absolutely no success at having intercourse during baseline, and we also looked at the most severely abnormal RigiScans to see what their clinical responses were.
		This is the definition of severity based on the IIEF, and if we look at the most severe subgroup of this, those who had severe erectile dysfunction, which was fully 39 percent of the patients, baseline levels are as you would expect, extremely low, a small increase for placebo, statistical and clinical significance of both 2 and 4 milligram levels with Uprima.
		Every patient was assessed for their baseline response, and some patients had absolutely no erectile ability during their baseline period.  These are the patients we're showing here.  So, you'll see no yellow bars because the number is 0.  However, taking this most significantly incapable group, you can see that both 2 and 4 milligrams had a clinical and statistical improvement in erections.
		Taking a maximum tip RAU units on the RigiScan, less than 9.5 is a published way of identifying those with most severe degrees of erectile dysfunction using the RigiScan measure.  This group of patients actually looks very similar to what we've seen before with statistical significance and clinical significance of both 2 and 4 milligram levels for improvements with Uprima.
		We, therefore, feel that Uprima is demonstrated to be effective in patients with severe erectile dysfunction as evaluated by IIEF or baseline success rates or with those with profoundly abnormal NPTs.  We've also shown that Uprima is effective in patients with mild or moderate ED.
		There are other endpoints and some of these are very important.  We're going to look at some home-use endpoints and some validated questionnaires.
		The timing of erection is a critical factor in patients' appreciation of the treatment they're receiving.  In this figure, which you may take a little while to digest, you'll find that Uprima acts in the same time frame as does placebo.  The important thing is the erection is firm enough for intercourse only 33.8 percent of the time on placebo and it is effective 54.4 percent of the time on 4 milligrams of Uprima.  This is a natural time course in the context of the clinical trial, and these numbers are not dose related.
		The patients' assessment of the treatment success was based on having success in more than 50 percent of attempts, and by these criteria, both the 2 and 4 milligrams, as many as 60 percent of patients were deemed a treatment success.
		If we look at the percent of patients with mean intercourse attempts achieving satisfaction over 3, which is mostly satisfied, on their home diaries on a per attempt basis and who had an improvement over baseline, we see again an improvement that is clinical and relevant at both 2 and 4 milligrams.
		If we look at the partners' response in exactly the same context, the numbers are very similar.
		And if we look at the 4-point improvement in erectile function domain of the IIEF, which has been regarded possibly as the most statistically evident way of proving clinical validity, we see that the numbers are exactly overlapping what we have seen almost in all other methods of measurement and to an appropriate statistical value.
		So, the phase III crossover studies show clinical significance at all dose strengths and in all subgroups whether you look at patients with coexisting organic disease or no evidence of coexisting organic disease or the subgroups of hypertension and so on.
		There is robustness of the Uprima efficacy results demonstrated by the fact that this persists across a variety of home-use efficacy endpoints and is confirmed by the results of validated questionnaires.
		There was an issue potentially about the clinical relevance of 2 milligrams.  This is statistically superior compared with placebo in all phase III crossover studies for the primary endpoint and virtually all secondary endpoints.  
		It shows a 4-point improvement on the IIEF erectile function domain in 45 percent compared to only 27 percent of placebo.
		It's statistically significant compared with placebo in patients with moderate to severe ED, as well as patients with a variety of organic diseases.
		And intercourse rates, most importantly, increase from a placebo rate of 29 percent to 42 percent for Uprima at 2 milligram, which is a 13 percent increase, which compares favorably with the 16 percent increase seen with Viagra at its lowest dose.
		Let's briefly look at the efficacy in diabetic patients.  The diabetic patient subgroups were in a separate trial, crossover design, similar to that which you've seen previously, were studied at 4 and 5 milligrams.  This was, as a whole, a more severely affected group than the previous combined studies, with 61 percent filling in the severe erectile dysfunction category.
		If you look at the 4 milligram and the combined groups, both statistical and clinical significance is obtained with the effect of Uprima, and it's interesting to note that in this group of patients, the baseline level of function for the erections firm enough for intercourse is as you would expect, significantly lower.
		If we look at the diabetics who took part in the phase III crossover studies and look at them as a subgroup, the efficacy of 2 milligrams and 4 milligrams is displayed here, again in a similar pattern to that which you've seen previously.
		In conclusion, about efficacy in diabetic patients, this is similar to the results seen in other clinical studies where efficacy in diabetic patients is lower than that seen in the general population.  The crossover study specifically suffered from a randomization imbalance, but statistically significant results were noted in the 4 milligram arm and both dosing groups combined from the specific diabetes crossover study.
		In the diabetic patients, who were naturally enrolled in the phase III crossover studies, efficacy improved approximately 10 to 20 percent over placebo in all dose strengths.
		There was one parallel design study that I should report on here which is a slightly different structure from that we've seen previously.  Obviously, the absence of crossover within each arm is there.  So, there was a fixed dose at 5 milligrams, 6 milligrams, and a voluntary titration phase where patients were allowed to adjust their dose upwards. 
		These are the data from this study and obviously the subgroups will not have their own placebo group.  But the placebo and baseline for the study as a whole is exactly as we have been seeing.
		If we look at the dose optimization efficacy on the primary efficacy outcome, which is erections firm enough for intercourse, we see an overall of 53.9, and if we truncate it to the applied for doses of 2 and 4 milligrams, the efficacy is seen at 47.6 percent.
		If we take the partners' view of exactly the same situation, the partners ratify that at 2 and 4 milligrams in the dose optimization structure, they're able to obtain erections at 48 percent. 
		And if we look at whether the attempt resulted in intercourse, this is inevitably a few percentage points lower, but nonetheless the statistical and clinical significance is fully maintained.
		How about the long-term studies?  An important issue of discontinuations.  Obviously, the long-term studies were designed primarily to collect safety information, and within these studies, a number of factors clearly contributed to patient discontinuation such as lack of efficacy, which we would expect, adverse events, which we would expect.  But there were the additional factors of the approval of new compounds, the arrival of new compounds on clinical prescription in the marketplace, and in particular Muse and Viagra both came out during this period.  
		These studies were long and had very stringent patient requirements because, you remember, all these data are acquired on a per-attempt diary completion, and there were, in addition, competing investigational studies.
		Nonetheless, this is the complete data set for all doses for the 6-month progress, and you'll see that by the end of 6 months, 83.5 percent of the time patients had erections firm enough for intercourse.  The n value has decreased from 1,000 to 426.
		This shows that in short-term studies we know that treatment success can be achieved in 50 to 60 percent of patients, and yet 80 percent of patients actually entered into long-term studies.  So, we're going to expect a 20 to 30 percent dropout based on patients enrolled who had no efficacy.
		Also, dropout rates were significantly influenced by adverse events, the approval of Viagra and other competing trials, and the burden of patient inconvenience associated with frequent visits.  Despite this, over 42 percent of patients reached the 6-month time point in the long-term studies and demonstrated sustained and reliable efficacy.
		So, if we look at all doses and look only at those patients arriving out at the last data point and project back, what their level of success was is demonstrated here.  At the conclusion of the 6 months, they are achieving reliable per-attempt erections firm enough for intercourse at the 83.5 percent level.  And if we limit this to 2 and 4 milligrams, which are the applied-for doses, this number shows that patients who are successful on 2 and 4 will maintain a very satisfactory level of function, around 88, 89 percent repeated attempts at intercourse, having erections firm enough for intercourse, on every occasion.
		So, efficacy in the long-term studies demonstrates that patients remain in long-term studies and will have sustained and reliable responses with erections in more than 80 percent of attempts.
		Patients obtaining efficacy in long-term studies are similar to all Uprima patients if you look at their baseline success rates.  
		The overall efficacy conclusions can be stated thus.  The clinical trials included patients who are representative of the general ED population.  They were similar to those done in community studies and similar to those done in other clinical trials.
		Uprima at 2 and 4 milligrams has been shown to be statistically and clinically significantly better than placebo in large scale controlled studies.  
		At 2 and 4 milligrams, Uprima has demonstrated a clinically relevant improvement in IIEF erectile function domain, which is a 4-point increase, in comparison with placebo.
		The Uprima partner efficacy data has been shown to be almost identical to the patient efficacy data, with a 98 percent concordance.
		And patients remaining in the long-term studies have substantial and reliable responses with erections in more than 80 percent of attempts.
		It has been demonstrated that Uprima is effective in all subsets of patients and they have been identified to you before.  
		Uprima efficacy has also been demonstrated in all severities of ED.
		Uprima has been shown to have a rapid and natural onset of action.
		And it has been demonstrated to have significance in all satisfaction and erectile function indices in the psychometric scales that you have listed.
		Thank you for your attention.
		DR. AZZIZ:  Let's go ahead and take 10 minutes for questions.
		DR. FRESTON:  Mr. Chairman, I wonder if I could make an explanation to the committee about a change in plans.  We have obviously deleted several slides from the projector that are before you.  We wanted you to have a full set, but you can catch up to where the speaker is simply by flicking forward.
		DR. AZZIZ:  Thank you.
		Questions from the panel, please.  Dr. D'Agostino.  And please identify yourself as you ask questions.
		DR. D'AGOSTINO:  Ralph D'Agostino.
		Can I ask a question about the subsets of individuals, the diabetics, hypertensives, and so forth?  Given the entry criteria of the NPT scale, you do get these individuals but you get them -- for example, the diabetics.  Do you get them at a more favorable position?  You put the Viagra data up there.  I'm just trying to see how I should evaluate it.  It's not diabetics as one would necessarily recruit in a study, but it's diabetics who have a favorable NPT score.  Can you say something about that potential confounder in terms of interpreting some of these results?
		DR. FRESTON:  I think the first point to make here is that we would not want you to compare our data against Viagra's in diabetics or anybody else.  These are separate studies.  That's just for your point of reference.  We want you to compare the data versus placebo and baseline.
		DR. D'AGOSTINO:  Well, but still in terms of trying to understand what these rates mean, you unfortunately gave me the Viagra comparison.  But forget the Viagra comparison.  In terms of am I trying to evaluate what's going on in these subsets and trying to interpret them, given this added feature of the entry criteria.  Can you tell me something about how I should look at that data?
		DR. FRESTON:  Yes.  We'd like to call on Susan Buttler right there who can clarify that.
		MS. BUTTLER:  Hi.  I'm Susan Buttler from TAP.
		There might be some confusion that wasn't quite conveyed to you in the 804 study which was our diabetes study.  The specific study done in diabetics did not have NPT testing as a facet of it.  It was not part of the inclusion/exclusion criteria.  So, hopefully that addresses your concern.
		DR. D'AGOSTINO:  Well, I still have those subsets in the other studies, and I'm just trying to get a sense.  I mean, it's going to lead, obviously, to the safety question also, what are these individuals like and what are you really measuring in terms of the ability of the drug.
		DR. FAGAN:  The exclusion criteria excluded people with systolics over 180 and diastolics over 100.  The diabetics were excluded with fasting glucose, I think, over 240.  So, only the most uncontrolled patients were excluded, ones that you wouldn't want to clinically treat with this drug anyway.
		In addition, if you look at the 804 study at the baseline success rate of about 10 percent, you know that in fact you were getting patients with quite severe erectile dysfunction and severe diabetes.
		DR. FRESTON:  Our calculations indicate that our exclusion criteria excluded about 10 percent of patients with hypertension who failed to meet these entry criteria and about 5 percent of diabetics.
		DR. GRABOYS:  Yes, Graboys, Boston.
		Two subsets that maybe you will be able to expand upon.  One is the African American population because, as I saw the numbers, you're looking at a relatively small subset.  And the second is the elderly patient population because in cardiology we're seeing a lot of these folks come in who are 76, 75, 80, 82, 83, and if you have any other information on that, I think it would be helpful.
		DR. FRESTON:  Well, it's been particularly difficult to recruit African Americans to ED studies.  We're not the only ones who have had trouble.  We don't understand it entirely, but it appears to be something cultural within that population.  We can't get them in.  We tried.
		With respect to the elders, we had a cutoff because in keeping with the development of most drugs, one likes to span about 90 percent of the target population and then later go and focus on other minorities, be they children, not for this drug but for other drugs, or very elders.
		Now, the data we do have above age 60, for example, shows enduring efficacy at that age and higher versus the younger. 
		DR. GRABOYS:  65 to 70, right?  Because the cutoff was 70.
		DR. FRESTON:  Yes.
		DR. FAGAN:  When we get some of the safety data in the specific interaction trials and patients on multiple cardiovascular drugs with a mean age of 67, that will probably be of some use.
		DR. TIEFER:  Dr. Tiefer.
		Did you have any corroboration by the partner about these inclusion criteria?  For example, when you required that a patient be able to have an erection sufficient for intercourse during the preceding 3 months, this was on the patient's report alone?  And how often was it just a morning erection or a masturbatory erection?
		DR. HEATON:  This was on the patient's report and we noted in the studies, that there was extremely good corroboration in the patients and the partners in all of these studies.  Susan Buttler has further information.
		MS. BUTTLER:  In all of our clinical trials, we involve patients and partners, and partners were required to come in not only for the informed consent process, but also to address the issue that you're talking about, whether or not the patient's data was corroborated.  And it was in their medical histories and the information that was documented at the site. 
		In addition, if you look at the baseline performance of patients, we knew what our patients were at baseline both on what the patient said at baseline and the partner's data.  We probably did point out to you, but I'll mention it again.  98 percent of the patients' data and partner data correlated very well, so it was a high rate of correlation.
		DR. TIEFER:  Well, I understood that those were the data during the drug trial, but I wondered did you ask the partner about the preexisting situation and whether the patient was capable of erection, intercourse, masturbation, what, during the previous 3 months.
		MS. BUTTLER:  The primary information would have come from the patients, but the patients and partners were required to be at the visit to be assessed to be included in the trial.  Whether or not partners would have disputed the patient's information in front of their partner, I can't really expand on, but we did make every effort we could to corroborate that data.
		DR. KOWEY:  I actually do not want to wander too far from my expertise, but I have a few questions about design. 
		One problem I have -- and the agency brought up in the briefing booklet -- was that patients should have naturally been unblinded from their therapy.  The question is, when you're using a subjective questionnaire, can you give us some idea of how much you thought there was unblinding in this study?  I mean, from your perspective.  There's no way to answer this question definitively, obviously, and I'm not sure there was unblinding.  But it is an issue when you're using a drug that produces a fairly high incidence of nausea.  So, could you answer?
		DR. FRESTON:  Let me start on that first.  First, it was a very low incidence of nausea.  98 percent of the patients at 2 milligrams had no nausea at all, and I'll show you those figures.  So, nausea was usually not present.
		Moreover, we looked at the efficacy data in patients who experienced no nausea and it's the same as in those who experienced nausea.  So, we don't think the presence of nausea, or any other effect, led to unblinding.
		DR. KOWEY:  That's 2 percent that didn't get nausea?  That's not what that says.
		DR. FRESTON:  This excludes patients who had no nausea.  So, we're just looking at the efficacy in patients who had no nausea, and you can see that it still stands up.
		DR. AZZIZ:  Dr. D'Agostino?
		DR. D'AGOSTINO:  I had a similar question.  In terms of looking at the data, given the way you presented the data, I'm presuming that there was no interaction between the first and second period of the crossover.  I'm asking this, though I'm saying it in an affirmative way.  But then the results for the first period and second period would be the same.  So, even if the blinding was broken, it didn't sort of carry itself into the second period from people thinking they were on treatment, or now thinking they might be on placebo.  Is that all true?
		DR. FRESTON:  Anthony Edmonds, statistician, will answer that right behind us.
		MR. EDMONDS:  I'm Anthony Edmonds from TAP.
		Yes, we looked at sequence effects, and there was no evidence of carryover effects in the studies.  
		We also did an analysis of the first period only, if you would like to pull that slide.  The results from this analysis are very similar to what we've seen before, so that even if there were a concern about this, these data are very consistent with the data that we've already presented to you overall.
		DR. AZZIZ:  Let's go ahead and continue so that we can give the sponsor sufficient time to present.  We will have plenty of opportunity to ask questions, of course, in our deliberation later on as well.
		DR. FRESTON:  Thank you, Mr. Chairman.  Let me now continue with the safety assessment.
		In this safety assessment, I would like to provide an overview of the treatment exposures, the dimensions of the exposure, and then we'll go on to address the overview of adverse events.  We'll then concentrate on syncope, and obviously we're going to spend the most time in this very important area of hemodynamic effects.  We'll take up syncope as part of that and we'll show you the results from some specialized prospective studies in diabetics where we had them hooked up to monitors and stressed them, and similarly with patients on antihypertensives, nitrates, and those given Uprima with alcohol.  Then I'll come back to nausea and close with some additional safety issues.
		Now, let me remind you of the database from which the safety assessment has been drawn.  We have information on over 3,000 patients at all doses.  I'll show you data at the 2 and 4 milligram dose drawn from just under 2,000 patients.  It's important to realize that in this kind of treatment, every dose administration is a separate treatment event with its own efficacy parameters and its own potential for adverse reactions.  Thus, we're going to be talking about 75,000 treatment exposures at all doses and 35,531 at 2 and 4 milligrams.
		We have 461 patients who have been treated for at least 6 months and 127 treated for at least a year.
		This shows the age distribution, coming back to your concern.  Yes, there are not as many elders in there as we'd like, but we have quite a few between 61 and 70.
		Now, with respect to this population, I'll remind you again that it's very similar to the Viagra population and quite relevant to the ED population at large.  
		Most of the patients in the Uprima trials were taking other medications.  In fact, 90.6 were taking other medications, and I've shown the different classes, major classes here.  You can see that they are mostly drugs for cardiovascular diseases.
		This shows the list of the adverse events that occurred in more than 5 percent of patients, more than 5 percent of patients, not more than 5 percent of dosage administrations, which is another issue we'll come to.  The AEs in order are shown here. 
		The first point to make is that there is a dose-response relationship.  At the recommended doses, for example, nausea, 15.5 percent of patients experience that, and at higher than recommended doses, it was higher.
		The second point I want to bring out is that I've highlighted certain of these AEs because they tend to track together.  They, in fact, form a cluster of AEs which serve as a useful prodrome for heralding the potential of syncope, and we'll come back to that.
		And we'll do it right now.  Dr. Fagan.
		DR. FAGAN:  I'd like to address four of the points raised by the agency. 
		First is syncope.  Syncope is a sudden, transient loss of consciousness with lost of postural tone associated with spontaneous recovery as soon as the patient is supine.  Published estimates are that syncope may occur in up to 40 percent of the population during their lifetime from a variety of causes. 
		There are cardiogenic causes of syncope which are primarily due to arrhythmias.  We're more interested here in non-cardiogenic.  Most common to this is vasovagal.  Published estimates range from 50 to 80 percent of all syncope.  It's biphasic.  There's an initial phase of apprehension, anxiety, and increased heart rate, followed by a vasodepressor phase, with decreased heart rate, blood pressure, cardiac output leading to a faint or syncope.  There's usually prompt resolution when the patient is supine.  It's self-limiting, and usually accommodation occurs so that a stimulus that may produce vasovagal syncope one time usually doesn't.  60 to 85 percent of people who have syncope never have another episode.  There are other types of noncardiogenic syncope, but they represent a small percentage and aren't really relevant here today.
		Why do we think that the syncope with Uprima is noncardiogenic?  There are a number of reasons.  It appears to be vasovagal because of the timing and the pattern of the syncope.  There's a typical prodrome.  There's an absence of association with evidence of cardiovascular disease, and we have data from Holter monitors.
		We did a total of 1,702 Holter recordings beginning before and continuing for several hours after the doses of Uprima.  This was in a total of 344 subjects and patients.  We included in this patients in the diabetic study, patients in the nitrate and antihypertensive interaction studies, and patients in the alcohol interaction studies.  Basically what we saw was a similar incidence of arrhythmias in the patients when they received Uprima compared to when they received placebo or prior to receiving Uprima.
		What's the overall syncope in the Uprima studies?  I'll make two points here.  One is that it's obviously dose related, going from .2 percent at 2 milligrams to 2.1 percent at 6 milligrams.  There appears to be some reduction when the dose is optimized, although it certainly isn't eliminated.
		We looked at a number of demographic characteristics to try and see who might have syncope and who might not.  There were no associations with that long list of concurrent medications that Dr. Freston showed you.  There were prodromal symptoms.  They're listed here, and any one or more of those is considered to represent the prodrome and would be things that you would warn the patient about, about possible impending syncope.
		How well does it work?  Well, whether you look at all doses or just 2 and 4 milligrams, 85 percent of the patients of the syncopal episodes were associated with the prodrome at that administration.  Whereas, with 2 and 4 milligrams, less than 2 percent of administrations without syncope had the prodrome.  So, about 85 percent had one or more prodromal symptoms and rarely did the prodromal symptoms come without syncope.  So, it distinguishes quite well.
		Of the nearly 2,000 patients who received 2 and 4 doses of Uprima, we had 13 episodes of syncope.  That's about 1 per every 2,700 doses.  What does that mean?  Well, let's say the average couple who chooses to use Uprima uses it twice a week.  That's 100 times a year.  So, that couple can expect 1 episode of syncope in 27 years.
		Now, if you go back to the development of this drug, the early syncopal events were unexpected, and because they were unexpected, there were some strong reactions on the part of the physicians.  There were some interventions and there were two injuries associated with these syncopal episodes.  However, since that time, with education of the patients and the physicians basically telling them to lie down if they have any of the prodrome, there have been many fewer interventions and no serious injuries.  And there were no sequelae in the two injuries that occurred early on.
		The incidence of syncope is 0.6 percent of patients having syncope at some time if the dose is optimized to 4 milligrams.  It's 1 in 2,700 doses at 2 or 4 milligrams.  85 percent of the patients will have the prodrome which will warn them of the possibility of syncope, and all of the syncopal episodes occurred within 1 hour of dosing.  So, past that time, they should be relatively safe. 
		In the context of the usage and instructions to remain recumbent, we should have a further reduction in the risk of syncope, and that's been evaluated in a large study with nearly 1,000 patients that was submitted to the FDA but has not yet had a chance to be fully evaluated. 
		Now, in conclusion, the syncope question.  The patients who have a syncopal event will have a vasovagal prodrome to warn them.  Most of them will be recumbent, which means that they won't have syncope in the vast majority of circumstances.  They will be accompanied by a sympathetic partner, and they're unlikely to be doing anything dangerous like driving a car or operating heavy machinery.
		For context, let's think about a few other marketed drugs that have the same or higher rates of associated syncope, drugs that are used for non-life-threatening situations:  bupropion, used for depression and smoking cessation; alpha blockers for BPH; and Muse for erectile dysfunction.
		How about hypotension?  The mean maximum decrease may not be familiar to everyone here.  Basically this is a way of looking at the worst case as far as decreases in blood pressure.  You take each individual patient across multiple time points, find the one point where they had the greatest decrease in pressure.  You do that for each patient and average those numbers.  Obviously then the averaged maximum decreases are going to be much more than you'll see on the average at any point in time.
		Placebo then will tell you what the random variation of blood pressure is in the absence of any pharmacologic intervention.  Now, those of us who do a lot of ambulatory blood pressure monitoring or have patients who bring in lots of home blood pressures, know that there's a great deal of variability throughout the day in response to meals, anxiety, cold, smoking, and that this is something that is really not any problem for the patient, although many times they're surprised when they see how much they vary.
		This is the mean maximum decrease in blood pressure from the third phase III crossover study looking at supine and standing blood pressure and at the recommended doses of 2 and 4 milligrams.  There are no statistically significant differences between placebo and Uprima, and in fact, there are totally clinically insignificant differences as well.
		If we look over time with 2 milligrams, there's no difference. 
		If we look at 4 milligrams, there's no difference, supine or standing.
		How does this look compared to Viagra?  This is as good as a comparison as we can do, but there are some differences.  The prime thing here is that we're looking at 2 hours spread out on this scale with Uprima, and the first 2 hours with Viagra just fall in here.  Basically we see no statistically significant decrease in these 150 or so patients with 4 milligrams of Uprima, and numerically it's only about 4 millimeters of mercury, whereas we have about twice that decrease with the maximum recommended dose of sildenafil.
		How often did hypotension occur?  You're going to get a chance to see some of these episodes in detail.  They're quite infrequent at 2 milligrams, and when the dose was optimized as high as 5 milligrams, there were no events.  When you optimize up to 6 milligrams, 2.5 percent of the time.  None of these patients had injury.  None had sequelae, and the only thing that they had to do was lie down for a period of time, which was variable.
		In addition, these events are essentially all vasovagal.  It's not that this drug is a direct vasodilator and decreases everybody's pressure.  In most people, it does absolutely nothing, and only the ones who have this vasovagal effect have a decrease in pressure.  In fact, 52 of the 53 who had hypotension had the prodrome.  So, the prodrome predicts hypotension just as it predicts syncope.
		In summary, we didn't see anything at 2.  We didn't see anything at 4.  I didn't show you 5 milligrams in the interest of time.  There were statistically but not clinically significant mean decreases.  The decreases you see with the highest marketed dose of Viagra is about twice what you see in the supine position, both supine, with the highest proposed dose of Uprima.  
		Less than 5 percent of patients reported hypotension overall, and 98 percent of them had a prodromal warning.
		What about safety in diabetics?  These are patients who have high incidence of cardiovascular disease.  It's just as likely that you'll have a myocardial infarction if you have diabetes and no known coronary disease as if you've already had a myocardial infarction.  We also know that their autonomic nervous systems are not all that they might be in a younger, healthier patient, and therefore, conceivably these patients could be at higher risk. 
		But in point of fact, what do we see as far as the mean maximum decrease in blood pressure with Uprima compared to placebo?  Absolutely no difference.  As you'll see later, this and other higher risk subgroups actually have numerically less adverse events than younger, healthier patients, and you'll see that in detail a little bit later. 
		So, the adverse event profile, which I haven't shown you, was very similar to what we see in all the phase III trials in all the patients.  Remember that this was done at 4 and 5 milligrams, so half the patients were higher than a recommended dose.  When we looked at the Holter monitors, we saw no abnormalities that could be attributed to Uprima, and there were 3 of 205 patients who had syncope.
		With regard to nitrates, well, we all know that in the field of ED that there is certainly concern with nitrates and with other hemodynamic interactions.  Because of this, a trial was designed to look at pretty much the worst possible case.  We took patients with significant coronary disease -- I'll show you some of the other things -- and then subjected them to a much worse situation than they might otherwise be subjected to clinically.  So, at 5 milligrams of Uprima, above the recommended dose, 162 patients.  We did our pressures with a Dinamap so we wouldn't miss any, if anything exciting happened.  We did Holter monitors in all these patients and recorded adverse events. 
		How was this tougher than the normal situation?  It's a higher than recommended dose of Uprima.  There were multiple concurrent drugs.  18 of the 20 patients on short-acting nitrates were on at least one other drug that could lower blood pressure and about 16 or 17 were on two or more drugs that could also lower blood pressure.  In the long-acting nitrate group, it was similar.  And then we made them stand up and down and stand up and down and up and down, which as we know being in the standing position is where you get the blood pressure drops, it's where you get the symptoms.  And the treatment is to stay lying down.  So, we did exactly what you should tell your patients not to do just to see how bad we could make it.
		They were an older group, average 67 years, a variety of other agents.  Some of the short-acting patients were on not only antihypertensives but long-acting nitrates at the same time, and they had just a few other things wrong with them:  hypertension, previous myocardial infarctions, previous revascularization, stroke, diabetes, congestive heart failure, and atrial fibrillation.  So, I would submit that these are about as sick a patient as you want to prescribe a drug for ED.
		Mean maximum decrease in pressure.  Basically the only place we see a statistically significant difference is in the standing position with either the short- or long-acting nitrates.
		When we look at the time course, we of course see this very nice response to sublingual nitroglycerin, which is very obvious.  There's no statistically greater decrease in the combination of nitroglycerin and Uprima which is shown in the magenta here.  The nitroglycerin was dosed at this point in time; Uprima was dosed here.  So that we could see the maximum pharmacodynamic effects based on when we knew that the Cmax would coincide.
		When we look at the long-acting nitrates, we see that there is in fact some statistically significant difference.  If you remember how much variation we saw just with placebo, about plus or minus 9 millimeters of mercury from baseline in healthier patients, then you see that that's about how much of a decrease, although obviously this is systematic and not random, but it's within the range that we often see clinically.  There was a significant decrease in diastolic, but it's a matter of about 3 or 4 millimeters of mercury.  And there's no statistical or clinical decrease in blood pressure past 1 hour.
		Now, how does that compare to Viagra?  These are obviously two different studies, and there are some differences.  In fact, this comparison is loaded in favor of Viagra.  How so?  We have higher than a recommended dose of Uprima.  We have a mean middle recommended dose of Viagra.  These patients are standing.  The Viagra patients were sitting.  The timing is a little bit different.  You just saw this.  And we know that out here is where Uprima was dosed, nitroglycerin here, and there's the decrease.  Viagra was dosed here, sublingual nitroglycerin here.  You see that the decrease due to nitroglycerin is pretty much identical in the two studies, but there's a much greater decrease in systolic pressure of about 27, 28, 30 millimeters of mercury with the combination of sublingual nitroglycerin and Viagra. 
		The other thing you'll notice is that by 1 hour, the pressure with sublingual nitroglycerin -- this is actually an hour and a half after Uprima -- that it's back to baseline, whereas here we're still very much below baseline and don't really seem to be increasing very fast, although we don't really have that data.
		If we look at diastolic blood pressure, we see exactly the same thing.  No difference from placebo with Uprima.  Big difference with Viagra.  And a decrease about as 6 times as large with the combination there as with this combination.
		If we look at the long-acting nitrates -- again, you've seen this graph before -- you know that a few of these points are statistically significant but they're not very large.  You see that there's a much larger -- nearly 45 millimeter mercury -- decrease when Viagra is given to patients receiving a long-acting nitrate.  Here again, we're using a higher than recommended dose of Uprima and a median dose of Viagra.  The doses of long-acting nitrates were not identical, but they were quite similar overall.
		If we look at diastolic blood pressure, we see exactly the same thing:  3 or 4 millimeters of mercury here, gone in an hour and a half; 23 millimeters of mercury here and still persisting after a couple hours.
		So, in conclusion, as far as nitrate and Uprima interaction, we had no syncopal events.  We had no Holter changes that we could attribute to Uprima.  We saw them on nitroglycerin alone.  We saw them before Uprima, but nothing that was specifically with Uprima and not at other times.  
		The blood pressure decreases with Viagra were considerably larger and longer in duration than those with Uprima.
		The patients who did have clinically significant decreases in blood pressure also had prodromal symptoms.  So, again, they would have been warned and, in fact, had no syncope. 
		We believe that with adequate patient instruction, basically reinforcing what you tell everyone, that Uprima can be administered to patients taking nitrates given some degree of clinical judgment.
		Now, fully 30 percent of the ED population can be expected to be taking antihypertensive drugs, and we can think of certainly pharmacodynamic interactions.  Drugs that lower blood pressure, given together, usually lower it further.  So, the same trial included five different classes of antihypertensives.  I'm not going to show you the time course because nothing happened.  There's no statistically or clinically significant differences here except this statistically significant difference which is because on placebo there was abnormally low variation in that group.
		So, in conclusion regrading the antihypertensives, there's no clinically significant mean changes from baseline in blood pressure or heart rate with the five different classes.  The adverse events, which I haven't shown you, were similar to other Uprima I, II, and III studies.  There were no Holter monitor changes which we could attribute to Uprima except some that were attributable to a vasovagal effect, sinus pauses, rare instance, secondary heart block.  Those were occasionally associated with adverse symptoms and sometimes were totally asymptomatic. 
		Only 1 of the 122 patients had syncope.  That patient was on a beta blocker.  Again, that's not a higher incidence than we see with 5 milligrams in the other trials.
		What about alcohol?  In an early phase III trial, there was a syncopal event in a patient who drank a whole lot.  He liked lots of things, different kinds of hard liquor, beer, all at once, and because of this syncopal event, it was thought that it would be appropriate to conduct some alcohol interaction studies.  
		In the first study, we used a relatively high dose of Uprima, 5 milligrams, and a relatively high dose of ethanol.  This corresponds to about 4 to 6 ounces of 80 proof hard liquor depending on body weight of the person.
		There were two serious adverse events.  They were serious adverse events by virtue of being admitted to the hospital.  They were not serious because they had infarctions or strokes or any sequelae, but they made that definition because they were hospitalized.  
		But because of this, it was decided to start out with a little lower dose of ethanol.  So, 6 milligrams Uprima, 0.1 gram per kilogram of ethanol.  No SAEs.  There were 4 patients who had nausea and pallor and were given oxygen as a precaution, but they were not hypoxemic.
		Further trials were then conducted with 6 milligrams of Uprima and .3 and .6 grams of ethanol.  I'm going to skip the .3.  But the design was exactly the same, double-blind, randomized, all the good things.  There were three periods.  In each period, the patient on all 3 days got Uprima or a placebo tablet, and on the last day they got either ethanol beverage or a placebo beverage. 
		Now, the other thing that's different about this third day is that only on the third day, when they got the combination, they also stood up and down, stood up and down, and had bloods drawn.  That didn't happen on days 1 and 2 when we were looking at Uprima alone.  So, when we see some increased adverse events, there's really a confounder here.
		Again, we wanted to see what was the worst thing that could happen.  So, we had a higher than recommended dose of Uprima.  We had a high dose of ethanol.  It was consumed within a short period of time.  We stood them up and laid them down and stood them up.  We drew blood frequently.  Also we confirmed that the time of peak alcohol concentration was also the time of peak apomorphine concentration.
		What do we see?  We see that only in the standing position do we see any differences between ethanol alone and ethanol plus Uprima.  Those of us who have dealt with this know that ethanol in fact is a vasodilator and does lower blood pressure to some extent.
		This is the low dose study and I won't bother with it. 
		With the higher dose study, we do have during the first hour some decreases in blood pressure on Uprima plus ethanol that are greater than ethanol alone or Uprima alone.  But again, this only extends out to the first hour.  It's relatively small decreases in pressure.  Again, the ones that really cause this decrease are the ones that have vasovagal events and hypotension related to that.  The ones that don't have those events don't really decrease, except of course, you can see that ethanol -- because this is the two ethanol groups -- does lower blood pressure and that does persist for some period of time.
		If we look at diastolic blood pressures, we see exactly the same thing.  Supine we see nothing.  Standing we do see a few millimeters of mercury difference.
		Adverse events.  We could go into a lot of detail here and you'll hear more in the FDA presentation.  It's true that the adverse events were higher with the combination, but this was also the day that they didn't get to just lie supine the whole time.  They had to be stood up frequently and they got needles stuck in their arms frequently.
		So, what were the instructions to the patients in the clinical trials?  The instructions were what you see here.  They should limit themselves -- it says minimal.  I'm not sure that is minimal, but this is the amount they were told to limit themselves to during the 6 hours prior to study medication, not prior to 6 hours, but during that 6 hours.
		What do we see if we look at patients in the crossover trials who have 1 or more drinks a day versus people who don't drink at all?  Is there a difference in adverse events?  No.
		So, in conclusion, the subjects were stressed with high doses of Uprima, high doses of alcohol, standing up and down, and getting stuck with needles.  There were mean decreases in standing blood pressure greater with Uprima plus ethanol than ethanol alone during the first 60 minutes, but not beyond that.  There was an increased incidence of adverse events.  There were some probably clinically insignificant changes in pharmacokinetic parameters, and when we look at the phase II and III trials, we don't see any differences in adverse events, including syncope.
		There were no Holter monitor changes due to Uprima except some that were due to vasovagal effects.  They went along with the symptoms, and there were no increased vasovagal changes with the combination compared to Uprima alone.  So, that didn't appear to be enhanced by adding the alcohol at all. 
		Now, Dr. Freston is going to wrap it up.
		DR. FRESTON:  Thank you, Dr. Fagan.  We're just going to discuss a few extra AE considerations, adverse event considerations, and then summarize. 
		This shows the frequency of AEs shown along the left again as a function of dose, 2, 4, 5, and 6 milligrams.  Again, I'll draw your attention to the fact that nausea was the most common AE and there was a dose response for it and virtually all of the other AEs, which of course is the main reason why we're recommending 2 and 4 milligrams, particularly with dose titration.
		About nausea, we had the opportunity, after each dosing, to ask patients if they experienced nausea and we did.  If they did, we asked them to grade it mild, moderate, or severe.  
		We draw your attention to the 2 milligram dosing.  Nausea was very uncommon, occurring in only about 2 percent of all patients treated at that dose.  If we look at the patients who experienced severe nausea, there were none in the 2 milligram dose.
		Let's look now at the 4 milligram dose.  Again, 80 percent of the patients had no nausea at all.  If we concentrate on those having severe nausea, it turns out to be 0.2 percent.
		If we analyze the data with respect to what are the chances of having nausea with any given treatment episode, I remind you that there are about 35,000 treatment episodes at the 2 and 4 milligrams.  The incidence of nausea per administration was 2.2.  Using the theme that Dr. Fagan just sounded about what does this mean in the real world of 2 treatments per week for a year, that means that there would be about 2 episodes of nausea in a year at the 2 and 4 milligram dose and they would be mild.  Incidentally, we did the same analysis for vomiting.  The incidence there is .2 percent.  In other words, there might be 1 episode of vomiting in 5 years.
		Now, the effect of nausea also wore off with the repeated administrations.  We can see that here and in other ways.  This shows the incidence of nausea with the first dose and with successive doses.  We've included only those patients who took at least 8 doses or had at least 8 treatment episodes.  So, you can see after the first couple of episodes, the chance of having nausea on any successive dose is well under 3 percent.
		So, to summarize the nausea, there was no impact on efficacy.  We looked at the data in patients with nausea and those without.  It was the same.  We showed you those data earlier.  It was mostly mild.  There was infrequent antiemetic use.  I've provided that in your handout.  It's not in the slide to save time.  Very few patients were discontinued because of this, and the incidence declines with continued use.
		Now, the FDA briefing document addressed patients and described them in detail who had suffered adverse events, and they were described whether or not they related to the drug, unrelated, or due in fact to placebo.  They were all described there.  For the most part, they involve syncope and hypotension, and Dr. Fagan has already dealt with those.  
		I would like now to briefly address the serious adverse events, the SAEs, and the reasons for premature termination.
		I'd like to clear up a misunderstanding.  In your briefing document and I believe on one of the slides that I saw from the agency this morning, it says that the definition of SAEs was changed during the trials.  That's not in fact true, and we apologize for that misunderstanding.  This is the definition of AEs that was used by TAP throughout all of the Uprima trials.  It includes all of these facets and conforms to the FDA and ICH SAE definition. 
		What happened was in some of the reports and summaries, certain parts of this definition were not mentioned, but I can assure you that all of the SAEs were, in fact, reported to the agency.
		Now, what were they?  Well, the agency briefing document described 49 patients with SAEs.  However, a number of these were described twice and even three times.  If we back those out of the calculation, we find that there were 30 patients who may have had SAEs.  The agency felt that 21 of these were possibly related to the drug.  The investigators themselves thought just 15 were, leaving 6 unresolved, and I'd like to just run through those very briefly so that you can understand the nature of these disputed cases. 
		The first is a 59-year-old man who had taken 4 doses at 2 milligrams.  One day after taking his fourth dose, he suffered an MI for which he was hospitalized.  The investigator felt that since this drug was long gone from his body and he had an MI a day later, that that was unrelated to the drug.  We agree.
		The next case was a 68-year-old man who had taken 10 doses of 2 milligrams.  12 to 18 hours later, he developed unstable angina, was hospitalized, worked up, treated appropriately.  He had had angina for some time, and in fact had had an MI 8 months before.  He completed the study and in fact took another dose.  The investigator felt that that was unrelated.  We agree.
		The next case is a 59-year-old who, after his second dose -- and we're not sure when he took his second dose.  It seemed to have been sometime within the previous 3 days or so, but we're not positive.  In any case, the patient was a passenger in an automobile that was involved in an accident, and he was banged up by the accident and discontinued from the study because of the disability related to the accident, not of course to Uprima.
		A 56-year-old person had a 4 milligram dose, 4 days later developed a classical case of viral gastroenteritis.  It was treated appropriately.  
		A 51-year-old person after the ninth dose, 4 and a half hours, developed lightheadedness, nausea in the context of a febrile illness and an episode of bigeminy.  That patient was hospitalized.  He had previous episodes of bigeminy before, and the febrile illness resolved.  And the investigator felt that that was unrelated to the drug. 
		And finally, a 49-year-old person who had taken 15 milligrams at the 5 milligram dose had diaphoresis, dizziness, nausea, and syncope 90 minutes after taking the dose.  He was taken to the hospital, in fact had hypoglycemia for completely inexplicable reasons.  Haven't seen it before, haven't seen it since.
		Now, these are the cases then that we described in the NDA.  There are 15 cases of serious adverse events conforming to that specific definition that I set out.  Three of those occurred at the 2 and 4 milligram dose, and all of those were the syncope cases.  You can see that the remaining 12 occurred at the above recommended doses. 
		Incidentally, for your reference, there were also a lot more SAEs that were reported that were not associated with the drug.
		Turning now to the final issue of premature terminations from the study, this shows the reasons why patients discontinued prematurely.  The reasons are listed along the left.  You can see that there was no single overwhelming reason for discontinuing.  In fact, the cases were distributed among all of these different reasons, including adverse events, noncompliance, lack of efficacy, patient request, and partner request, and so on.
		Let me draw your attention here.  There was one discontinuation due to an adverse event at the 2 milligram dose, that is 1 percent.  There are four cases.  And 5 percent of the whole were discontinued because of an adverse event in the 4 milligram dose.  So, these were unusual at the recommended doses.
		We're now looking at the discontinuations for adverse events specifically to see what the causes were.  Nausea was the most common AE, obviously.  You can see that very few patients were discontinued because of nausea.  Obviously, very few in addition were discontinued because of syncope.
		Now, we looked at subsets of all the patients, the special populations with respect to their AE profile, and we found no differences between them.
		We also looked at subgroups in detail particularly hypertension, diabetes, and patients with coronary artery disease.  Now, this is a little bit complicated, but it's a very important slide so I'd like to walk you through it. 
		We show the AEs down the left.  Here we show the patients with hypertension and compared against those without hypertension.  So, let's just focus on that for a moment.  We show the n's and the percentages.  You can see that those with hypertension didn't have more nausea than those without.  And that holds as we go right down the column.
		Going now to diabetes, those with diabetes had 11.7 percent nausea.  Those without had 15.9 percent. 
		Coronary artery disease.  Those with CAD, 15 percent had nausea, 15.4 percent did not.  
		In other words, we consistently don't see any more AEs in these special groups and numerically sometimes less. 
		Now, we have tried our best to address the issues raised by the agency in which they requested your special attention.  I am now going to skip forward.  I've provided in your slide booklet a summary of each issue.  We have covered all of them, but they're there for your reference so you can get to them quickly during your discussion period.  They are set out like this.  Each issue is followed by a one-page summary of what we've presented to you today, and it goes right on through the efficacy in diabetics, the key points, why patients were discontinued in long-term studies.  The hemodynamic data are summarized for you there for your convenience.  The nitrate interaction data, the summaries are there for you, and finally the information you need about the alcohol interaction story.
		So, Mr. Chairman, ladies and gentlemen, I'd just like to summarize. 
		Erectile dysfunction is a common condition with multiple etiologies and important health consequences according to the NIH.  It's associated with a number of diseases and conditions, as we have described. 
		Drugs with different modes of action are useful in this situation to deal with different mechanisms of action.  Current therapies are obviously limited.  There's no single drug that works for all patients.  Each drug has its own unique adverse event profile and there's no ideal treatment for any patient.  And all of the drugs work by a peripheral mechanism.
		Treatment is strongly influenced by couple and physician choices.
		So, new drugs with a different mechanism of action ought to be of potential benefit in this setting.  Uprima does, in fact, act through a unique central mechanism.  Its efficacy has been evaluated using consistent and relevant endpoints after each attempt, plus unique supporting partner data and utilization of RigiScan data. 
		The Uprima trials represent, therefore, a significant advance in the state of the art of ED clinical trials.  The efficacy of Uprima 2 and 4 milligrams was demonstrated in all the studies with all endpoints in patients with all of those different concomitant diseases and in patients with no known organic disease.  
		Both patient population and successful intercourse rates were similar to those seen in the Viagra trials.
		The safety of Uprima has been evaluated in 27 studies involving over 3,000 patients and over 75,000 doses.  The duration of treatment has exceeded 1 year in 127 patients, and 461 have been treated beyond 6 months at the time of the NDA.  Of course, we have much more data now.
		The AE profile was similar in patients with all of these concomitant diseases.
		Uprima can be taken with alcohol, provided patients don't exceed the recommended levels.  Uprima can be taken with nitrates, using the recommended patient instructions. 
		There were no pharmacologic interactions between Uprima and five different classes of antihypertensive drugs.
		There were no deaths or major illnesses like MIs or CVAs.
		Nausea was the most frequent adverse event occurring in 15.5 percent of patients at the 2 and 4 milligram dose and in just 2.2 percent of treatment administrations.  Accommodation occurred to nausea.
		Syncope occurred in 0.8 percent of patients at 2 and 4 milligrams and only 0.4 percent of treatment administrations and was minimized by titration of dose.  The syncope was nearly always associated with a prodrome or early warning system.
		In conclusion, Mr. Chairman, ladies and gentlemen, Uprima is a safe and effective treatment for ED in patients with and without known organic disease.
		With respect to risk-benefit, at the 2 milligram dose adverse events were in fact rare and efficacy was demonstrated in all phase III studies.  At the 4 milligram dose, also there were few adverse events, and the efficacy was particularly robust.  And there were no deaths, MIs, CVAs.  Therefore, the risk-benefit is clearly in favor of Uprima.
		Uprima is a useful and needed addition to the treatment of ED because it has a unique central mechanism of action, a novel delivery system, given sublingually, which allows it to work rapidly and consistently in about a half an hour. 
		Patients, couples, and physicians will have another choice of a safe and effective noninvasive drug with a different mechanism of action.
		Thank you.
		DR. AZZIZ:  Thank you very much.
		Since we are a little bit past time, I'd like to hold questions until we return, and then we'll have the FDA staff presentation.  Let's take a break.  Thank you.  Let's just make it 15 minutes.
		(Recess.)
		DR. AZZIZ:  I'd like to restart. 
		A point of information.  We're simply going to move up the lunch time by 30 minutes, meaning we'll have lunch starting at 12:30 or as soon as there's time, and then reconvene at 1:30.  So, we'll still have one hour for lunch.
		Before we begin, Dr. Raczkowski would like to make a few comments.
		DR. RACZKOWSKI:  Good afternoon.  I'm Dr. Victor Raczkowski from the FDA.
		Both Dr. Freston and Dr. Fagan in their presentations made a number of direct comparisons of Uprima with other agents for erectile dysfunction.  They made these comparisons numerically in terms of both safety and efficacy.
		FDA believes that such data are very difficult to interpret because no direct comparison trials have been performed between Uprima and other agents.  There's the potential that different patient populations have been studied, and oftentimes these were based on small studies. 
		So, what we are asking the advisory committee to do today is to focus on the safety and efficacy data that is before you for Uprima on its own merits.  You will notice that none of the FDA slides or any of the FDA questions have references to comparisons with other treatments for erectile dysfunction.
		DR. AZZIZ:  Thank you. 
		I think we're going to start out with Dr. Shames.
		DR. SHAMES:  Welcome to the first meeting of the Urologic Subcommittee.  Thank you for the work you have already done and perhaps the more difficult work you're about to do.
		My name is Dan Shames.  I'm the team leader for Urologic Drugs in the Division of Reproductive and Urologic Drug Products.
		During my brief presentation, I will mention the FDA presentations you will hear this morning.  I will make a few remarks regarding the etiology, diagnosis, and treatment of ED, and I will then offer you six points to consider while listening to the FDA presentations. 
		The FDA presentations and presenters are Dr. Jarugula, who will discuss pharmacokinetics and drug alcohol interactions.  He is from the Clinical Pharmaceutics and Clinical Pharmacology Section.
		Dr. Hirsch, who is a urologic medical officer, will discuss clinical safety and efficacy.
		Dr. Mann will discuss drug-antihypertensive interactions and also summarize.
		Historically the etiology of erectile dysfunction has been classified as either psychogenic or organic.  We now recognize that this classification system is oversimplified and that many patients have a combination of psychogenic and organic factors to explain their erectile dysfunction.  
		The Nocturnal Penile Tumescence test, or NPT, evaluates erections that occur during REM sleep.  This test, although somewhat controversial, has been used to assure that no major end organ or penile pathology exists which may prevent development of a normal erection.  It is thought that men who have erectile dysfunction from a variety of causes, such as peripheral vascular disease, will have diminished nocturnal penile tumescence activity.
		In the majorities of the studies submitted by the study sponsor, a normal NPT or at least erectile activity and therefore the potential for normal erections was required for study entry.  The men with erectile dysfunction entering into the study were thought by the study sponsor to have no major end organ disease and no major organic etiologic component of their erectile dysfunction.  This subpopulation of ED patients with normal NPTs does not represent the general ED population.
		Dr. Heaton did an excellent job of reviewing ED in general.  I just would like to reiterate at this point, we have two products on the market, intracorporeal, intraurethral treatment, and in 1998 an oral treatment was approved.
		I would now like to place for your consideration six points to use while you're reviewing our presentations. 
		The first point to consider relates to the select population studied in these trials.  Patients with no major organic component who were in generally good health were included.  Patients were excluded from the trials if they had any significant medical conditions that could adversely affect their health.  These patients in most of the trials had NPTs which demonstrated erections.  They must have had erections within the last 3 months, and they must have had up to 50 percent successes during the baseline period.
		You should next consider the interaction with alcohol and apomorphine.  Apomorphine has been used as a behavior altering agent in alcoholics most likely due to its emetic properties.  Patients in these trials were cautioned to limit alcohol intake "to a minimum" for the 6 hours prior to dosing.  In addition, you should pay attention to the alcohol interaction remarks that will be made by Dr. Jarugula.
		The next point we would like you to consider is, are these trials appropriate to predict real-life simulation?  We know that clinical trials never simulate real life, but we believe that the design of the trials here performed may have resulted in an underestimation of the adverse events that would be observed in the general ED population.  
		The treatment periods were generally 1 month in duration, which is a relatively short period in which patients were exposed to the drug.  The first dose and increases in doses were administered in the office.  This meant that there was opportunity to treat adverse events, perhaps preventing more serious consequences.  Remember, the sponsor proposes at-home dosing if Uprima is approved for marketing.
		Food intake was restricted in the 1 hour right before dosing.  No large meals were allowed during that period of time.  This may have reduced the incidence of nausea and vomiting.
		Alcohol intake was restricted, as mentioned, to a minimum within 6 hours of dosing. 
		Various inclusion and exclusion criteria may have defined a healthier subpopulation compared to the general ED population.  This might indicate that a larger proportion of adverse events would be expected from the post-marketing population compared to the clinical trial population.
		3 milligrams was not studied in these trials.  Therefore, you must conclude that both 2 and 4 milligrams are safe and effective to allow marketing of all three doses as proposed by the sponsor. 
		5 and 6 milligrams were dropped from development by the sponsor because of a "less acceptable risk-benefit profile."  The highest dose that the sponsor wants to market is 4 milligrams, and as you will hear from Dr. Jarugula, Uprima has wide pharmacokinetic variability causing concern about the risk-benefit profile of 4 milligrams in some patients.
		Please evaluate whether statistical differences expressed for efficacy parameters will translate into important meaningful differences for patients.
		Please evaluate the clinical relevance of the effect size.  For example, if the proportion of patients that reach an endpoint is 32 percent in the placebo arm and 46 percent in the Uprima arm, the effect size, or the improvement due to Uprima, is a difference between the two, or 12 percent.
		How well do patients accept Uprima doses over longer-term periods?  In longer trials, what proportion of patients remain at 2 milligrams when given the choice of dose?  And how many patients discontinued treatment at higher doses?
		The sponsor proposes to market this drug to all ED patients, yet study primarily patients with ED of nonorganic etiology.  The sponsor, however, did a moderate sized trial in patients with diabetes.  Please pay particular attention to the effect size in this trial.
		This particular issue was mentioned by Dr. Freston, and I'm going to proceed to explain the issue because this is what had to deal with in the NDA and we can sort it out perhaps in the discussion period. 
		The definition of serious adverse events, it appeared, was changed in mid-development of the drug.  The more inclusive definition was used for the first 20 percent of the patients and includes the phrase that is highlighted in yellow.  To paraphrase, a serious adverse event is "any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, results in persistent disability and incapacity, or events that require intervention to prevent impairment or damage."  The less inclusive definition, which removed the "intervention" phrase, was used, as far as we can determine in 80 percent of the patients studied.
		Because of the change, we believe there would be consequences as to how events were reported.  For example, a patient that experienced hypotension and bradycardia in the physician's office required treatment with IV fluids and oxygen and then recovered was not considered to have experienced a serious adverse event if the yellow phrase was removed.
		The FDA calculated both syncope and reports of hypotension as important adverse events, and for this reason, some figures regarding proportion of important adverse events in various trials and at various doses may differ between FDA and the sponsor. 
		Regarding reports of hypotension in the NDA, the FDA found that there were approximately 140 patients who had hypotension reported as adverse events in the total patient database of 3,035.  Some were not included as serious adverse events.  Some were not included in the main body of the report but were found in the appendices.
		Regarding reports of hypotension in the sponsor's briefing document, which you received, the FDA calculated that only 2 of the 140 patients who had hypotension reported adverse events were mentioned in the sponsor's briefing document sent to the committee.  These two cases were defined by the sponsor as serious adverse events.  
		As mentioned, the FDA considers hypotension important in the evaluation of the risk-benefit profile of Uprima.  Our analysis of syncope and hypotension will be shown to the committee during our presentations.
		Finally, we would like to ask you to hold all questions until the end of all of our presentations.  Now Dr. Jarugula will discuss the pharmacokinetics and alcohol interaction.
		DR. JARUGULA:  Thank you, Dr. Shames. 
		I'm Venkateswar Jarugula, pharmacokinetic reviewer with the Division of Reproductive and Urologic Drug Products. 
		Now I am going to present on pharmacokinetics and drug-alcohol interactions of Uprima.  Over the next 20 minutes, I'm going to briefly discuss the general pharmacokinetic features of Uprima, the pharmacokinetics of Uprima in special populations, particularly in subjects with hepatic or renal impairment, and then I'll discuss a little bit about pharmacokinetic variability observed in one of the phase I trials for Uprima.  Then I will discuss in detail the pharmacodynamic aspects of the drug-alcohol interaction studies that were submitted in the NDA.  Finally, I will summarize my comments.
		The general pharmacokinetics of the drug.  Apomorphine is rapidly absorbed from Uprima tablets following sublingual administration, with maximum plasma concentrations occurring in about 40 to 60 minutes, and it is rapidly cleared from the circulation with a terminal phase half-life of about 2 to 3 hours.  
		Apomorphine is extensively metabolized by liver mainly via glucuronidation and sulfation.  Apomorphine sulfate is the major metabolite that is found in plasma.  This metabolite is a conjugate and it is not believed to be pharmacologically active.
		Following radiolabeled administration, apomorphine accounted for only less than 1 percent of the total radioactivity circulating in plasma, indicating again the extensive metabolism of this drug.
		Pharmacokinetics of Uprima was investigated in subjects with hepatic impairment or renal impairment.  The subjects were classified as mild, moderate, or severe hepatic impairment based on their scores, and subjects with renal impairment were classified as mild, moderate, or severe based on their serum creatinine clearance values.
		As we can see here, in subjects with hepatic impairment, there was a significant increase in mean peak plasma levels, the Cmax, and also a significant increase in area under the plasma concentration curve, which is a measure of the systemic exposure of the drug.
		In subjects with renal impairment, although there was no significant change in the Cmax, there was about 52 to 67 percent increase in the area under the plasma concentration curve in moderate to severely renally impaired patients.
		This slide summarizes the PK variability noted for two PK parameters, the Cmax and the AUC, from a single-dose crossover PK study.  This study looked at doses 2 milligrams, 4, 5, and 6 milligrams in a crossover fashion.  Listed here are the range of values that are observed for Cmax and AUC.  As one can note, the range of values for these PK parameters, particularly for Cmax, are quite overlapping at the higher doses, 4, 5, and 6 milligrams.  As was mentioned before by the sponsor, the percent variability for Cmax ranged from 40 to 80 percent in this study.  The range of variability that was noted for the Cmax here makes it particularly difficult to distinguish doses of Uprima that are so close together, 4, 5, and 6 milligrams.
		The pharmacokinetic and pharmacodynamic correlation of Uprima.  Based on the analysis of data from the phase I studies from which the data blood levels were available, no significant correlation between the Cmax, AUC, and blood pressure changes was noted.  However, the significant adverse events, such as syncope and hypotension, occurred in the phase I studies usually at the time of maximum plasma concentrations, and these events occurred in the subjects when they had Cmax values that were relatively higher than their group averages, indicating that the Cmax may be an important PK parameter.
		The safety may be difficult to predict based on the dose of Uprima due to the variability that was noted in Cmax, as was shown in the previous slide.
		Now I will turn my attention to the alcohol interaction studies.  Four alcohol-drug interaction studies were conducted and were submitted in the NDA.  These studies have looked at the interaction of Uprima at 5 or 6 milligram doses and alcohol doses ranging from .15 grams per kilogram to .6 grams per kilogram. 
		Among these studies, study M97-762 looked at the interaction of Uprima at a low dose of alcohol, .15 gram per kilogram, and this study did not reveal any significant pharmacodynamic or pharmacokinetic interaction.
		In all of the studies, there was no significant pharmacokinetic interaction noted except for the fact that at the highest alcohol dose, there was about a 23 percent increase in mean Cmax values.
		Let me briefly explain how Uprima and alcohol were dosed in these studies, except for the low-dose alcohol study.  Just to give an idea, .15 gram per kilogram alcohol dose is approximately equivalent to 1 ounce of vodka based on a 70 kilogram body weight.  Alcohol was administered as vodka diluted in 450 ml orange juice and it was ingested over a 30-minute period, and then Uprima was administered 1 hour after start of the alcohol ingestion.
		While this may be a feasible method of dosing of alcohol to look at the interaction, it should be noted that in real life the timing of Uprima dosing in relation to the alcohol consumption or the amount of alcohol consumed by the patients may be variable.  It should also be noted that phase III clinical trials restricted alcohol intake to a minimum for 6 hours prior to drug administration.
		Study M97-745 looked at the interaction between 5 milligram Uprima and .6 grams per kilogram alcohol dose, the highest alcohol dose studied in these studies.  This study was terminated due to significant adverse events noted in two of the subjects that participated in the study.  There were no definite conclusions because of the premature termination of the study and because none of the subjects received both alcohol and placebo beverage.
		This slide summarizes the significant adverse events that led to the premature termination of the study.  There were 2 subjects who experienced these events.  
		One subject, after experiencing significant vomiting and diaphoresis, lost consciousness for 1 minute at approximately 40 minutes after dosing with 5 milligram Uprima.  This subject did not receive any ethanol as per the protocol.  He had hypotension.  His blood pressure was 71/37 and his pulse was 41.  He was administered with IV fluids, oxygen, and followed by .5 milligram atropine.
		A second subject experienced hypotension.  His blood pressure was 55/38 at 30 minutes following Uprima dosing.  This subject also received ethanol prior to Uprima dosing.  He was found to have the second highest Cmax of Uprima and also the highest ethanol level in his group, indicating that there could be a pharmacodynamic interaction between Uprima and alcohol.
		Additionally, 2 other subjects also experienced prolonged hypotension in this study.
		Study M98-838 looked at the interaction between 6 milligram Uprima and .3 gram per kilogram alcohol.  .3 gram per kilogram alcohol dose is approximately equivalent to 2 ounces of vodka in this study.
		Shown here are the mean maximum drop in blood pressure from baseline following each treatment, Uprima alone, ethanol alone, and Uprima plus ethanol combination.  As can be noted here, the mean maximum drops in standing systolic and standing diastolic for the combination Uprima and ethanol were higher than either Uprima alone or ethanol alone, with the difference with the ethanol arm being statistically significantly different from the combination arm. 
		Similarly, there were higher orthostatic changes both in systolic and diastolic for the combination, the difference with the ethanol being statistically significant here.
		This slide summarizes the incidence of treatment emergent adverse events that are pharmacologically related to apomorphine.  As can be noted here, the combination of Uprima and ethanol resulted in a higher incidence of adverse events when compared to Uprima alone or ethanol alone.  Particularly the incidence of dizziness, vomiting, and hypotension are increased twofold in the combination when compared to the Uprima arm alone.
		To summarize the effects of Uprima with alcohol at .3 gram per kilogram dose, which is equivalent to 2 shots, 2 ounces, of vodka, there is a trend toward a greater drop in blood pressure with the combination.  There was also higher incidence of abnormally low blood pressure values and there was also a greater sedative effect with the combination.  The results of these two bullets are not shown here.  However, the results were included in the briefing package for the committee.
		As mentioned earlier, an increase in the incidence of adverse events was also noted for the combination at this dose of alcohol.
		Study 98-891 looked at the interaction between 6 milligram Uprima and .6 gram per kilogram alcohol dose, which is equivalent to 4 ounces of vodka, again based on a 70 kilogram body weight. 
		The mean maximum drops in blood pressure from baseline are shown here.  The mean maximum drops in standing diastolic and supine systolic are significantly different with standing diastolic being statistically significantly different from Uprima alone or ethanol alone.  And that for supine systolic is only statistically significant from Uprima alone.
		This slide summarizes the incidence of treatment emergent adverse events.  Again, the combination of Uprima and ethanol resulted in a much higher incidence of adverse events compared to Uprima alone or ethanol alone.  Particularly the incidence of dizziness, pallor, and hypotension are about two- to threefold higher in the combination arm.
		Shown here is the incidence of abnormally low blood pressure values.  Abnormally low blood pressure values are defined as less than 80 millimeters mercury for systolic and less than 40 millimeters mercury for diastolic.  As can be seen here, the combination of the Uprima and ethanol resulted in significantly higher incidence of abnormally low blood pressure values for both systolic and diastolic values when compared to Uprima and ethanol alone. 
		To recap the effects of Uprima with alcohol at a higher dose, .6 gram per kilogram, there were greater drops in systolic and diastolic blood pressure values with the combination, a higher drop in blood pressure at the time of peak Uprima and ethanol concentration, and there was also an increased sedative effect with the combination.  Again, the results of these two bullet points are not shown here but were included in the briefing package for the committee.  And there was an increased incidence of adverse events with the combination, as was shown with the lower dose of alcohol.
		To summarize my comments, the bioavailability is higher in patients with renal or hepatic impairment.
		Pharmacokinetic variability is too high to distinguish among Uprima doses that are so close to one another. 
		There is a pharmacodynamic interaction between Uprima and ethanol.
		Uprima is associated with higher incidence of adverse events when dosed with moderate -- that is, 2 ounces of alcohol -- and higher amounts -- that is, 4 ounces of alcohol.
		Thank you very much.
		DR. HIRSCH:  Good morning.  My name is Mark Hirsch and I'm the primary reviewing medical officer for Uprima.  For those of you who are new to the drug regulatory process, the role of the medical officer is to conduct the initial assessment of the clinical data in a new drug application.  Then working with a team of scientists, an overall assessment of the safety and efficacy of the drug is made.  Our team is fortunate to have access to experts like those on this panel who can offer their advice and opinions as we deliberate.
		In a relatively brief period, I'd like to review quite a bit of material.  First, we will look carefully at the efficacy and safety of the 2 milligram and 4 milligram doses individually.  Then I'll touch briefly on the 2 milligram to 4 milligram dose titration regimen.  Then we'll look at the results from the diabetic trial.  Finally, I believe it is essential to understand the safety concerns associated with the 5 milligram and 6 milligram doses, doses which the sponsor chose to discontinue during phase III.
		The clinical data set for Uprima consisted of the results from six controlled phase III trials and six open-label safety trials.  I believe that the most substantial clinical evidence comes from the three crossover trials.  These three studies tested single p.r.n. doses of 2 milligrams, 4 milligrams, 5 milligrams, and 6 milligrams in randomized, placebo-controlled, crossover designs.  Each crossover study included a 4-week no-treatment baseline period, followed by two 4-week treatment periods, separated by a brief washout. 
		So, starting with the 2 milligram dose, was the 2 milligram dose shown to be effective in the three crossover trials?  The results shown on this slide are in agreement with the analysis conducted by the sponsor.  The division has no major differences in this regard.  However, we ask that you look carefully at these results and then provide your interpretation of these data and comment on whether you believe they demonstrated clinically meaningful efficaciousness.  
		The primary endpoint for all these trials was the proportion of attempts per individual which resulted in an erection sufficient for intercourse.  Approximately 130 patients were randomized to the 2 milligram dose in each of these three studies.  Here you see the results for the primary endpoint for each of the three crossover studies.
		Here you see the combined results for a responder analysis.  A responder, or treatment success, was defined as an individual who had at least 50 percent successful attempts during a treatment period.  In this secondary endpoint, there is an absolute difference of 12 percent.  We have presented this secondary endpoint to offer you an additional perspective on this data.
		Was the 2 milligram shown to be safe in the placebo-controlled crossover trials?  Here I've listed the incidence rates of adverse events as reported in each of the three crossover trials.  Although the overall adverse event profile appears relatively benign when compared to placebo, I'd like to turn your attention to two very important adverse event terms, hypotension and syncope.  Hypotension was reported in a range of 0 to 1.2 percent of 2 milligram patients, and syncope in a range of 0 to 0.7 percent of 2 milligram patients.  Please be aware that these are reported adverse events.
		Of all patients who received 2 milligrams in the entire new drug application database, exactly how many reported syncope or hypotension as an adverse event and what ultimately happened to them?  The answer is a total of exactly 7 out of 964 patients, or 0.7 percent, experienced hypotension or syncope as an adverse event.  You should understand that these were individual and unduplicated adverse event reports and no patient was counted twice.  Specifically, if a patient was reported as having both syncope and hypotension, he was counted only once as syncope.
		Three brief narratives from this group of 7 may help you better understand what actually happened during these events.  One patient experienced nausea and syncope after taking two 2 milligram tablets within 4 hours.  He was reported to be unconscious for approximately 4 minutes.  I should highlight that this patient actually did take two 2 milligram tablets within 4 hours. 
		One patient experienced nausea, diaphoresis, vomiting, and syncope 30 minutes after an in-office dose of 2 milligrams.  His syncopal event was reported to last approximately 3 minutes. 
		In addition to the cases of syncope, there were five adverse event reports of hypotension.  I'd like to present one of these narratives here.  A 50-year-old patient experienced hypotension, bradycardia, and sweating approximately 40 minutes after his first dose of 2 milligrams.  The hypotension and bradycardia lasted for 5 and 10 minutes respectively.
		I believe that the most important question regarding the 2 milligram dose is this.  How many patients will actually use it?  Well, in the long-term, open-label, flexible-dose studies, only approximately 6 to 11 percent of all patients remained on 2 milligrams when they were offered the opportunity to use higher doses.  This table also demonstrates that most patients titrated to the maximally allowed dose.  Therefore, if patients tend not to remain on 2 milligrams when offered higher doses, the more important question is, what is the safety and efficacy at higher doses?
		What was the efficacy demonstrated with the 4 milligram dose in the three crossover studies?  Again, the division has no substantial disagreement with the sponsor in terms of the absolute efficacy data.  We ask, however, that you assess these results in light of the safety concerns that I will try to delineate.  Before we leave this slide, I again would like to point out that these are the results for the primary endpoint from the crossover trials and that approximately 120 patients were randomized to the 4 milligram dose per trial.  Again, we agree with the sponsor's analysis of these figures.
		Here you see the results of a responder analysis for the three crossover trials combined.  There is an absolute difference between placebo and Uprima of 24 percent.
		In my opinion the truly critical question to answer is now before us, and that is, is the 4 milligram dose safe?  In order to answer this question, we should look first at the overall adverse events reports for the 4 milligram fixed dose in the three placebo-controlled crossover trials.  Here we see incidence rates of nausea of approximately 20 percent, dizziness of approximately 14 percent, somnolence or sleepiness of approximately 10 percent, sweating of about 10 percent, and vomiting around 1 to 4 percent.  But I'd ask you to please focus on the incidence rates of hypotension of 3.1 to 6 percent and incidence rates of syncope of 0.9 to 2 percent.  Again, please recall that these are investigator reported adverse events.
		We think it is important for you to know exactly how many 4 milligram patients in the entire NDA database experienced syncope or hypotension as reported as an adverse event and what actually happened to these folks.  By our count, 42 patients out of 1,279 dosed with 4 milligrams, or 3.3 percent of the entire population, reported one of these events.  I'd like you to focus on that rate, approximately 1 in 30 patients, as you listen to these case narratives.
		A 33-year-old man received 4 milligrams and was observed for 30 minutes in the office.  While driving home -- and he was the driver in this case -- he became nauseated, fatigued, flushed, and sweaty.  He attempted to stop his car, but he lost consciousness, lost control of his vehicle, and crashed into a fence.
		A 36-year-old experienced pallor, sweatiness, and syncope approximately 30 minutes after his first in-office dose.  He lost consciousness for only a few seconds, but he remained tired, weak, and flushed for 8 hours.
		A 50-year-old man experienced nausea after his in-office dose of 4 milligrams.  He requested Compazine from the nurse.  He had previously tolerated 2 milligrams without any incident.  Upon her return, the nurse found him unconscious, apneic, unresponsive, diaphoretic, and incontinent of urine.  He awoke spontaneously and began to breathe.  His heart rate was 42 beats per minute.  He was administered IV saline, oxygen, and Compazine.  His bradycardia persisted for over 1 hour, requiring hospitalization.
		A 60-year-old man experienced syncope 35 minutes after an in-office dose of 4 milligrams.  He was unconscious for several seconds.  It was necessary for the nurse to "adjust his head and rouse him."  He was pale, hot, diaphoretic, and vomiting.  He was placed supine, and he improved over 1 hour.
		A 69-year-old man complained of diaphoresis 38 minutes after his first dose of 4 milligrams.  His blood pressure at that time was 117/50 and his heart rate was 60.  He then fainted and was unresponsive for 2 minutes.  He was treated with oxygen and intravenous fluids.
		It is notable that there were twice as many adverse event reports of hypotension as compared to reports of syncope, and again these are unduplicated.  Our assessment reveals that many of the hypotension cases were of no less significance.  As evidence, I'll present a few narratives reflecting these events.
		A 60-year-old male experienced hypotension with a blood pressure of 70/41, bradycardia with a heart rate of 45 beats per minute, pallor, fatigue, and sweating, 35 minutes after dosing.  These symptoms abated within 2 hours of dosing.
		A 56-year-old received 4 milligrams of Uprima despite presenting to the clinic with a complaint of diarrhea and abdominal cramping.  After the dose, he experienced severe hypotension and he became unconscious for 15 to 20 minutes.  He woke up, vomited, and was then transported to the emergency room where he again lost consciousness.  His blood pressure was 60 millimeters palpable in the emergency room.  His EKG revealed nonspecific ST-T wave changes and he required admission to the intensive care unit and intravenous fluids.  This case is particularly concerning since it might signal problems in patients with low baseline volume status or low borderline blood pressure.
		Finally, a 59-year-old patient experienced hypotension, dizziness, nausea, and sweating 25 minutes after his first dose of 4 milligrams.  His blood pressure was 72/50 and his hypotension persisted for 105 minutes. 
		The sponsor conducted a single controlled trial designed specifically to assess the impact of dose titration versus fixed dose regimens.  Although patients in the study were allowed to titrate up to 6 milligrams, we do have data specific to the use of the 2 through 4 milligram doses.  In this trial, you should be aware that patients were randomized to a 5 or 6 milligrams fixed dose arm, placebo, or a dose titration arm of 2 to 6 milligrams in which all patients were started on 2 milligrams and allowed the opportunity to dose upward as desired.
		The data was analyzed for both the use of 2 through 4 milligrams and 2 through 6 milligrams.  Was the 2 through 4 milligram dosing regimen effective in this trial?  In regard to these actual figures, we have no major disagreement with the sponsor.  We ask you to assess whether these results are clinically meaningful on their own and whether the benefits of these efficacy results outweigh the known risks.
		Did dose titration actually limit the incidence of syncope and hypotension in this study?  If we look at the incidence of adverse event reports for the term "hypotension" and the term "syncope," the incidence for these events was actually highest in the dose titration group compared to the 5 milligram, 6 milligram, and placebo fixed dose arms. 
		We know that diabetes is a major risk factor for erectile dysfunction.  The sponsor conducted a single controlled phase III study in well-controlled, relatively healthy diabetics.  Was Uprima effective in this study?  Here we see the results of the primary endpoint for the 4 milligram dose, that is, percentage of successful attempts per individual.
		Here we see the results of the secondary endpoint, percentage of successful responders.  Again, we ask you to consider these results and decide for yourself whether these differences from placebo are meaningful, whether efficaciousness was demonstrated in diabetics, and whether these results outweigh the known risks of the product. 
		What was the incidence of hypotension and syncope reported as adverse events in the diabetic trial?  The combined incidence was 4 percent in the 4 milligram Uprima group versus 1 percent for 4 milligram placebo and 3.8 percent in the 5 milligram group compared with 0 for the 5 milligram placebo group.
		Finally, we have extensive phase III trial data concerning 5 milligrams and 6 milligrams.  The sponsor voluntarily decided not to request approval of these doses, but we believe that an understanding of the risks of 5 and 6 milligrams is critical to the understanding of the 2 milligram and 4 milligram dose.  The overall adverse events, as reported in the three crossover trials, reveal incidence rates of nausea of approximately 30 percent for 5 percent and 40 percent for 6 milligrams, rates of dizziness of approximately 20 percent for both doses, rates of sweating of approximately 15 percent for 5 milligrams and 20 percent for 6 milligrams, rates of somnolence of approximately 10 percent for both doses, and rates of vomiting of about 10 percent for both doses.  
		But I ask you to pay particular attention again to the incidence rates of hypotension and syncope.  For the 5 milligram dose, these rates were 2.3 to 6.5 percent for hypotension and 2.3 to 3.5 percent for syncope.  For the 6 milligram dose, these rates were 4.3 to 4.8 for hypotension and 2.1 to 2.3 for syncope.
		Is there evidence of risk due to syncope or hypotension in this NDA?  One case clearly demonstrates the risk potential.  A 42-year-old man received a 5 milligram dose in office.  He had previously tolerated doses of 2 and 4 milligrams.  1 hour after dosing, he felt nauseated.  He stood up to find someone.  He was found unconscious, bleeding from a tongue laceration and from a head abrasion.  After smelling salts, he awoke.  Within 15 minutes, he felt better and went home.  
		5 days later he complained of a headache.  CT scan revealed a left occipital skull fracture with a cortical contusion of the frontal lobe.  MRI confirmed a left-sided nondepressed skull fracture and also reviewed a contra-coup injury of the right frontal lobe. 
		An additional 63-year-old patient was given a dose of 5 milligrams in the office.  He had previously tolerated doses of 2 and 4.  Shortly after dosing, he felt nauseated, lightheaded, and clammy.  He last recalled going to the door for assistance.  He was later found by the nurse with a head laceration.  It was assumed he struck his head on a nearby table.
		Finally, I believe that the bottom line is this.  How many patients actually remained on any dose of Uprima for an extended period of time?  Well, results from the long-term trials reveals that approximately 60 percent of patients prematurely terminate use before 6 months and about half of these discontinuations are due to lack of efficacy.
		Since I've presented quite a bit of information in a short period of time, I'd like to present several summary comments that I hope you will consider in your deliberations. 
		First, in terms of the 2 milligram dose, we agree with the sponsor's analysis of efficacy.  However, we would encourage you to consider whether the benefits demonstrated over placebo are truly meaningful benefits.  As an example, please consider whether a difference in the proportion of treatment responders from 36 percent with placebo to 48 percent with Uprima is a meaningful difference.
		Second, the overall incidence rates of syncope and hypotension, as reported as adverse events by the individual investigators, was 0.7 percent. 
		Finally, it appears likely that few patients will actually remain on the dose of 2 milligrams when offered the opportunity to take higher doses. 
		In terms of the 4 milligram dose, we wish to emphasize that the combined rate of syncope and hypotension was 3.3 percent, or 1 in 30 patients.  Some of the case narratives for these patients describe concerning events, including persistently low heart rate, prolonged hypotension, serious injury, and the need for urgent medical intervention to prevent serious injury.
		It is important to note that the majority of syncopal events at 4 milligrams occurred in the confines of a physician's office and were generally, but not always, limited to the first dose or first increase in dose.
		In terms of the dose titration regimen, we ask that you look at the efficacy results from the titration study and seriously consider whether the 2 to 4 milligram dose titration regimen provides a real clinical benefit to erectile dysfunction patients.  In addition, we wish for you to understand that dose titration itself did not limit the incidence of the combined report of syncope and hypotension.
		In terms of the results in diabetics, we ask that you look at this efficacy data and seriously consider whether the 4 milligram dose provided a real clinical benefit to diabetic patients with organic erectile dysfunction.  Here it is important to recall that the diabetic trial was the only well-controlled study in which the entrance criteria did not require patients to have at least one normal or nocturnal erection greater than 55 percent rigidity.  These results in diabetics may cast some doubt on whether Uprima was demonstrated to be effective in the larger population of erectile dysfunction patients without evidence of normal nocturnal tumescence.
		Finally, we believe that you cannot understand the potential safety issues with Uprima unless you aware of the safety results at doses of 5 and 6 milligrams.  At these doses, all Uprima-related adverse events were reported at higher incidences.  The incidence rates of hypotension and syncope in the crossover trials were actually higher at doses of 5 and 6 milligrams.  If the sponsor has decided not to request approval of these doses, why then are we presenting the results to you?  You might recall that the serum blood levels or pharmacokinetics of Uprima are variable and pharmacologically doses of 4 milligrams, 5 milligrams, and 6 milligrams may be indistinguishable in any given patient.
		I thank you for your attention, and I'd like to introduce our Deputy Director, Dr. Mann.
		DR. MANN:  Finally, the last speaker of the morning.  Thank you for your patience and endurance in going through all of these multiple presentations with us.
		I want to briefly review the drug-antihypertensive interaction study that was performed by the sponsor, and in doing so, I'd like to compliment them on doing a very nice job of extensively looking at the potential for drug interactions with Uprima in a wide variety of antihypertensive agents.
		You've heard about the study design and some of the results this morning from TAP, so I will go through these slides somewhat quickly.
		The study design was geared to look at the tolerability of a single 5 milligram dose of Uprima versus a single dose of placebo in patients taking a wide variety of antihypertensive therapies as shown on this slide.
		24 males were geared to be enrolled in each group, and they were to be on at least 4 weeks of single agent antihypertensive therapy and be stable on that regimen.  It was a double-blind, crossover study design with a 24-hour washout period between placebo and Uprima dosing.  The patients were randomized in a randomized fashion to receive either Uprima 5 milligrams followed 24 hours later by placebo or placebo followed 24 hours later by a dose of Uprima 5 milligrams.
		As part of the study, blood pressure and pulse measurements were obtained in every patient, and both standing and supine measurements were obtained.  Several measurements were done prior to dosing and multiple measurements were done post-dosing as shown.
		In addition, adverse events were recorded for each patient.  An ECG and Holter monitoring were performed in each patient.  
		Of note, however, no pharmacokinetic sampling for either Uprima or antihypertensive drug levels were done in this trial.
		As the sponsor presented this morning, I don't believe the FDA has any disagreement that the mean blood pressure results showed no significant effects for the non-nitrate groups or for the short-acting nitrate group.  The long-acting nitrate group did show some statistically significant changes in blood pressure, but again, we agree with the sponsor that on average those changes were under 10 millimeters of mercury and were not highly clinically meaningful.
		As Dr. Jarugula presented earlier this morning with the alcohol interaction study, though, sometimes mean blood pressure changes don't give you the whole picture.  So, the FDA also performed a per-patient analysis.  In this analysis, adverse events for each patient were examined.  Significant adverse events were considered to be nausea, vomiting, diaphoresis, hypotension, syncope, and there was one case of palpitations that was considered significant.  The reason these were considered significant is, as you can recognize by now, these are the recognized adverse events attributable to Uprima.
		There were occasional if not rare patients who presented with other adverse events.  Those included headache, upper respiratory infection, fever, shortness of breath, tinnitus, rash, and asthenia.  Since these were not attributable to study drug, they were not considered very relevant in this analysis. 
		Blood pressure results were also observed.  The standing blood pressure results in particular were observed carefully in this analysis done per patient.  Any patient who had an absolute systolic blood pressure reading less than 85 or a diastolic blood pressure reading less than 45 after receiving study drug was considered notable.  In addition, any patient who experienced a fall in systolic blood pressure by 30 or diastolic blood pressure by 20 was considered potentially meaningful.
		Overall, this analysis done per patient for the 162 subjects enrolled in the entire trial, all antihypertensive groups combined, showed that there were 26 subjects who had an adverse event of concern.  In 24 of those patients, they were noted to have suffered both an adverse event and one of those clinically relevant blood pressure findings I mentioned in the previous slide.  2 subjects had solely an adverse event.  One was a Uprima patient and one was a patient.  Both of those patients had experienced nausea as their adverse event.
		Breaking it down by group, the non-nitrate therapies are shown on this slide with the adverse event results shown per patient.  For example, there were 25 patients enrolled into the ACE inhibitor arm of this study.  1 of those 25 patients reacted to placebo versus 2 who reacted to Uprima.  The results for the other non-nitrate therapy arms are shown on this slide, and as you scan across, you can observe that in general there were more adverse events associated with Uprima versus placebo, so that for the sum total of non-nitrate therapy patients, 1.6 percent of patients had an adverse reaction following placebo dosing versus 9 percent of patients who had an adverse event following Uprima dosing.
		There was one syncopal event of note in the non-nitrate therapy arms which I'd like to mention briefly.  This was a patient in the beta blocker group.  His baseline blood pressure of 105/75 fell to 71/30 about 20 minutes after receiving Uprima.  He had associated dizziness, nausea, and diaphoresis as well.  He was placed supine, given IV fluids, and was later hospitalized for 24 hours of observation.
		In summary, for the non-nitrate therapies, adverse events of concern were noted in 1.6 of subjects who had taken placebo versus 9 percent of subjects who had taken Uprima.  There was one serious adverse event, a syncopal event, in a beta blocker subject who had taken Uprima.
		We can conclude from this that patients did not tolerate Uprima as well as placebo.  It is difficult to conclude that there is a drug-drug interaction between Uprima and antihypertensive therapies because the question arises could these events possibly just relate to adverse events associated with a 5 milligram dose of Uprima.
		What about the nitrate therapy arms?  There were 20 patients enrolled in each arm, and there were 6 Uprima reactions for the short-acting nitrate arm versus 0 placebo reactions.  For the long-acting nitrate arm, there were 5 Uprima reactions versus 2 placebo reactions.  Overall, 28 percent of patients had an adverse reaction following a single dose of Uprima versus 5 percent who had an adverse reaction of note following a dose of placebo.
		That is summarized on this slide in the top bullet.  Again, we feel that patients did not tolerate Uprima as well as placebo when they were receiving concomitant nitrate therapies.  I think the fact that we did notice a somewhat higher percentage of reactions overall to Uprima in the nitrate therapy arm versus the non-nitrate therapy arm may in fact suggest somewhat of a potential for a drug-drug interaction between nitrates and Uprima.
		I'm going to switch gears and do a brief summary of the summary comments you've already heard.  I apologize if we seem somewhat redundant here, but before we lead into the questions for the panel, I did want to just recap briefly our summary of concerns. 
		The first concern that the FDA has raised on several occasions was that the patient population selected for controlled trials was somewhat selective in that patients with organic erectile dysfunction were excluded as part of the exclusion criteria, and moreover patients in all three of the randomized, controlled crossover trials that we went over this morning were required to have a normal Nocturnal Penile Tumescence test as part of their inclusion criteria.  As Victor Raczkowski presented, we do not care to present comparisons to other drugs, but I will state for the record that in all other drugs approved for erectile dysfunction, these particular inclusion and exclusion criteria did not exist in the pivotal trials.
		We feel that this selective patient population has relevance to potential efficacy concerns and safety concerns that we've raised for you today.  
		With regards to efficacy, I think it's possible that Uprima could work better than placebo in patients with organic ED, and we may see a more dramatic effect in this population of more severe patients possibly if they are, indeed, more severe.  Uprima may not work as well in patients with organic ED.  That's the other possibility.
		With relevance to safety, our major concern is that we feel that patients with more organic causes of erectile dysfunction may, in fact, be predisposed to more underlying cardiovascular disease and that in such patients Uprima may pose more serious safety concerns.
		What kind of data do we have in patients with organic erectile dysfunction?  There are two trials in this application that look at patients with organic ED specifically.  One of those trials was done in a limited number of patients who were status post-prostatectomy.  I believe the number was 44, something like that.  That trial was neither powered to show efficacy and the safety data was relatively limited.  So, we have, instead, focused on the diabetic trial of patients to look at organic ED patients and how they responded to Uprima.
		In this population, as Dr. Hirsch presented, there was a 25 percent successful attempt rate of the primary endpoint in the Uprima arm versus a 15 percent successful attempt rate in the placebo arm.  We ask that you carefully consider this primary efficacy result in light of the safety data that we have presented for 4 milligrams of Uprima.  That safety data focuses on an overall syndrome of vasovagal events with particular emphasis on a 4 percent overall rate of hypotension and syncope noted in this particular trial. 
		The 2 milligram dose of Uprima.  I think we have gone over some safety issues, but our primary concern there is also efficacy.  We've noted that overall success rates of 44 to 47 percent were noted in the three randomized, controlled clinical trials, the crossover trials, versus a placebo response rate of 32 to 38 percent.  We ask that you carefully consider this efficacy in terms of safety.  
		Few patients, about 10 percent, remain on a 2 milligram dose of Uprima long term when given the option to titrate upwards.  We again feel that this fact needs to be considered carefully in terms of the efficacy of this dose.
		For the 4 milligram Uprima dose, we've laid out mostly safety concerns.  Nausea and dizziness occurred in about 20 percent of patients overall, sweating and somnolence in about 10 percent, and vomiting in anywhere from 1.5 to 4 percent of patients.  Overall, there was a 3.3 percent rate of syncope and hypotension in the clinical trials.
		I'd like to note briefly that the FDA feels that the hypotensive events, when they are recorded as an adverse event, are potentially relevant and important to mention here.  We understand that when clinicians code these terms, they have the possibility to record dizziness as just that, dizziness.  We feel the term hypotension connotes perhaps a more serious concern.
		Finally, we feel there is a narrow margin of safety provided with the 4 milligram dose of Uprima, and this is based on the safety data we reviewed for you with 5 and 6 milligram doses. 
		What about going from 2 to 4 milligrams in a titration fashion?  Does that alleviate some of these safety concerns?  And does it still provide substantial evidence of efficacy? 
		There is one study -- this is the parallel arm study -- that compared placebo, 5 milligrams of Uprima, 6 milligrams of Uprima, and 2 going up to 6 milligrams of Uprima for both efficacy and safety.  In this study, there was a 48 percent successful attempt rate in the 2 to 4 milligram level of titration versus a 35 percent successful attempt rate with placebo.  We again ask that you look at this gain of 13 percent for the primary endpoint carefully in light of safety concerns.
		And what about safety?  Was the dose titration approach successful in ameliorating our safety concerns or at least reducing them somewhat?  
		We have safety results for the 2 to 6 milligram titration arm that show a 5.4 percent rate of hypotension and syncope.  Compared to either the 5 or 6 milligram doses of Uprima arms in this controlled trial, the 5.4 percent rate was actually the highest.  So, we did not feel that titration reduced our concern in this regard.
		We have also raised concerns about interactions with other drugs.  Dr. Jarugula presented his data on the alcohol interaction studies performed.  We believe concerns are raised with the equivalent of approximately 2 ounces of vodka and go up higher as increasing alcohol doses are administered. 
		Is there a nitrate interaction?  I believe it's possible, and that would be supported by the increased reporting of adverse events of nausea, vomiting, diaphoresis, dizziness, and hypotension noted with patients on nitrates versus the similar results of these adverse events reported with patients on non-nitrate therapies, but it is difficult to tell for sure.
		As we address our questions for the committee, again keep in mind these points that we've brought up.  I wanted to also bring up the uses in real life as the bottom bullet. 
		The sponsor has presented this morning an assessment of adverse events that were done using the total number of doses taken in the denominator and further projecting out an event rate per year for an individual patient.  We ask that in real life you look more at the adverse event data done per patient in these clinical trials.  We feel it gives the most realistic approach to safety and that the other approach possibly could underestimate event rates as the denominator is inflated with the number of doses taken per patient.  It's obvious that patients who do not tolerate study drug are going to drop out from that denominator over time, thus giving you a perhaps inflated denominator that would underestimate safety concerns.  So, we wanted to address that briefly.
		Moving on to our questions, the first question for the panel doesn't deal so much with safety and efficacy profiles and risk-benefit assessments.  We merely ask that you address does the patient population that has been studied support the proposed indication statement for the treatment of erectile dysfunction.  If you believe so, please elaborate, and if not, please describe your concerns.
		The second question:  Do the data presented support an acceptable risk-benefit profile for the 2 milligram dose of Uprima?  Again, we ask you to elaborate if you feel this is so, and if not, please describe your concern or concerns and include additional descriptions of a study or studies that might address these concerns.
		And finally, the question for the 4 milligram dose is identical to that for the 2, so I won't put you through the pain of reading it thoroughly again. 
		Those are our questions for you, and now we are ready to take your questions for us.  Thank you very much.
		DR. AZZIZ:  In order to stay on time, as I said earlier, let us go ahead and go to a break now.  We will return to the questions for the FDA staff following lunch, and then the open forum.
		It is now 12:30.  Let us reconvene at 1:15.  Thank you.
		(Whereupon, at 12:30 p.m., the subcommittee was recessed, to reconvene at 1:15 p.m., this same day.)

	AFTERNOON SESSION
	(1:18 p.m.)
		DR. AZZIZ:  We'll reconvene if all the members can please sit down.
		What I'd like to do this afternoon is, one, stay on time.  Two, I'd like to begin with the public hearing portion of today, and then go ahead and go a session where we can just simply ask questions of both the sponsor and the FDA staff because we obviously have not had much time to ask questions.  But we would like to make sure that we don't extend that question and answer period forever because we do need to answer the questions that have been posed to the committee.
		Just one speaker and one person to respond?  Is that right?  We have only one speaker and that is Donald Vieth, I think.  If I said that incorrectly, I'm sorry.  If you would please state your relationship to the sponsor, any potential conflict of interest, and so on.  Thank you.
		MR. VIETH:  My name is Donald L. Vieth.  I'm 59 years of age.  I want to thank you for the opportunity to recount my experience with the drug Uprima.  TAP Pharmaceuticals invited me to testify today, and they are reimbursing me for my travel expenses. 
		In late 1997, I began to realize a decline in my sexual capabilities.  The decline in capability was manifested in a slowness in the ability to achieve an erection and the inability to maintain it over a reasonable period of time once attained.  With this condition, a successful attempt at sexual intercourse was becoming more tenuous.  To put the situation in proper perspective, let me say I went from a condition of erection on demand with a significant orgasm to a point where it was possible to have an ejaculation without benefit of erection or orgasm.  So, that is just the sense of where I was.  In essence, sexual enjoyment as I had known it had completely disappeared.  For a man who had been married for 37 years and enjoyed a robust, imaginative, and intense sex life with his wife, the impact of this emerging condition was very troublesome.  Although a marriage is based upon far more than sexual activity, the conscious realization that the erotic pursuit of the industrial strength, multiple orgasm was no longer an option constituted a devastating blow for both my wife and myself. 
		Considering the enormity of the situation, I consulted a urologist.  I was diagnosed as having erectile dysfunction.  Viagra was prescribed to determine if it was possible to mitigate my condition.  There was no improvement in my condition or performance with the use of Viagra.  
		The urologist also indicated that they were conducting evaluations of new drugs to mitigate the factors causing erectile dysfunction and wanted to know if I would be interested in participating in the evaluation of these drugs as they became available.  I indicated that I would and my wife strongly supported my involvement. 
		I've been involved in phase III of clinical testing of Uprima since September of 1999.  I want to note that my experience with Uprima has been remarkable.  When taking Uprima, 30 to 60 minutes before the initiation of sexual interaction, I was always able to achieve an erection in a relatively short period of time after the initiation of physical stimulation, that is, within a few minutes.  I have always been able to have sustained intercourse without difficulty and realize a quality level of orgasm.  The use of Uprima has restored my ability to perform competently and achieve sexual satisfaction.  I have been able to enjoy a significant turnaround in my sex life without experiencing any identifiable side effects.  The use of Uprima has restored my sense of confidence that I can perform in a manner that satisfies both my wife and myself.
		Based upon my personal experience, I would strongly support the approval of the drug Uprima. 
		If there are any questions about my situation, I'd be happy to address them.
		DR. AZZIZ:  Thank you very much for your comments.  We generally don't have questions.  But your comments will be taken in consideration.  Thank you.
		Without further ado, I don't think we have any other public speakers, so anybody in the audience who wants to take the opportunity, this is an open forum.
		(No response.)
		DR. AZZIZ:  Thank you. 
		Let us go ahead and go to questions from the committee to both the FDA staff and the sponsor regarding the extensive data that was presented this morning.  Again, please identify yourself before you speak. 
		DR. HANNO:  I just have a question regarding whether the FDA has any policy with regard to drugs that might affect libido and whether the sponsor has data on the effects of Uprima on libido.
		DR. MANN:  I'll take the FDA portion of that question, if you don't mind.  We don't have a specific policy on drugs for libido per se.  I believe we look at all drugs in terms of their efficacy and their safety profiles, and if there's meaningful clinical benefit obtained, we will look at that, including potentially drugs for libido, as well as we have many other examples of drugs for quality of life type endpoints that are like that.  I think each is taken on a case-by-case basis and look at safety and efficacy.
		DR. HEATON:  Jeremy Heaton in response.  Any drug that works on the central nervous system has to raise that possibility.  This is a slide that demonstrates the change in sexual desire domain of the International Index of Erectile Function, a score which you've seen several times today.  There are no clinical changes and, indeed, only one very slightly statistical change in the sexual desire domain in these patients as a result of the treatments given.
		DR. AZZIZ:  Dr. Greene.
		DR. GREENE:  I have four specific questions of clarification I'd like to address to the sponsor.  Do you want me to do all four of them right now?
		DR. AZZIZ:  If they're quick.  If they're not, we'll cut you off.
		DR. GREENE:  Okay, fine.
		The first question was on three slides you mentioned vasodilatation as an adverse event, but I wasn't sure exactly what the definition of vasodilatation was.
		DR. FRESTON:  It was in the eye of the beholder.  If the investigator thought he saw flushing or something like that, he would call it vasodilatation. 
		DR. GREENE:  Okay.  So, that presumably did not overlap then with other things like sweating or dizziness?
		DR. FRESTON:  These symptoms commonly track together as that prodrome that I mentioned.  I should also re-mention in this regard that frequent mention has been made today of hypotension.  I would emphasize that also was in the eye of the investigator.  It was not documented by blood pressure recordings.
		DR. GREENE:  That was another question.
		Another question, quickly, is in the patients that were Holter monitored, why was the Holter monitoring done?  Was that done because there was an a priori concern about dysrhythmias or because of experience with the drug?
		DR. FAGAN:  It was not done on account of experience with the drug.  Because there had been some syncope, TAP was very anxious to establish what the mechanism was, and to be certain that in fact it wasn't inducing serious arrhythmias.  Therefore, prospectively this was included in a number of the studies so that that could be evaluated. 
		DR. GREENE:  So, it was done in response to the experience with the drug, specifically syncope.
		DR. FAGAN:  Yes, the early experience with syncope and then these studies were designed.  It was not done in response to any experience of any significant arrhythmias.
		DR. GREENE:  Okay.
		DR. FRESTON:  Could I just add to that for clarification?  These syncope cases, these anecdotes that we heard about today, occurred, for the most part, very early when the investigators were using this drug for the very first time.  The spontaneity of all this caught everyone by surprise, and in many cases there was quite an alarming, what turns out in retrospect to be, an overreaction.
		Subsequently, we got on top of this, and part of the way we got on top of it was to decide whether or not these were cardiogenic syncopal attacks or noncardiogenic, i.e., vasovagal.  So, the Holter monitoring and other measures were put in place to study that prospectively.
		DR. GREENE:  A question came up this morning with regard to the blinding and the efficacy of blinding in the study in the placebo.  One of the ways of addressing the issue of blinding is simply to ask subjects during a placebo-controlled blinded trial whether they thought they were taking drug or placebo and then seeing if they were correct.  Was that done in these trials?
		DR. FAGAN:  That was not done in these trials, but as you saw, there were analyses of the first period only and analyses in patients without symptoms.
		DR. GREENE:  And the final question that I had was with respect to the durability of the effectiveness of the drug, was there data to suggest that the efficacy of the drug was the same, let's say, in the first month that it was taken and the last months that it was taken and over how long a period of time?
		DR. HEATON:  The answer is yes, there are data that will show that.  The other issue is the long-term data.  The patients who were responding respond at an 80 to 90 percent sustained response rate, which means that 80 to 90 percent of attempts continue to be successful.
		DR. GREENE:  Thank you.
		DR. GRABOYS:  Yes.  I have concerns about the hemodynamic issues referable to the syncopal issue.  As folks get older, they increase vagal tone anyway, so we see a lot of folks in their 70s and 80s who have vasodepressive syncope in the setting of increased vagotonia.  The question really is, number one, how are you going to address this with tutoring physicians to prescribe this agent, and will there be a trial in the physician's office?  How do you anticipate tutoring?  I think that's really the bottom line on this.  In an event that is very difficult to predict that may increase because of increased vagal tone and you don't have data on an elderly population that we're trying to address the specific issue to.
		DR. FAGAN:  There's a couple of answers to that.  It's true that there isn't data on very many patients over the age of 65.  However, as you recall, we did show adverse events in those over 65 versus those -- actually, we probably didn't show that.  Could we show that?  And in fact, the adverse events are not greater in that group.
		The other thing, you remember, is that this is vasovagal, so it's not just the vagal tone, but it's a withdrawal of sympathetic tone.  Our sicker patients, which you might say were physiologically older, the ones with coronary disease, the ones with diabetes, had numerically less adverse events than the younger patients.
		DR. FRESTON:  I would also add that we want to capitalize on what we have learned in this regard, elders who are taking drugs that might cause them to have syncope from other examples.  You remember in the early days of prazosin, the elders were getting syncopal events, and we'd say take this medication at nighttime.  That's basically what we're saying should be done with this.  
		Likewise with Hytrin which reduces the frequency of urination overnight by just one micturition.  We ask those patients to take it at nighttime and to lie down.  
		So, we want to incorporate some of these features into the patient information package.
		DR. FAGAN:  On the slide here, we have the older patients.  The ones over 65 basically have the same nausea rate, same dizziness rate, similar sweating rates as the younger patients.
		DR. GRABOYS:  Someone said -- I'm not sure who -- in the discussion they would advise physicians to use their "clinical judgment."  And this is in regard to the alcohol and in regard to nitrates.  Again, whose clinical judgment are you talking about?  Urologists, cardiologists, primary care physicians?  I think this needs really to be fleshed out.
		DR. FAGAN:  Well, obviously it's whoever is prescribing the drug.  We know that the majority of these drugs are provided by primary care providers, internists, family practitioners, nurse practitioners, so that's who we're going to be talking about.  
		Again, the general instructions pretty well cover everything.  If they are supine, with one of the prodromal symptoms which are in 85 percent of the syncopes and 98 percent of the episodes of hypotension, then they shouldn't have any problem.  And that's a fairly simple instruction.  
		As far as who you aren't going to give it to, I think you're probably more comfortable giving it to patients with more cardiovascular disease than most of the primary care practitioners will be.
		DR. FRESTON:  I would like to add that one expert actually portrayed the prodrome as perhaps an advantage and he likened it to tinnitus that occurs in patients who take aspirin.  If they start to get the dose too high, you get tinnitus, and then you stop doing that.  In many ways the symptom of nausea can be viewed in that fashion.
		DR. AZZIZ:  Dr. Califf.
		DR. CALIFF:  Rob Califf from Duke.  I had two questions.
		One is I want to make sure that I'm understanding the basic math on the efficacy side here in terms of intention to treat with regard to the subjective questionnaires.  Did 100 percent of the patients return their questionnaires?  And if not, what was the count given to a patient who didn't return the questionnaire?
		DR. FRESTON:  That's a good question, and I'd like to ask Susan Buttler.  The issue is, how are the patients counted when don't fill out their questionnaire?  Are they counted as treatment failures as in an ITT analysis?  Anthony Edmonds will help us with that.
		MR. EDMONDS:  Actually we did an analysis in which we imputed the answer of no for patients who did not complete a questionnaire.  In most of the analyses you've seen, we didn't include those data or those lack of data.  But as you can see here for the analysis, the very conservative analysis, where we impute no for patients who did not fill out a questionnaire, you can see similar efficacy results for the 2 milligrams, 4 milligrams, all highly statistically significant.
		DR. CALIFF:  So, it must have just been a few people who didn't return the questionnaires.
		MR. EDMONDS:  Correct.
		DR. CALIFF:  The second one is a little bit hard to get at specifically, but I think one of the really critical issues is trying to understand what the likelihood is -- the patients, for example, with coronary disease who got into the trials were like most people with coronary disease that you see in a clinic.
		Maybe one way of getting at this would be -- this is a rough thing I usually use -- how many exclusion criteria did you have for your typical protocol?  Was it 10, 20, 30, more than one page?
		DR. FAGAN:  Well, let's look at it another way.  Let's look at it from the standpoint that these patients were enrolled in the studies by physicians who treat a large amount of erectile dysfunction, that they were not difficult to recruit, that very few people didn't meet the criteria, and there are the exclusion criteria.
		DR. FRESTON:  In this regard, we continue to be puzzled about the statement that these patients don't represent the larger population.  Basically the only patients we excluded were those with unstable medical disease.  We described that in the case of the hypertensives, as shown there, and the diabetics.  They couldn't have had any ketoacidosis in the antecedent months, and they had to have their blood sugars not very well regulated.  And we excluded patients with spinal injury and total prostatectomy, and we excluded patients who had 0 erectile function.  
		Now, according to MMAS, only 10 percent of the ED population had complete ED.  So, we might have missed 10, but we're puzzled about what this larger population is because we had them all in the study just like Viagra did.
		DR. AZZIZ:  Dr. O'Leary.
		DR. O'LEARY:  O'Leary from Boston.
		With regard to the nausea situation, do I understand it correctly that there's a learning effect, if you will?  In other words, with increased use of the drug ‑‑ or is it simply that they -- because they're staying on the drug, presumably it's efficacious and they ignore the nausea or they tolerate it.
		DR. FRESTON:  It may be all of those considerations plus one other consideration.  We don't believe there's any evidence for pharmacologic tolerance.  This is a short-acting drug that's given intermittently, after all.  We think, understanding the accommodation is better understood in the context of what happens to people when they experience a vasovagal episode with syncope -- think of yourself the first time you saw an operation.  You may have fainted.  You didn't do it again.  People adjust to that first episode, and we think that's taking place in these patients.
		DR. O'LEARY:  So, it's a learning effect.
		DR. FRESTON:  Yes, we think so.
		DR. FAGAN:  Here where people took at least 8 doses so that it wasn't an effect of people dropping out, clearly it decreases very rapidly and after the fourth dose, it's below 3 percent.
		DR. AZZIZ:  Dr. Kowey?
		DR. KOWEY:  I have just a few questions related to the vasovagal syncope.  I think what we're seeing here is a drug which has a cholinergic effect producing vasovagal syncope.  85 percent of them have prodrome.  Am I to understand that 15 percent of the people who had syncope did not have a prodrome?  Is that correct?  You said 85 percent of patients had prodromal symptoms.
		DR. FAGAN:  That's true.  In the 2 and 4 milligrams, 11 of 13 did have prodromal symptoms.  I think cholinergic, though -- we've never said cholinergic.  It's not direct cholinergic, but it's --
		DR. KOWEY:  It's provoking the response which I think we probably can net out even though it may not have a direct cholinergic action.
		The question I have is do patients who had vasovagal syncope -- you had some actually in the placebo group as well as in the treated group.  Did you make any effort to screen out patients with a prior history of vasovagal syncope in the exclusion criteria, or do you know how many people had it before they got the drug or got placebo?
		DR. FAGAN:  We don't know and they were not screened out.
		DR. KOWEY:  Would you like to make that part of your labeling perhaps, that people who have a history of vasovagal syncope might not be good candidates for this drug?
		DR. FAGAN:  I think someone who's a frequent fainter with multiple repeated episodes probably would not be a good candidate.  I don't think you should eliminate people who have had only one episode because that may have been entirely -- yes, you'd exclude 40 percent of the population, and it wouldn't really help.
		But the other question is whether this should be given in the office.  Given the very uncommon occurrence of the syncope, you'd be putting roughly -- by my previous calculation, which I'd have to go through again, about 500 patients would have to come into the office and sit there ‑‑
		DR. KOWEY:  Well, you're not only screening for syncope in the office, you're looking for severe hypotension, which brings me to my next question, which was, did you prospectively define hypotension in the protocols, or was that left to the investigator to tell you when he thought somebody had hypotension?
		DR. FAGAN:  This is the standard sort of drug study, COSTART term, and that's the --
		DR. KOWEY:  So, you didn't prospectively say to the investigators this many millimeters of mercury you should report hypotension, or percentage drop in blood pressure.
		DR. FAGAN:  No, it was not.  In fact, most of the studies, blood pressures weren't measured.
		DR. KOWEY:  And my last question is we're making a presumption here based on data that you've presented that what we're seeing is a response which is autonomically mediated.  You saw some pauses on the Holters that were pretty prodigious.  As I recollect, there were some that were stretching out close to 20 seconds of asystole.
		DR. FAGAN:  The 20 seconds was related to a blood draw on a patient who did not receive Uprima.
		DR. KOWEY:  I'm just saying that in people who got the drug and some people who didn't get the drug.
		DR. FAGAN:  Right.
		DR. KOWEY:  Okay.  But clearly, for some people who got the drug, you had a concern about bradycardia because that's why you got the Holters put into the protocol.  You knew that there was an incidence of this.  From any other piece of data, ECGs or any other kind of information you may have extracted, how can we convince ourselves, especially given Tom's problem with older individuals and having a gross under-representation of the very elderly, that this drug does not have a direct electrophysiologic effect on the conduction system, in addition to an indirect effect?  
		In other words, how do we know -- and maybe Joel can answer this question, maybe he can't -- that the drug, in addition to having what appears to be an effect to cause vasovagal syncope, how do we know it also doesn't have a direct effect to cause sinus slowing for example?  Do we have any piece of information that would tell us that?
		DR. FAGAN:  Yes.  Let me say one thing and maybe Dr. Morganroth can respond.
		The 20-second pause was in a patient who had his blood drawn and did not receive Uprima.  There were 10- and 11-second pauses seen in 2 patients who did receive Uprima. 
		And the other piece is that we know that this drug has been given worldwide and in clinical trials to thousands and thousands of patients at doses manifold higher, orders of magnitude higher, than we're talking about giving to these patients when they're treated for Parkinson's --
		DR. KOWEY:  No.  That doesn't answer the question because I don't care about that, you see?  I don't care how many times it has been given at what doses.  
		What I'm asking is if you give this drug to somebody that has a conduction system disease and you do not have those patients represented in your database because you don't have a lot of old people in your database, are we sure that we're not going to also, in addition to having a vagomimetic effect, have a direct effect on the conduction system?
		For example, do you have paired ECG analyses showing changes in PR interval or in heart rates in people that got the drug that did not become vagal?  Do you or don't you?  Do you have that information?  That's what I want to know.
		DR. FRESTON:  Yes, we have a lot more information.  Dr. Morganroth.
		DR. MORGANROTH:  I believe in every one of the trials, ECGs were obtained for and on drug, and in the analysis that you're requesting, there was no change in heart rate or in PR interval, which would suggest there is not a direct effect.
		DR. FRESTON:  Let me also add because this is a very important issue.  There undoubtedly some additional subsets of patients that we haven't looked at, like those who had preexisting conduction disorders.  We don't know those.  My suggestion would be in the label it will need to be discussed what patients were included and, by implication, all those others were not, and maybe they can be specified and then investigated later in a prospective way.
		DR. AZZIZ:  Dr. Jacobs, Dr. Califf, and Dr. D'Agostino.
		DR. JACOBS:  I have two questions.
		The design of the study included only people who were NPT, Nocturnal Penile Tumescence, positive.  I didn't see anybody coming up with NPT negative on here.  NPT could be negative for both a central reason and a peripheral reason.  Have you got any collection of data on NPT negative people?
		DR. FRESTON:  Well, the NPT issue -- everyone has been confused about this today, and I suggested to Dr. Azziz that we have Dr. Ron Lewis come up and answer this question and put this in perspective for us.  He doesn't like to admit it, but he's the father of the RigiScan.
		DR. LEWIS:  Not really.  I won't take credit for that. 
		I appreciate the opportunity.  Ron Lewis, and I have been a consultant to TAP and am currently President of the International Society of Impotence Research.
		We've got to go back to the history of NPT.  NPT has clearly been stated in our literature -- and it's clearly stated in all erectile dysfunction literature -- it does not distinguish between organic and non-organic disease.  NPT does not make that distinction, and that's clearly established in our literature.  So, to use this as a criteria for selecting patients to be either organic or non-organic, it is not in our literature.  It's not supported by that.
		There are three types of erections.  There are erections that occur nocturnally, at night.  There are erections that occur with sexual stimulation, and there are erections that occur with sex-stimulating visual-related erections.
		In the literature, it is clearly established that these are all different.  So, a man can have impotence in a sexual situation and still have normal NPT.  So, I think that's extremely important.
		What is happening in impotence is that we are finding that probably questionnaires -- it's much like BPH.  We thought we had everything as urologists figured out by BPH by using flow rates and everything else, and then we started using a symptom score.  And we found out that the symptom score was actually more predictive of the degree of disease in the patient and the response to medication.
		Similarly, we're finding this out with the questionnaires, the IIEF.  We have shown in this study and TAP has shown I think this morning, that 75 percent of the patients either had moderate or severe erectile dysfunction that is more likely to indicate organic disease.  These are patients that we are seeing in our office.
		Finally, I want to remind why this selection of NPT was really put into the study in the first place and why it was not used with Muse, why it wasn't used with Viagra.  This is a new agent.  It is an opportunity to have an agent that acts centrally.
		Now, to understand if this is going to have any relevance for the patients that we see, we didn't want to have severe end-organ disease.  What the NPT does by using the criteria of only one episode of greater than 55 percent base rigidity for no longer than 10 minutes on two successful nights, this indicated that there at least is some functional tissue in the end organ where a central agent might have effect.  That was the only reason that the NPT was selected.  And by all criteria which determines whether NPT is normal or abnormal, this clearly, by using only one episode of 55 percent less than 10 minutes, lies at the lower range of being considered normal NPT.  By most people, it is not considered normal NPT.  
		So, I've heard that NPT has been used to sort out.  It really can't be used in this situation.  It was simply used as a tool to select those patients who have still an acceptable end-organ tissue response to an agent that's going to work centrally.  
		So, I've heard that this doesn't represent real patients.  It does represent real patients.  The urologists who participated in the studies -- and I was the central NPT reader and actually only recently participated in a study of patients that isn't even considered at this time, but basically what I found out from the people who were sending in to me as an NPT reader is that they had a very, very easy job of recruiting these patients from their practice.  And I think that that's what we should be left with.
		Thank you.
		DR. JACOBS:  Are you saying that an NPT negative patient is not a candidate for this?
		DR. LEWIS:  No.  In fact, that was actually pulled out too.  When we were going to address the NPT data, it was noticed on those two slides that were shown this morning that clearly the bell-shaped curve was far to the left of what has been described by Dr. Levine as normal studies.  These were more likely patients who had severe disease.  When we looked at the response of tip rigidity -- and that's rigidity area under the curve under two criteria, number one is less than a certain percentage.  It was actually presented in two different rigidity measurements.  But even when we look at the most severe, less than 9.6 area under the curve, still those patients had the same response.  So, with very severe disease even by NPT, they too responded.  So, both groups did have a response.
		DR. JACOBS:  My second question actually had to do with the drug most likely to be taken with this drug in the real world and that's Viagra.  Are there any patients that have taken both drugs?
		DR. FAGAN:  There's been a pilot trial with the combination, and there's a combination trial which has been planned but not initiated.
		DR. JACOBS:  And there's no safety data to report on that pilot trial?
		DR. HEATON:  There are no data from that trial available today.
		DR. FRESTON:  Mr. Chairman, could I follow up too on just one point that Dr. Lewis was alluding to?
		There was confusion in one of the FDA slides today and I'd like to clear it up about whether or not these people really did have erectile dysfunction.  This has to do with the 50 percent success rate at sexual stimulation.  That was the cutoff beyond which we didn't want patients to participate.  That's not to imply that most patients hit up against that 50 percent level.  As a matter of fact, 39 percent of our patients had absolutely no sexual response at all in the preceding 1-month baseline period.
		DR. AZZIZ:  Thank you.
		Dr. Califf?
		DR. CALIFF:  I'm sorry to keep coming back to this.  What I'm really struggling with here is to try to get the best estimate of the treatment benefit and the treatment risk at the 4 milligram dose.  
		Twice you've said that people that had taken the treatment 8 times somehow gave us a better estimate of what the effect, in terms of inducing hypotension, was than other data, when I would have thought it just the opposite.  Usually if someone takes a treatment 8 times, we call it the healthy survivor effect.  That is, if I got hypotension or got nauseated the first 3 times, I probably wouldn't take it the fourth time.  So, I need to understand that point better.  I would think that would be underestimating the risk if you had people that really took the treatment.
		DR. FRESTON:  Well, it's a very good point, and this is different from what we usually see.  Again, we have the phenomenon of the adverse events diminishing over time, and that occurs, by the way, whether we look at the 2 milligram, 4, 5, or 6.  Again, we think it's just a combination effect that we alluded to before, presumably related to learned behavior.
		If I may, I'd like to also point out the agency in its presentation today pointed out that most patients, maybe upwards of 90 percent, gravitate up from 2 to 4 milligrams.  The implication was that now they're going to have 4 milligram AE rates.  That doesn't follow because of the accommodation.  There's a balancing effect that takes place.
		DR. CALIFF:  I don't think you're answering my question.  I mean, typically people who have adverse events drop out.  Those who are left have a lower rate of adverse events.  That's seen in almost every treatment.  How do you account for that in your analysis?
		DR. FRESTON:  Dr. Jennings.
		DR. JENNINGS:  Dennis Jennings from TAP.
		In the tables you see of our adverse events, they are as Dr. Mann suggested, presented as per patient.  So, if somebody had an adverse event during their first two attempts, they are shown in those percentages.  The nausea slide you saw put up trying to show the declining in the adverse events was just noting that if we did take the patients who stayed in for a while, we see that those are declining.  In fact, nausea for example was not something that very many people were dropping out from because, if you notice, the adverse event rate on the first dose was pretty close to the total adverse event rate that we saw in that study.
		DR. CALIFF:  So, to be scientifically clear, we can't use these data to say that there's actually a diminution in nausea because you really haven't separated out the effect of dropout.  It would be almost impossible to do so.
		DR. JENNINGS:  Well, I think the slide we put up does do that to some extent because what we're saying is there's a very small number that are dropping out due to nausea.  But if you take the patients who had sufficient exposure so we can look at how their nausea rate changed over time, those ones are clearly declining.  So, there's a little mix in there, but I think it's helpful.
		DR. FAGAN:  Let me make one other point, and that is, of the 13 patients who had syncope on 2 or 4 milligrams, 7 continued in the trials, took a total of 150 doses, and nobody had syncope a second time.
		DR. D'AGOSTINO:  I have two questions.  You have to forgive me if I don't have sort of the background to put this in for the particular condition, but we're talking about, from the sponsor's point of view, that in fact the patient population is representative and similar to other patient populations that have been used in these type of studies.  Down the road when we start coming to the questions, we're going to be asked about the patient population with the implication that some of the FDA -- more than implication, the explicit writing that it's not typical.  So, you have to forgive my ignorance that I don't have all the literature sitting in front of me, but I need some sense of why is this patient population that we used in the studies different.
		DR. HIRSCH:  To my knowledge, no other sponsor used the following two inclusion/exclusion criteria:  the phrase "no major organic component."  And frankly, I'm not sure how that was used.  I'm not sure what an investigator did to decide that a patient had no major organic component.  For example, if a person had bad diabetes and that was what was thought to be causing his erectile dysfunction, did the investigator say, well, he had a major organic component and I can't include this person?  I think that's what happened, but I could be wrong.  I don't know how that was used. 
		The second this is I don't know of any other studies that used NPT at all as an inclusion or exclusion criteria.
		DR. D'AGOSTINO:  And what would be the problem with the NPT?  Is that you would think you'd have a population that -- it slices the target population, obviously, but that somehow or other the effect from the efficacy or from the safety or from both would not be representative in these studies?
		DR. HIRSCH:  Well, I think it's fairly simplistic really in that a patient with one erection in two evenings, which is greater than 55 percent rigid compared to a hard plastic rod is a person who can get physiologically an erection greater than 55 percent of a rigid plastic rod, which means they can in the evening.  Whether they can during sexual stimulation or they can during erotic arousal, I agree that might not be true, but they physiologically can get something of an erection.
		DR. D'AGOSTINO:  Let me ask the second question.  Does anybody want to respond?
		DR. HEATON:  I'd like to take the opportunity to answer those two issues. 
		First of all, the expression, the phrase, "no organic component," was used based on discussions to give a general overall gestalt to the patients who were being admitted to the study as of the perspective of 1995-1996.  This is a time when the whole issue of organicity and psychogenicity of erectile dysfunction was in a state of flux, and it was a point of interest.  "No organic component" was meant to guide the investigators to the kind of patient who did not have a prostatectomy, who had not had spinal cord injury, who didn't have Parkinson's disease, who did not have MS, they had not had penile prostheses or penile surgery, and they did not have any end-stage or unstable diseases.  
		So, the actual expression itself was not a criterion of admission, and it resulted in, as I tried to demonstrate quite clearly earlier, that there is a very substantial proportion of patients with organic co-morbidities.  Now, that's a cautious term because that does not imply that I know that the hypertension or the coronary artery disease is absolutely the cause of the ED in that patient.  However, when you have the organic co-morbidity present and it's present at the same rate as in comparable clinical trials and in a patient population sample, such as the MMAS, I'm reasonably well consoled that this is a representative population.  
		I really have to take up again the issue of the NPT.  55 percent on one occasion for 10 minutes is not a normal erection.  These patients were chosen not to have normal erection.  The RigiScan was introduced after extensive discussion with the agency with a desire to introduce some organic level of -- some objective level of measure, and in the early 1990s, this was a very good standard of objective measure.  So, the purpose there was to, as Dr. Lewis stated, just avoid the appearance of people with no end-stage penis and, therefore, people who were basically inappropriate for a pharmaceutical trial.
		This slide is another way of looking at that same idea.  This is one we showed before where if you have absolutely no success during baseline, which by any standards would have to be a very robust measure of erectile dysfunction, these patients had fairly similar values compared with the group as a whole at a decent statistical level.  We could again go through the IIEF criteria that also resulted from the application of this.  So, we could look at the people who had the very low RigiScan scores, which is under 9.5, again showed a very substantial spectrum of efficacy.  
		So, it's a difficult issue, and NPT actually has been something that urologists have been wrestling with for its utility.
		DR. AZZIZ:  I'd like to have Dr. O'Leary comment.
		DR. O'LEARY:  I'll actually be a little more blunt, Dr. Heaton.  I don't think we should get too focused on the NPT.  There are a lot of urologists who don't use it, who think it's of very little value.  In fact, with all due respect to Dr. Lewis, there are some urologists who refer to it as the RigiScam rather than the RigiScan.  So, I think it's important that we not get too focused on that.
		DR. DONATUCCI:  Craig Donatucci from Duke, urology.
		I want to second that.  In essence, I think first off people say RigiScan and I think the statement was made this morning it's a reflection of REM erection activity that makes -- it occurs during REM sleep and in fact it doesn't measure REM sleep.  So, if the patient doesn't have REM sleep, it's not measuring anything.  It's just too inaccurate to hang anything on.
		DR. AZZIZ:  Let me just ask a question of Dr. O'Leary and Dr. Donatucci because your comments were timely, but how does this impact?  You just said that the NPT isn't really of much value.  There seems to be an agreement with those of us who don't do NPTs.  Does this impact in any way --
		DR. D'AGOSTINO:  Yes.  How does it help my question?
		DR. AZZIZ:  How does it help dissect this issue --
		DR. O'LEARY:  In some ways I don't think it really does, and I don't want to say that I've completely discounted it.  
		But the treatment -- and I thought I would wait till later, but I may as well just get this out now.  The treatment of erectile dysfunction is largely goal oriented for those of us who specialize in it, who are interested in it, and take care of these patients on a daily basis.  Certainly there are some patients that if we can, we like very much to have a precise diagnosis, to be able to use those objective parameters that are available to us, most of which, by the way, are invasive, to be able to precisely determine what the etiology of their ED is.  But for the most part, when I see a 60-year-old man in the office who has hypertension, maybe he's on a diabetic medication, and he tells me he has erectile dysfunction, I believe he has erectile dysfunction and I go ahead and I treat him. 
		I don't routinely do NPT.  The NPT monitor is sitting in my closet gathering dust.  I will occasionally do penile doppler studies and so on, but I think that most urologists who have an interest in this would agree with me that we're goal oriented.  That's how we treat people.  So, in evaluating the patients that are in this population, in this database, they look pretty much to me like the kind of people that I see every day.
		DR. AZZIZ:  So, the NPT doesn't add or detract.
		Dr. Tiefer, please.
		DR. TIEFER:  Can I just speak to the NPT issue?  Because I agree with Dr. Lewis that these patients don't have normal NPTs.  But I think the presence of so many NPTs in so many patients is of interest to those of us who did collect thousands of NPTs of patients for a very long period of time, and my sense is that these are better NPTs than the patients who walk in the door.  Patients who walked in the door with a variety of etiologies did not have 55 percent of maximum base for 10 minutes on at least one occasion when measured for two consecutive nights.  This is just better.  
		So, if that's relevant then -- and I think in conjunction with the subjective question which was asked, namely have you had an erection sufficient for intercourse in the last 3 months, to which again the random selection of patients who walks in the door typically is very equivocal about that.  And you press them and press them and then a lot of times, they say, no, they had an erection, a partial erection, a floppy erection, but it wasn't sufficient for intercourse.  So, those two pieces of information taken together do suggest to me that these patients are in better shape than the random assortment of patients walking in the door at the present time.
		DR. O'LEARY:  Well, I'm not so sure I agree, but I'm not sure that that's germane necessarily.  I do not happen to believe that the RigiScan is of much value.  Period.  That's my opinion.
		DR. TIEFER:  Well, I think it's of no value when it shows no response because you have no idea why it's showing no response.
		DR. O'LEARY:  Right.
		DR. TIEFER:  But when it in fact shows a substantial and prolonged response, though not a perfect and normal response, that didn't happen by fairies through the air.  Something produced that. 
		DR. O'LEARY:  No, but it may very well be that that patient has -- I'm sorry to get into a debate about the RigiScan.
		DR. AZZIZ:  We're not going to debate too much longer, but I think we need to just go ahead and finish your statement.  Go ahead.
		(Laughter.)
		DR. O'LEARY:  It's possible that the patient can have a positive RigiScan or negative RigiScan by having a good erection and not be able to perform at all.  And we see this all the time.
		DR. AZZIZ:  Well, this is very unusual to have disagreement in the medical community.
		(Laughter.)
		DR. AZZIZ:  Dr. Hanno.
		DR. HANNO:  Yes.  I have a couple comments in terms of what Mike has been saying.  I don't think issue of the RigiScan is related to how useful is it clinically.  The point is, I think, that it enriches the patient population.  The use of the criteria that the sponsors put out enriches the population they're looking at.  I don't use the RigiScan clinically, but I think we're looking at an enriched patient population and that we have to keep that in mind. 
		I have a couple of questions for the sponsor.  One is that since about 90 percent of the patients are going to be taking the 4 milligram dosage based on what we've seen, in the label do you think that you should list the side effects of the 4 milligram dosage separately rather than combining it with the 2 milligram?  Because I think the combination tends to make it look like the side effects would be less. 
		And then I have one other one about the label.  Would you put anything about eating?  Some of the comments that you made with regard to the study and not eating a lot within 1 hour of taking the medicine, would you want to put those in the label as well?
		DR. HEATON:  We think those are both good ideas to consider for the label.
		DR. FRESTON:  We want to get the very best label that we can that capitalizes on the experience we have gained as these studies have unfolded, especially now that we've gone to the first dose at home studies and learned a lot from them.  Some of those features I think could be helpful.
		DR. AZZIZ:  Again, labeling issues we'll bring up as we discuss a little bit further, but right now we need to concentrate on getting our data clear.
		I have a question for the FDA staff.  Maybe I am not understanding this, but there is a great variability which I think is demonstrated in the 4 milligram, 5 milligram dose, 2 milligram.  In other words, great variability in the Cmax and the AUC.  But I am unclear as to what does it matter because, yes, we know that there's great variability and that there's overlap in the Cmax, for example, up to 5 or 6 milligrams.  But if you had never studied the 5 or 6 milligram, the population of 1,200 patients or so that apparently were started with 4 milligrams should have taken into account that variability.
		So, in this case I'm not quite sure just because it overlaps with the 5 and the 6 milligram dose, I am unconvinced that this represents "the same dose."  And so, I think I may need to have a little bit of clarification in that regard.
		DR. MANN:  I'll speak in general terms to your question.  I do agree with you that the most germane data is the 4 milligram data compared to placebo and the 2 milligram data compared to placebo.  As we delve into the 5 and 6 milligram data, I believe the only point we wanted to make there is that on an individual patient level at least, we cannot always distinguish what kind of pharmacokinetic profile a given patient is going to have.  But you're absolutely right in that the main focus of safety should deal with the 4 milligram data in the clinical trials.
		DR. FRESTON:  Dr. Azziz, if I may on this issue of variability, it's one of the things that we wanted to bring up and we're glad you opened it.  The clinicians around the table know very well that clinical data trump pharmacokinetic data.  We have no looked at those different doses in 75,000 exposures, and we do see a dose response there even if we didn't in the kinetic data.  So, the PK data are used to try to predict the future, but you still have to test it in patients versus subjects.
		DR. AZZIZ:  Since you brought that up, the clinical efficacy data is, of course, very important, and you have your diabetic data, which I am looking for right here in front of me.  At the 4 milligram dose, we have a 16 percent success, which means 50 percent success, which really means that not everybody had erections every time, but 50 percent erections is probably satisfactory.  16 percent for placebo, 25 percent for Uprima in the diabetic population of n of 90.  Is that correct?  
		And if that is correct, is the 25 percent, i.e., a 9 percent plus, really clinically relevant from a practitioner point of view?  Because if I have a drug that's 25 percent successful, unless it was life-threatening, it would be very tough to sell.
		DR. HEATON:  That's certainly a good issue and there are two ways of looking at the diabetic data.  This the diabetic patients from the crossover studies where you see the numbers are slightly different to those within the diabetic study itself.  If I could have the previous slide.
		In the 804 study, the numbers that you mentioned are, indeed, lower, but the baseline entry point of a patient is 5 percent of erections firm enough for intercourse.  The achievement of 25 percent of erections represents a 5-fold gain for that individual. 
		The point that Dr. O'Leary referred to earlier is extremely important in understanding what are the clinical measures of significance in this study.  This is a goal oriented treatment, we are not in a position to sit in judgment of the diabetic patient to assess what he would consider an appropriate clinical gain.  It's a difficult question.  I can answer it more extensively if you wish.
		DR. AZZIZ:  No, no.  Wait a minute.  You said 5-fold.  I'm not interested in baseline.  I'm interested in placebo versus drug.  There's not a 5-fold increase there.  Maybe I just missed that as you zipped through there.
		DR. HEATON:  The 5-fold gain I stated was from baseline up to the response at 25 percent.  The placebo response was 15 percent, and so if you take that as a sustained placebo response, there would be a therapeutic gain there of about 10 percent.
		DR. AZZIZ:  Right, but not 5-fold.  Placebo to drug is really what we're interested in.  Okay, thank you.
		Dr. Donatucci.
		DR. DONATUCCI:  I just wanted to say that my experience treating patients for this condition is even a 25 percent chance is certainly satisfactory.  Basically I've given patients options and they've selected a drug when I told them there's almost virtually no chance it would work, and they still select it.  So, when you're talking about this particular condition, you just can't count that out.
		DR. AZZIZ:  Thank you.
		Dr. Califf?
		DR. CALIFF:  I just want to make sure that we have agreement between the FDA and the sponsor on just what the data are that we're discussing.  I think the key data on page 6 and 7 of Dr. Hirsch's presentation, the 4 milligram dose -- from what I understand from the presentations, basically placebo is about a 35 percent response rate and treatment in the low 50s with some discounting below that because of these were only people who responded to the questionnaire, but not much discounting because almost everyone responded.  So, about a 20 percent increase overall.
		On the --
		DR. AZZIZ:  Before you continue, I'm sorry.  Do you all have a copy of the FDA's presentation somewhere?  No, no.  The sponsor.  Because I think they're looking for it.
		DR. CALIFF:  What I'm confused about is I felt some dissonance between the two presentations of the sponsor and the FDA.  If we can at least agree on what the data show, then we can argue about how to interpret it.
		DR. HEATON:  Again, the page number, sir?
		DR. CALIFF:  Page 6 of Dr. Hirsch's.
		DR. MANN:  Could you clarify which slide, Dr. Califf, on page 6 you're speaking of and the data that you're asking about?
		DR. CALIFF:  Yes.  We could look at both of them.  I was initially just talking about the top slide, the primary efficacy endpoint.
		DR. MANN:  And this is for the 2 milligram dose of Uprima?
		DR. CALIFF:  4 milligram.
		DR. MANN:  Okay.
		DR. AZZIZ:  Are you all ready to answer that question please?  Page 6, the top, begin with the top slide.
		DR. MANN:  I'm sorry.  You're looking at a different version of our slides than we are, so we're a little confused.  If you could give the title of the slide and the data on that slide, that would help. 
		DR. CALIFF:  It says Uprima efficacy of the 4 milligram dose, and the bullet says primary efficacy endpoint.
		DR. MANN:  Okay.
		DR. CALIFF:  I think that you would agree on that slide, the numbers are about a 20 to 25 percent improvement, and then on page 7, safety of the 4 milligram dose is the one that I'm really wondering whether you agree on where it shows, for example, nausea, 20 percent; dizziness, 14 percent, hypotension between 3 and 6 percent, and syncope between 1 and 2 percent.
		DR. MANN:  Just for clarification for the sponsor, these ranges given on this slide come from the three controlled clinical trials, and I believe they were in agreement with your backgrounder package but you can clarify that if you wish.
		DR. AZZIZ:  Could we get a response from the sponsor?
		DR. HEATON:  We agree with the slide.
		DR. MANN:  Go ahead.  You can describe your slide.
		DR. FAGAN:  This shows the syncope rates at different doses and with different regimens.  At 4 milligrams, we see that overall it's 1.2 percent.  When the patient started with 2 milligrams prior to 4 milligrams, it was 0.6 percent.
		DR. CALIFF:  And your hypotension rate at 4 milligrams?
		DR. FAGAN:  Well, the hypotension again is a subjective thing, and if we had a good definition, if we had measurements everywhere, we could probably --
		DR. CALIFF:  You know, in most clinical trials where it's been looked at, relying on sporadic reporting of something hypotension grossly under-reports the phenomenon.
		DR. FAGAN:  That's why we did the prospective clinical trials in patients with significant cardiovascular disease and also the 491 trial where we did blood pressures sequentially after the first dose in about 450 patients.
		DR. CALIFF:  So, your estimate then of the rate of hypotension is --
		DR. FAGAN:  It's in the crossover studies at 2 milligrams, 0.7 percent, around 4 to 5 percent at the higher doses; with dose optimization up to 5 milligrams, 0 percent, 0 of 146 patients; and at 2 to 6 milligrams, 2.5 percent.
		DR. CALIFF:  Okay, thank you.  That's helpful to frame the issue.
		DR. AZZIZ:  Well, that was nice to clarify.
		DR. KOWEY:  One of the things that I'd like to know, did you do a formal analysis of dose to response, a statistical measurement of incremental response past 4 milligrams?  One of the things you guys have been saying all morning is that you didn't see any more benefit at 5 and 6 milligrams, but there are lots of times when there appeared to be some increment in benefit on some of the graphs.  
		For your primary endpoint, did you do an interaction study between dose and response and can you show us what that statistical analysis looks like?  When you have it.
		DR. AZZIZ:  Dr. Tiefer?
		DR. TIEFER:  Yes.  I wanted to ask about the concurrent medication issue.  You list on your slide that 18 percent of your patients were taking psychotherapeutic agents and then separately you list that 15 percent were taking anxiolytics, sedatives, and hypnotics.  So, I wondered are the psychotherapeutic agents SSRIs or what was going on there?
		DR. FRESTON:  Yes.  I think I'll need to ask Susan Buttler or the statisticians to help us with that.  It's my impression that they were mostly SSRIs and tricyclics, and the anxiolytics were separate, but I'd like to get a precise answer for you.  Susan, can you help us?
		MS. BUTTLER:  Some of the med classes that you've seen do overlap a little bit, and in fact, the percent of patients were taking Compazine also fell into the psychotherapeutic class.  But it also did include patients who were on SSRIs as well as patients who were on anxiolytics, went into the anxiolytics group.  So, it's a somewhat complex system of looking at the drug.  So, it did include both of those.
		DR. TIEFER:  I just asked that because I think the question raised earlier, what is going to be the most likely combination which I think we could all debate, but I think the drug-related erectile problems, drug-related libido problems, drug-related ejaculatory problems are a growing concern.  So, any erection drug, particularly one that's supposedly acting centrally, we'd like to know as much about the conjunctive psychotherapeutic agents as possible.
		MS. BUTTLER:  If I could just add a point to that, I think you're concerned with something we noted when we designed our studies.  Thus, we had appendices that included many of these medications with known side effects.  SSRIs are one of them of which are several other medications.  In fact, it's a very long laundry list.  We required that patients that participated in our studies did not do alterations in their dosages so that we wouldn't know what we were measuring.  In other words, patients with SSRIs were allowed into the study, but they were not allowed to be changing their dosage because the simple change in dosage could alter their erectile dysfunction ability.  So, we did address your concern in that regard, so we really did measure efficacy of Uprima, not efficacy of changing the dose of a concurrent med.
		DR. FRESTON:  Anthony has additional clarification.
		MR. EDMONDS:  Anthony Edmonds with TAP.
		Actually I was going to answer the previous question about comparisons among specific doses. 
		On this slide, we have a first period analysis of placebo, Uprima 2 milligrams, 4 milligrams, and 5 milligrams.  Although the studies weren't powered to detect differences between doses, you can see that among the 4, 5, and 6 milligram doses, there aren't any statistically significant differences, but the 2 milligram dose is not as good as the 5 and 6 milligram doses.
		DR. AZZIZ:  Thank you.
		I have a couple of questions that are addressing some of the FDA's concerns.  One is the issue of the changing in definition of a serious adverse event.  Again, go to Dr. Shames' handout that you have.
		DR. FRESTON:  Yes.
		DR. AZZIZ:  On page 5, that last phrase, "or events that require intervention to prevent impairment or damage."  I want to make sure that this is correct, and if so, I'd like you to explain that. 
		DR. FRESTON:  Yes.  I'm pleased to have the opportunity to clarify this.
		In the collection of SAEs and submission of such AEs to the agency, the complete definition in all of its elements was rigorously complied with.  Thus, the agency has received all SAEs by their definition. 
		The problem that happened was inadvertently some of the summaries and intermittent reports that came to the agency didn't include all of those elements.  It was an oversight, but all the protocols and case report forms contained the full definition and we complied with that.  All the SAEs were reported.
		DR. AZZIZ:  The full definition meaning it includes that phrase, "or events that require intervention to prevent impairment or damage."
		DR. FRESTON:  Absolutely.
		DR. AZZIZ:  Dr. Hirsch, could you comment?
		DR. HIRSCH:  There is no question in my mind that there were cases that required intervention which were not defined as a serious AE.
		DR. AZZIZ:  And that is a difference again between the numbers of, say, 30 or so versus 15 or so.
		DR. HIRSCH:  I believe so.
		DR. FRESTON:  Could we go back to the definition?  Because to require to prevent impairment and damage is the full definition, not just requiring any sort of intervention.  And a good illustration of the difference is in those early cases when patients had syncope and the investigators didn't know what they were dealing with, they put in a nasal catheter.  That's an intervention.  Is that an intervention to prevent permanent impairment or damage?  No.  So, I think, Mr. Chairman, that may be the point of contention.
		DR. AZZIZ:  Well, certainly putting a nasal catheter may not be to prevent impairment, but the reality is I think this is where we're splitting hairs.  That is a fairly aggressive intervention.  Now, whether the investigator overreacted or not is a different point, but I mean, I think that certainly we'd like to hear that as adverse events.
		The second issue has been brought up that perhaps the Cmax or the AUC has been related to side effects or adverse events.  Was there any attempt to correlate Cmax or AUC in that the higher the Cmax, the more prone to adverse events?  Is there any data in that regard?  Yes, ma'am. 
		MS. BUTTLER:  Actually I wanted to address the prior comments regarding the SAEs.  I ran and I was overseeing all the clinical programs, and I just wanted to clarify a point about that required intervention to prevent permanent damage.  
		In fact, it was our investigators' opinion of that assessment.  So, despite the fact we may or may not have felt that they overreacted to the situation, if an investigator felt that it required intervention to prevent permanent damage, it was considered an SAE.  It always has been a part of our protocols.  It always has been a part of our case report forms.  
		And I sincerely apologize for our oversight in our clinical trial reports that have obviously caused this confusion, but I can assure you that all of those patients, regardless of what TAP or any of our consultants or anybody thought, if the investigator felt they required intervention, those went in as SAEs.
		DR. AZZIZ:  Thank you.
		Can somebody answer my other question please?  The correlation between Cmax or AUC and the incidence of adverse events.
		DR. FRESTON:  Dr. Bopp.
		DR. BOPP:  This slide will show the apomorphine Cmax in some of the subjects that experienced vasovagal events during phase I studies when we did have the opportunity to correlate Cmax with these events.  This is the Cmax for the individual subject and that is the mean Cmax for the group from which that subject was derived.  So, if you look down that list, you can see that many of the Cmax tended to be higher than the mean, but they were certainly not on the extreme side.  
		In a couple of instances, the event happened in conjunction with an ethanol interaction study, and the ethanol concentrations are shown in that second column along with the mean for that.  Occasionally some of them are lower.  Many of them are around the mean or within 1 standard deviation.  It is not occurring in subjects with very extreme Cmax.
		DR. AZZIZ:  Thank you.
		Does the committee have further questions right now for the sponsor or the FDA staff?
		DR. JARUGULA:  Could I add one more point to that?
		DR. AZZIZ:  Dr. Jarugula.
		DR. JARUGULA:  I agree with the just submitted analysis, but I would like to clarify a little bit more on the relationship between the Cmax and the syncope or hypotension events.  Looking at the table you just looked at, the most subjects had Cmax values that are higher than the group means.  The subjects that did have lower than the group mean and had hypotension or syncope also had taken alcohol.  So, you have to take the Cmax values of those subjects and also ethanol values in concentration when you are looking at the relationship between syncope and the Cmax.
		DR. AZZIZ:  Thank you.
		Now we're going to go ahead and proceed to questions that the FDA has posed to the committee.  Dr. Greene, did you have something?
		DR. GREENE:  Yes, just one question for Dr. Mann.  Two questions actually.
		DR. MANN:  Sure
		DR. GREENE:  It's similar to the question I asked the sponsor, which is there are several tables where you include vasodilatation.  Again, was that just from their report to you so there's not a precise definition for that?
		DR. MANN:  That's correct.
		DR. GREENE:  Then the other question was several places in your analysis where you state "there was patient reported hypotension," the patient doesn't report hypotension.
		DR. MANN:  Yes.  When I wrote these down, I took them directly from the case reports of the patients.  You're speaking, I assume, of the drug-drug interaction study where I gave individual case reports for those patients.
		DR. GREENE: Well, for example, on page 77, it says, "Comment:  It is noteworthy that 4 percent of patients reported hypotension at the 4 milligram dose."
		DR. MANN:  Oh, I apologize for that, and that's incorrect writing.  You're absolutely right.  I believe the hypotensive events were recorded by the investigator and it was their judgment.  As the sponsor has pointed out, the definition was not clear.  Not every patient had a blood pressure reading.  It was just the term they used to describe the event. 
		DR. GREENE:  Okay.
		DR. AZZIZ:  Thank you very much.
		Any other questions?  We won't be muzzled after this, but I'd like to proceed on because we do need to come up with some conclusions. 
		Could I ask the FDA staff to please put the first question up on the screen?  You're trying.  A computer glitch.
		Anyway, the first question is, does the patient population studied support the proposed indication "for the treatment of erectile dysfunction"?  If yes, we need to elaborate, and if no, we need to describe our concerns. 
		Any comments regarding this question first from the committee?  Dr. Califf?
		DR. CALIFF:  There are a lot of arguments I guess about the details of the patient population, but it seems to me they've got well-controlled studies that show statistically significant evidence of meeting the endpoint that was defined.  I haven't heard anyone say that the population is totally unrepresentative of patients that might be seen in the clinic.
		DR. AZZIZ:  Dr. D'Agostino?
		DR. D'AGOSTINO:  The thing I was trying to flush out was is it an enriched sample and does that make a difference, and I didn't hear any negatives.
		DR. JACOBS:  In fairness to the question of enrichment, it could be enriched the other direction too.
		DR. D'AGOSTINO:  Well, enriched in the clinical trials sense of enriched.
		DR. JACOBS:  In the clinical trials sense, there are patients they eliminated that this drug might work very well in.  For instance, I don't know what it does in MS.  Maybe it's a great drug for the MS indication.  I could see they're being enriched both directions.
		DR. KOWEY:  Can I ask the urologists on the committee, would you be able, as a urologist, to understand who you should treat with this drug if it were labeled the way it should be labeled?
		DR. DONATUCCI:  I would say several things about this.  First off, the risk factors -- I know there's confusion about the question of no organic cause, but the percentage of risk factors present in the population of the patients, hypertension, cardiac disease, et cetera, actually mirrors the data that I have in my own practice when I went back and looked at the risk factors in my patient population.
		Now, they admit that they have eliminated the bottom 10 percent, the most severe, based upon the Male Massachusetts Aging Study.  As far as the severity, they used the International Index of Erectile Function, and I believe the breakdown was about 39 to 40 percent with severe ED based upon that statistically valid parameter.
		So, I think that the population in my opinion is representative of the great majority of patients with erectile dysfunction.  It's not certainly 100 percent but I don't know that it needs to be.
		DR. AZZIZ:  I have a question.  Organic versus inorganic or organic and non-organic.  Is that an issue at this point?  Certainly the fact that they had an ability to achieve an erection obviously tells us that it's not fully organic.  So, is that something we should note here?
		DR. DONATUCCI:  I think traditionally this has been an issue.  It dates back to the point when we really were pretty ignorant in the pathophysiology, and 90 percent of patients were thought to be psychogenic.  Basically as we became educated, we realized that psychogenic erectile dysfunction is becoming less and less common, although obviously any patient with erectile dysfunction has a psychogenic factor.  I think there are a lot of patients who we even today label as psychogenic who probably have some underlying pathophysiologic process we can't elaborate, perhaps at a cellular level.  So, bearing that in mind, in my own opinion I'm not sure that's a critical distinction.
		DR. AZZIZ:  Dr. Tiefer.
		DR. TIEFER:  I find that it's a difficult question to answer because of how these drugs are used in the real world.  The official definition of erectile dysfunction is now relevant only for a certain proportion of people who are interested and who are using these drugs.  I think in addition to those with official erectile dysfunction, we've now got people with erectile worries and erectile insecurities who are perhaps making up the lion's share of people who are going to obtain and use these drugs, which brings me to my particular concern which happens to be the alcohol one. 
		There's now growing evidence of the availability of Viagra at least in clubs and alcohol-available settings, not to mention the Internet is another problem.  But if we're thinking about how these drugs are obtained, how they're used in the real world, we've been sort of discussing this in a very hermetic kind of a way as if patients who come into the urologist's office and have co-morbid disease and so on are actually the only population that's going to be addressed.  I think that we're too smart to do that, and therefore I'm having just a little trouble with the way this question is phrased.  It seems almost dated and old-fashioned.
		DR. AZZIZ:  But just to clarify, we do need to answer some questions.  Obviously, our function will be to determine if a population will be automatically treated if treat one, but we can't certainly regulate the illicit use of this drug on the Internet or in parties and so on.  We really need to be very careful that we give an answer to this first question which is does the patient population studied support the proposed indication for the treatment of erectile dysfunction.  So, I'd like to sort of just stay there, not to minimize that question, but --
		DR. TIEFER:  I agree to a certain point, but we're also interested in the labeling.  We're also interested in the potential advertising of these kinds of drugs because it's something that our concern for patients must make us concerned about.
		DR. AZZIZ:  Absolutely.  We're not going to get into labeling yet.  We just need to answer the question yea or nay, and then we'll move in to elaborate our concerns.
		Any other comments about yes or no?  Dr. D'Agostino.
		DR. D'AGOSTINO:  Did we hear an answer to the question if a patient comes into an office, they would know who to treat?
		DR. O'LEARY:  Well, you heard from one urologist.  Dr. Donatucci commented on it.  O'Leary.  I'm another urologist.  I don't think I have a particular problem with understanding what the indications for this medication would be.  I still have some concerns about safety issues.  We haven't gotten to that yet, but as far as does the population that was studied support the indication, I think I don't have any question that the answer is yes.
		DR. AZZIZ:  Dr. Hanno.
		DR. HANNO:  I just do have some concerns about the enrichment of the study.  I would say that the indication should reflect the fact that the studies that support the drug were enriched.  In other words, there's some loss of face validity if we don't say that this drug was tested in patients who did show erections in NPT and were able to get erections on their own, and that's how it was tested.  So, when we put the indication forth, that's what it should be indicated for.
		DR. AZZIZ:  But, Dr. Hanno, let me ask you this.  It says, "for the treatment of erectile dysfunction."  Would you change that?  Is there something you'd do to that wording?
		DR. HANNO:  I would change the wording to reflect the fact that it's indicated for treatment of erectile dysfunction in patients who have erectile activity on NPT and/or are able to get erections on their own.
		DR. AZZIZ:  Well, let's get to the labeling first.  Let's go ahead.  We haven't heard from everybody that needs to comment.  Let's go ahead and put that to a vote.  Does the patient population studied -- each of you has to vote and speak into the microphone and get it recorded on the Federal Register so that they can find you at home.
		(Laughter.)
		DR. AZZIZ:  Does the patient population studied support the proposed indication "for the treatment of erectile dysfunction"?  Let's start out around the table here to my right, the voting members.  Dr. Jacobs.
		DR. JACOBS:  Yes.
		DR. AZZIZ:  As far as I know, everybody can vote.  That's what I was just told. 
		Dr. O'Leary.
		DR. O'LEARY:  O'Leary, yes.
		DR. DONATUCCI:  Donatucci, yes.
		DR. LIPPERT:  Lippert, yes.
		DR. CALIFF:  Califf, yes.
		DR. AZZIZ:  Azziz, yes.
		DR. KOWEY:  Before I say yes, which I'm going to --
		(Laughter.)
		DR. KOWEY:  -- I know you don't want to talk about labeling here, but I do think that this is in part a labeling issue in that I think that they have studied a circumscribed, somewhat selected patient population.  So, as I say yes, it is with the stipulation that we will discuss somehow in the labeling what that indication is, that it's not a blanket erectile dysfunction claim.  It has some qualifiers.  So, the answer is yes with qualification.
		DR. AZZIZ:  I just want to remind the committee before we continue.  We're just an advisory committee.  We're just putting in our vote and we will give as many recommendations to the FDA who will then shove them in the back drawer and never remember them again.
		(Laughter.)
		DR. AZZIZ:  No, no.  But the point is we're just advisory, so yes, we can give all the concerns we have.  So, we will do it.
		DR. KOWEY:  And I just did.  Thank you very much.
		(Laughter.)
		DR. GRABOYS:  Graboys, yes.
		DR. D'AGOSTINO:  D'Agostino, yes.
		MS. SCOTT:  Scott, yes with reservations similarly talked about. 
		DR. TIEFER:  I like this new option.  Tiefer, yes with reservation.
		DR. GREENE:  Greene, yes.
		DR. HANNO:  And I'll say yes with reservations that it's reflected in the label.
		DR. AZZIZ:  Thank you very much.
		Let's go ahead.  If the answer is yes, elaborate.  At this point it seems to be unanimous yes, that the population studied supports the proposed indication.  Now we are ready to bring up some concerns for potential labeling changes or changes in population.
		Dr. Greene.
		DR. GREENE:  If I understand the comments of some of the urologists, may I interpret what you said to suggest that the sensitivity and specificity of this NPT testing is sufficiently poor that you wouldn't consider it very helpful one way or another in enriching or not enriching the population?
		DR. O'LEARY:  Yes.
		(Laughter.)
		DR. AZZIZ:  Dr. Kowey?  You better restate that, though.
		DR. KOWEY:  I am probably the least competent person to do this, and I'll defer to my urology colleagues.  It sounded like that there were some restrictions put on patient enrollment which could potentially have an impact on the patients who were entered in the trial.  And the FDA has said this.  I mean, we heard it clearly from the staff.
		So, the question is in the labeling what should be said -- and I don't know what should be said -- about the kinds of patients that were enrolled in the trial and how a clinician who's going to prescribe the drug may be able, in their clinical practice, to select those patients to optimize the chances that the drug is going to work. 
		And the reason why I'm being so persnickety about this is this is not an innocuous drug, and therefore I would like to see people who are not going gain benefit not be exposed to it.  It doesn't make any sense.  So, the risk-benefit, which we're going to come to is directly proportional to this question.  And if we can't define the population, then I'm not going to be terribly excited about letting the drug on the market, voting for approval.  If you can tell me that, yes, we can tell you who the population is with a reasonable degree of certainty, then that's very important to me.  So, that's up to you guys.
		DR. DONATUCCI:  Clearly there's a spectrum of disease, and I think it has been stated earlier that based upon the way the study was designed, those patients who had total erectile failure were eliminated from consideration in the study.  Based on clinical experience with other therapeutic alternatives, we know that the more severe and the long lasting the disease process is, the more risk factors, et cetera, the less likely.  In fact, there have been studies in the literature you can -- this is somewhat drastic -- biopsy the penis and quantitate the degree of smooth muscle present.  And as that percentage drops, responsivity and degree of erectile function drops. 
		So, clearly people at the end of the spectrum are not going to be great candidates for any drug therapy.  For those of us who do it every day, that's pretty obvious to us, but perhaps that should be spelled out in the labeling.
		DR. AZZIZ:  Dr. O'Leary?
		DR. O'LEARY:  I think one of the reasons why, as I'm reading through this data set, NPT was used to begin with was because it was the only thing that was "objective."  In an attempt to try to include as much objective data as possible, it was the only thing that was really available on a large scale.  In fact, most of us don't, as I think you've heard, use NPT very much.  It has very limited value in day-to-day practice.  
		So, while I understand what the goal of the study was, I've basically discounted it.  To me it's not a particularly important part of the data set or the inclusion criteria, for that matter.  The inclusion criteria, to my mind, reflect what we see in daily practice, as I said before. 
		DR. AZZIZ:  Dr. Jacobs.
		DR. JACOBS:  I know we're going to talk about labeling eventually, but this sort of fits into it too.  I think a sentence that says there is no evidence that this drug helps people with total erectile failure, spinal cord injury, multiple sclerosis, Parkinson's disease, would be the sort of sentence we would want to see in a label.  Not that it's forbidden.  There is no evidence that this helps those people.
		DR. AZZIZ:  In a second, we will be dealing with risk-benefit.  We have just simply decided that the population studied seemed to represent the population that you all see. 
		So, any other comments about the population studied?
		(No response.)
		DR. AZZIZ:  Let us move on to the second question.  Do the data presented support an acceptable risk-benefit profile for the 2 milligram dose of Uprima?  If yes, please elaborate.  If no, please describe your concerns, including additional studies that might address these concerns.
		I'd like to hear comments about this.
		DR. GRABOYS:  There is a population of folks out there that all of us in clinical medicine see every day and that's the coronary artery disease population.  In this population, these folks are biting at the bit for an alternative.  So, there is a huge market -- obviously you all know that -- for this agent or for any agent, anything that can help their erections.  
		So, what we are kind of trying to deal with is the issue of polypharmacy.  Since we are pushing in cardiology nitrates and at the same time we're trying to deal with folks who have got erectile dysfunction, well, this is fine in terms of the Viagra.  I think the message is out.  But in terms of your drug, the jury is out as far as nitrates.  I didn't hear anything about the dosing, about the long-acting.  I didn't know exactly what that was.  But we have folks that we are increasing their dose 20, 40, 60, 100, 180 milligrams of nitrates, while simultaneously they may be on your drug. 
		So, I don't know.  Do you feel sanguine about this in terms of how we're going to be educating physicians to prescribe the drug?  What about the patient population?
		I think that the polypharmacy issue is a significant one and the nitrate issue is a significant one.  And I couldn't vote on this until it's resolved.
		DR. FAGAN:  Would you like us to respond?
		DR. AZZIZ:  If there is direct data to answer that question, go ahead.  We'll take a short second or two.
		DR. FAGAN:  In the long-acting interaction trial, the doses of Imdur ranged from 30 to 120 milligrams a day in several patients.  It was dosed 4 hours before they got their drug.  Isosorbide was 40 b.i.d. in a couple of patients.  ISMO was I believe 20 b.i.d. in several patients, and there were several patients on various levels of patch therapy.  So, there were a few that were toward the upper end of the spectrum, and I think most of them were respectable doses.
		DR. AZZIZ:  Other concerns, questions?  Dr. Califf.
		DR. CALIFF:  Specifically with regard to the 2 milligram dose, it seems to me that as a specific question, it's kind of like old-fashioned medicine:  It's not much good, but it probably won't do much harm either.  It really seems almost not important relative to the 4 milligram issue.  The answer to the 4 milligram issue is if the risk-benefit ratio is adequate, then it seems like the 2 milligram, although it wouldn't stand on its own in my opinion, needs to be in because of the dose escalation issue and the likelihood that some patients may benefit.
		DR. AZZIZ:  A question for the sponsor again.  Just to bring up Dr. Califf's point, the vast majority of patients didn't seem to stay on 2 milligrams.  2 milligrams didn't seem to be very effective.  I mean, you have a few percentages above what it was before.  The only reason you are asking for approval is because of the titrated regimen.  Is that correct?  I'm unclear as to what the reason for that would be otherwise.
		DR. HEATON:  There are several points here.  Some patients do respond very satisfactorily and will stay on 2 milligram.  On the basis that patients should remain on the least drug that is effective, those patients should have the opportunity of a 2 milligram tablet. 
		The other thing is that the dose escalation is a logical thing to do and has been shown here.
		DR. KOWEY:  Maybe I can do my Ray Lipicky impersonation and bring up a point about that.  I think you're right, by the way, that there clearly are people who respond to 2 milligrams.  There might be people who respond to 1 milligram.  Perhaps, Rob, the risk-benefit equation there -- even though you would argue, gee, you're not really getting much of an effect at all, some people might respond at a milligram and get no hypotension.
		DR. CALIFF:  Maybe it would be best to start with placebo.
		DR. KOWEY:  You get a nice little rise with placebo.  Excuse the pun.
		(Laughter.)
		DR. KOWEY:  But I agree with Rob.  I think that the 2 milligram is easy in terms of risk-benefit because there's not much risk.  But I do think there is some benefit, and I would not want to see the 2 milligram not get approved if the 4 milligram were approved because there were responders to 2 milligrams.
		DR. AZZIZ:  But again, the majority of the use with 2 milligrams is part of a titrated regimen.
		DR. HEATON:  The majority is, yes. 
		There is a factor that has not been identified in discussion today about dopaminergic agents, which points out that there is a characteristic of this class of agents which means to say they are better prescribed in the appropriate dose than simply going up to the max.  This is characteristic of dopaminergic agents.  Otherwise, patients with ED will always migrate to the max. 
		DR. AZZIZ:  Thank you.
		Dr. O'Leary.
		DR. O'LEARY:  In response to the question, I'm looking at the data that say that somewhere between 40 and 46, 44, 47 percent of patients respond.  Now, I realize scientifically we're comparing this to placebo, but clinically I'm comparing it to somebody who doesn't respond at all.  So, if I've got a 2 milligram dose of this drug, I know that's not what we're supposed to do, but that's what happens in clinical practice.  And if I give this to somebody -- I wish the FDA would approve placebo, but they haven't approved it.
		(Laughter.)
		DR. O'LEARY:  Because I would definitely give that.  In all ED trials, it about a 30 percent response and it's the same, by the way, for lower urinary tract symptoms with BPH.  It's about a 30 percent response to placebo.  Now, maybe urologists are just luckier than other practitioners in terms of giving a pill to a patient.
		But to me a 2 milligram dose makes -- that's where I would start based on the data that I've been presented.
		DR. AZZIZ:  You're primarily treating men who are highly susceptible to the placebo.
		(Laughter.)
		DR. AZZIZ:  Dr. Tiefer?
		DR. TIEFER:  Let me just say that I think what happens is that in the real world most patients with erectile problems have very poor sex education, poor verging on none, no formal sex education, no opportunity to talk openly about erotic technique, and that the opportunity to talk with a physician often with the partner present is the first time certainly since the problem began and maybe in the person's entire life -- we've heard this a million times.  Right?  I've never talked to anybody about this before.  I think that's the active agent in the placebo effect, that the person is actually talking about with their partner the fact that they want certain things, they feel certain things, and so on.
		I would really like to see trials of sex education before we start throwing drugs at people.  We live in a country where there's no government approval for sex education, but tremendous institutional support for drugs.  So, when I see here, do the data presented support an acceptable profile for this drug, to me it's not acceptable because of the absence of any sort of formal sex education to the patients with this problem.  It's as if we were discussing a diabetes drug and the food pyramid was a federal secret and you weren't allowed to talk about these things with anybody because it just wasn't part of the medical model.
		So, again, I feel like the question kind of is not in the real world where the patients need information about sexual technique, age-related changes, and so on.
		DR. AZZIZ:  Thank you.
		Dr. D'Agostino.
		DR. D'AGOSTINO:  I just wanted to say if you travel from one field of medicine to another, these differences, placebo versus the drug effect, aren't trivial effects.  You may say they're trivial in your mind, that they don't look big, but getting a 33 percent increase over placebo is substantial.  And we have three studies that did it. 
		DR. CALIFF:  You're talking about the 4 milligram dose.
		DR. D'AGOSTINO:  No, no, even the 2.  We have those three crossovers, didn't we?
		DR. CALIFF:  They weren't significant, were they?
		DR. D'AGOSTINO:  Yes.
		DR. CALIFF:  All were?
		DR. TIEFER:  Statistically significant.
		DR. D'AGOSTINO:  Well, and clinically I don't think that this is a trivial margin.  It could be overwhelmed by safety, but I think on the basis here it's not trivial.
		DR. AZZIZ:  Thank you.
		Dr. Donatucci.
		DR. DONATUCCI:  Yes.  I just want to make one comment that addresses one of the FDA questions that came up earlier in the context of what we're discussing now.  This is a very variable condition, and it changes over time.  Patients are very motivated initially and they may lose their motivation with time.  There was a question I believe about long-term dropout.  My experience with every agent that I've used is that they all experience long-term dropout regardless of what we're using.  
		Michael O'Leary mentioned BPH earlier.  A senior urologist once said that's an unevaluable condition because all the tests we use to evaluate you can argue till the cows come whether they're reflective of the condition or not.  In a sense this is also similar.  So, it's a very difficult condition to pin down, particularly for any individual, but we have to do something and we have to make a decision.  I understand what you were saying earlier about sex therapy and just discussing the problem, but that doesn't help you make a decision that you have to make today.
		So, I think again that this 2 milligram dose has been shown to be statistically effective.  The clinical significance may not be apparent to someone who doesn't take care of these patients, but again I've had patients, I have literally told them this drug will not work for your condition, and they'll say I want to try it anyway, given the other alternatives.
		DR. AZZIZ:  I have a question maybe for the committee, but also for the sponsor.  Risk-benefit.  We've talked a lot about benefits.  I have to agree with Dr. Tiefer that I wish we could really have a study of sexual counseling.  That is an extremely important area that is underfunded and understudied.  But today we're here to study a drug. 
		But the risk issue has not been addressed, and I have a couple of concerns.  That is the alcohol use.  I can tell you some individuals will have responsible sex and not have a drink before they have sex, but most people will have more than a couple of vodkas.  I am unclear as to how safe it is in the face of a couple of vodkas.  You had one fellow there who had a rye, a bourbon, a vodka, and a beer, but that's pretty standard for a lot of the patients. 
		(Laughter.)
		DR. AZZIZ:  No sex education either. 
		(Laughter.)
		DR. AZZIZ:  But that is an issue I think I'd like to -- if you could just look at that alcohol adverse events please and review that because that is a concern, particularly because your proposed labeling does not have sufficiently explicit the potential for alcohol interaction.  You asked the patients not to take it before they use the drug, and then your alcohol studies were relatively modest because, in fact, you got scared when you used a good dose.
		DR. FAGAN:  Well, there's a couple of things.  First, the instructions were don't take more than two beers, two glasses of wine, or one shot of hard liquor, and obviously, just as in the real world, there were people in these trials who did that.  When you look at the alcohol users versus the non-users in the crossover trials, there really was no difference in adverse events.
		Again, in the interaction trials, we got back up to the same dose of alcohol that that very first trial was, with an even higher dose of Uprima.  The very first trial was 5 milligrams of Uprima, .6 grams per kilogram of alcohol.  The 891 study was 6 milligrams of Uprima and .6 grams per kilogram of alcohol.  
		DR. AZZIZ:  But that study was discontinued, was it not?
		DR. FAGAN:  No, no.  The one that was discontinued was 5 milligrams and 6 grams per kilogram of alcohol.
		DR. AZZIZ:  The first one.
		DR. FAGAN:  Right.  The final trial was 6 -- not 5, but 6 -- milligrams of Uprima and .6 grams per kilogram of alcohol.  Same dose.
		Again, we were making these people stand up repeatedly when the advice to these people is don't stand up in the clinical situation.
		DR. AZZIZ:  And what were the data for that study where they stood up and all this kind of stuff?
		DR. FAGAN:  That's coming.  
		But again, in their use at home, the alcohol users were no different. 
		Yes, when they had them together, everything was more common with the combination.  There's no doubt about that.  But again, remember, on the day that we were standing them up and sticking needles in them, that did not happen on the days when they got Uprima alone.  And when you analyze that, you can see that that is a portion of the increase.  Certainly a portion of the increase is related to the alcohol.  Maybe we'll teach people not to drink when they take Uprima.
		DR. AZZIZ:  Yes, but they're supposed to be having sex.  
		DR. TIEFER:  Thank you, Dr. Azziz.
		DR. AZZIZ:  They're going to be doing sort of up and down and things like that.  So, I'm sorry.
		(Laughter.)
		DR. AZZIZ:  This data is probably accurate for somebody who does drink four vodkas and takes Uprima.
		DR. FAGAN:  And stands up and down and gets needles stuck in them.
		DR. AZZIZ:  Or has sex, yes.
		DR. TIEFER:  And moves, tends to move.
		DR. AZZIZ:  Thank you.  Thank you very much.  That's good.
		Any other questions in this regard?
		DR. LIPPERT:  If you look at their purported instructions to patients at the end of the red book, the last page, what they're actually recommending is that Uprima can be taken following moderate alcohol ingestion.  I guess if we're going to talk about labeling in the 4 milligram dose, I do have some concerns.
		I think the most common drug that will be used with this is not Viagra, but is alcohol.  Just as alcohol alters one's perception of what is moderate, once you start drinking, maybe that will change.  Those who drive may not make good decisions.  I just think that the labeling should show that there is a greater risk than they would suggest with alcohol ingestion.
		DR. AZZIZ:  Any other comments before we vote on question 2 and then elaborate on our labeling recommendations?
		(No response.)
		DR. AZZIZ:  Let's go ahead and vote then.  Again, the vote is do the data presented support an acceptable risk-benefit profile for the 2 milligram dose of Uprima, and then we'll elaborate.
		DR. JACOBS:  Jacobs, yes.
		DR. O'LEARY:  O'Leary, yes.
		DR. DONATUCCI:  Donatucci, yes.
		DR. LIPPERT:  Lippert, yes. 
		DR. CALIFF:  I'm going to abstain until the 4 milligram dose discussion because I see the two as linked.
		DR. AZZIZ:  Azziz, yes.
		DR. KOWEY:  I'm going to do the same thing Rob did, abstain till we hear the 4 milligram discussion.
		DR. D'AGOSTINO:  D'Agostino, yes.
		DR. AZZIZ:  Dr. Graboys I think had to leave.  So, we have one abstention.
		MS. SCOTT:  Scott.  I'm going to abstain until I hear the 4 milligram.
		DR. TIEFER:  Tiefer, no.
		DR. GREENE:  Greene, yes.
		DR. HANNO:  Hanno.  I'm going abstain till the 4 milligram.
		DR. AZZIZ:  I'm not sure that abstention was actually an option.  This is a new thing.  I'd rather have the committee members not go abstaining because we do need to give an answer, a yes or a no, for this.
		DR. KOWEY:  We will give you an answer.
		DR. HANNO:  If you're saying on its own --
		DR. AZZIZ:  On its own.
		DR. HANNO:  If we want to do the 4 milligram dose by itself, then I would probably say no on its own, if we weren't considering any other dose.
		DR. AZZIZ:  I think we need to have a little clarification here.  All of a sudden, this run of abstentions bothers me.  Mary?
		DR. MANN:  I think we do wish for you to look at the two doses individually in part because, as we pointed out, the approvability of the 3 milligram dose is certainly contingent on each of these doses individually being found to be safe and effective.  I can understand the committee wanting to have more discussion on the total risks and benefits of the 4 milligram dose perhaps before answering the 2, although we do ask, as you answer the 2 milligram dose, specifically just deal with the data relevant to that particular dose.
		DR. KOWEY:  Two comments, though, Mary.  One is I don't know how in the hell we're going to approve a 3 milligram dose just off the bat because we have nothing to see for 3 milligrams.
		DR. MANN:  Absolutely, and we wish to clarify that.  From our standpoint, both the 2 and 4 would have to have acceptable risk-benefit profiles.  If they were both found to be acceptable, then the 3 would be implicitly approved based on the dose responsiveness noted and the dose proportionality noted.
		DR. KOWEY:  That's up to you, but if it were up to me, I would say no because there's probably going to be an intermediate risk at 3 milligrams that I don't what that risk is.  So, I couldn't approve a 3 milligram without knowing what that risk was, number one.
		Number two, to approve a 2 milligram dose without a 4 milligram dose is a bit of absurdity because nobody really envisions too many people staying at 2 milligrams.  You would never market 2 milligrams without having 4 milligrams.
		DR. MANN:  Right.  I think part of the confusion is arising from the need for dose titration, which a lot of you are focusing on starting with 2 and working your way up to 4.
		For this particular question, we ask that you solely address the data that you've seen with the 2 milligram dose alone and say do you think the risk-benefit profile for that data is acceptable or not.  We understand that when you get to the 4 milligram dose, you're going to be talking about the dose titration aspects, as well as the 4 milligram data.  Maybe that will make it clearer. 
		So, for this particular question, we are asking not the role of the 2 milligram dose as part of dose titration.  We are asking you to address the safety and the efficacy data for the 2 milligram dose given as itself. 
		Does that help?
		DR. AZZIZ:  I want to remind the committee again we are simply advisory positions.  The FDA makes their own administrative decisions after this.  All we're here is to say yea or nay for the 2, yea or nay for the 4.  If that appears to be yea for both, then maybe the 3 milligram dose, but that's not going to be up to us.
		So, I'd like to ask, Marianne, do you want to revote?  Like I said, you did not get people's understanding, and I'd like to go back.
		DR. MANN:  Yes, and I think if we all clarify, as we address this question, we are not talking about the approvability of the 2 milligram dose as part of a dose titration scheme up to 4.  We are talking solely about the risk-benefit profile of the 2 milligram dose alone.
		DR. AZZIZ:  Questions?
		DR. DONATUCCI:  Yes.  I just have a point of order.  If we're going to revote this whole question, is it possible to go to question 3 first?  This is just in order.  Does it matter?
		DR. MANN:  It's up to the Chair.  I think we're okay with that.
		DR. AZZIZ:  No.  I want to stay with this question.  We've just discussed the 2 milligram dose.  Let's vote on the 2 milligram dose and move on.  Thank you.
		Dr. Jacobs, your vote.
		DR. JACOBS:  Yes.
		DR. AZZIZ:  Dr. O'Leary.
		DR. O'LEARY:  Yes. 
		DR. AZZIZ:  Dr. Donatucci.
		DR. DONATUCCI:  Yes.
		DR. LIPPERT:  Lippert, yes.
		DR. CALIFF:  I guess if somebody wanted to bring forward a 2 milligram dose alone, I'd have to vote yes.  Yes.
		DR. AZZIZ:  Azziz, yes.
		DR. KOWEY:  Yes.
		DR. D'AGOSTINO:  D'Agostino, yes.
		MS. SCOTT:  Scott, yes.
		DR. TIEFER:  Tiefer, no.
		DR. GREENE:  Greene, yes.
		DR. HANNO:  Hanno, no.
		DR. AZZIZ:  Thank you.
		The yeas have them.  Please let's elaborate and give some labeling recommendations and other concerns that we have to the agency so they can utilize this later on.  Any comments for starters?
		DR. JACOBS:  It's unproven for use in people with no erectile function, MS, spinal cord injury, and Parkinson's disease, and it should be used with minimal alcohol intake.
		DR. AZZIZ:  I'd like to stress in the labeling I think it's minimizing the interaction with alcohol in both the patient instructions and the potential labeling.  It has to be very clear that this should be no more than one drink or two drinks.  Moderate drinking for my patients often means a six-pack a night, only a six-pack.
		(Laughter.)
		DR. AZZIZ:  So, that is of no help.  That has to be very clear, and potentially in a block in the label, in a separate block.
		Dr. Donatucci.
		DR. DONATUCCI:  I'd just like to say I think it's also important to, in block labels, mention the syncopal aspects of the drug.  It's not certainly the only drug we use for this condition that does that.  Already when we treat patients with other agents, we have to discuss those questions with the patient.  But I think it's important that that be emphasized and physician education.
		DR. MANN:  Can I just clarify?  When you say putting this in a separate block, are you implying a boxed warning, a warning with a box around it?  I just wanted to get clarity there.
		DR. AZZIZ:  Yes.  I would prefer a warning with a box because very often neither prescribing physicians nor patients ever look at this, and it's only the boxes that they look at.
		DR. MANN:  So, for both alcohol and I heard a recommendation for syncopal events.
		DR. AZZIZ:  That's our recommendation.  Correct.
		Dr. Greene.
		DR. GREENE:  I was going to, along those lines, suggest, given some of the vignettes, in that boxed label, with respect to syncope specifically, saying something about driving a car or operating machinery, that sort of thing.
		DR. AZZIZ:  I thought you meant the descriptions of the patients.
		(Laughter.)
		DR. AZZIZ:  Dr. Califf.
		DR. CALIFF:  I think this will be even more pertinent if the 4 milligram dose is approvable.  Several drugs have recently been approved that have required a patient leaflet which goes beyond the label.  Typically I find that less than 1 percent of physicians have seen a label in the last year.  So, I think it's highly unlikely that putting anything in the label is going to make any difference.  In fact, the cisapride experience pointed that out.  Even writing letters to physicians is not going to change the information that's passed on to patients.  So, I'd like to see it go a step beyond, as we'll get into in the 4 milligram discussions.  
		This drug is clearly going to kill some people and it's going to be most likely be people who have severe coronary disease and have hypotension and syncope.  I think it's really incumbent upon us to try to figure out what to do about the risk that's going to be unleashed at any dose.
		DR. KOWEY:  I guess I'm the token EP person who takes care of syncope day in and day out.  For those people on the committee that don't see a lot of patients with syncope, it's a devastating disease.  It's an absolutely devastating disease.  We haven't gotten to the 4 milligram discussion.  I voted yes for the 2 milligrams because we're dealing with a relatively low incidence.  The incidence is much higher at 4 milligrams, and that's why I'm sort of reserving a lot of my comments, as Rob just said, for the subsequent discussion of 4 milligrams.  Because I'm sitting here silently doesn't mean that I'm taking this lightly.
		Rob is right.  There will be some people who will probably lose their lives because they'll pass out at the top of a flight of stairs or they'll be operating a car at the time that it happens.  So, it's a very, very serious adverse event.
		I also want to just say that having known that there was syncope present in a substantial portion of this patient population, I'm flabbergasted that there was no attempt in the clinical trials to define hypotension.  I mean, how could we have an incidence of syncope this high and then let the investigators tell you when they had hypotension?  I think that's close to being irresponsible.  I think that there should have been protocol-defined endpoints to define serious hypotension when you have a drug that causes syncope because of a vasodilator response.  I'm really unhappy about this because we're now left with this free-floating anxiety about hypotension without being able to really nail down the number.
		DR. AZZIZ:  If you can respond please, make it brief --
		DR. FAGAN:  I showed you a trial with 450 patients that had blood pressures measured at frequent intervals.
		DR. KOWEY:  No, that's what I said.  Let me clarify exactly what I said.  There clearly were patients in your clinical trials who had SAEs that were hypotension.  When you have a drug that causes syncope, prospectively you can't not define what a serious adverse event is for hypotension.  You can't say to the investigator you figure it out, tell me when you think somebody got hypotensive.  You need to tell the investigator, when the blood pressure hits this number, you got to register that as an SAE so we can quantitate it. 
		Clearly some of the cases that Mark presented that were not coded as syncope were coded as hypotension were as serious as the syncope.  I think Mark said that during his presentation.  So, we're going to have a very difficult time now with this because we don't have that quantification.
		That's different than measuring blood pressure.  The vast majority of people in your studies didn't get hypotensive.  I agree with you.  You're right, but there were some people who became not only a little hypotensive, they became very hypotensive and some became syncopal, and it's a continuum.  We don't know those numbers because they weren't prospectively defined, and it's a problem for us.
		DR. FAGAN:  We have it in 450 patients and most of the doses of the 75,000 doses were taken at home.  So, you can't really get blood pressures there.
		DR. AZZIZ:  Thank you.
		DR. RACZKOWSKI:  Dr. Azziz?
		DR. AZZIZ:  Yes.
		DR. RACZKOWSKI:  I just want to follow up a little bit on what Dr. Califf said, and I'm interested in getting some additional advice from the committee on this.  We've had a number of drugs recently withdrawn from the market despite labeling changes and despite black boxes.  Dr. Califf mentioned cisapride.  There has also been Durac.  There's been Posicor.  I wonder what recommendations, that you could consider in your deliberations, the committee would have in terms of trying to ensure that labeling recommendations are actually followed.
		DR. AZZIZ:  Are actually followed?  What do you mean, they're actually followed?
		DR. RACZKOWSKI:  Well, if we put a black box in saying that you should use minimal alcohol, how do we ensure that that will have an actual impact on patient care?
		DR. AZZIZ:  Thank you.  When you said actually followed, I thought the sponsor printing it.  Okay.
		I think we will because that involves education and other programs, and we'll do that. 
		Dr. Califf.
		DR. CALIFF:  I was just going to say I don't think any of us actually know empirically now what does work.  The sponsors obviously will write down what you tell them to write down.  That's almost 100 percent.  Physicians reading what's written down or following the instructions ‑‑ there's actually no empirical base of research that I know that tells us what does work.  But at least I'm enamored now with patient activation as a concept, requiring that when the thing is dispensed, that the patient actually get a readable document that says, here's what you need to be worried about.  It ought to at least have some impact.  I'm not sure it will, but it might.
		DR. AZZIZ:  Dr. O'Leary.
		DR. O'LEARY:  I'm just trying to think of other instances of this in urology.  We know that when Viagra was approved, it was very clear that it was contraindicated in association with nitrates.  That was very clear.  I think every urologist knew it, and we told patients that if they took Viagra with nitrates, they would die.  And that was basically what I told patients.  Now, that didn't stop some people from doing it, and I had a number of patients who lied to me about whether or not they were on nitrates.  And then I found out subsequently from their pharmacist who called me and said you just wrote a prescription for someone who's on nitrates.  So, I don't think we can prevent patients from doing what they will do.
		But I think proper labeling and education of the physicians who are prescribing it -- I don't know.  Let me ask some of the other urologists here who routinely write for this drug.
		DR. LIPPERT:  When Viagra first came out, I was very disappointed that there was no patient handout.  I had to write my own.  There was one eventually that came out.  I'm pleased there actually is a template here for a patient handout.  Whether or not it will actually be available at the time the drug is approved, I don't know.  With Viagra, everybody gets a handout, everybody gets a lecture.  I think this is got to be the same for this drug.
		DR. GREENE:  Ricardo, if I may.
		DR. AZZIZ:  Yes.
		DR. GREENE:  There are two models out there for drugs that have a very high risk associated with their use where the companies have gone to extreme measures to advise potential users of those risks, and those are Accutane and thalidomide.  Both of those drugs are prescribable.  They're prescribable, in the case of Accutane, by any physician.  In the case of thalidomide, there is a very extensive program of not only patient education, but also the doctors who prescribe it have to register with the company, and the pharmacists who dispense it have to register with the company.  Now, that is a model that would be very, very difficult to implement for many drugs, but at least there are those two models out there, the Accutane model and the thalidomide model, where drugs have substantial risks associated with their use in the wrong setting, that the companies have been fairly successful in preventing rampant misuse, let's put it that way.
		DR. AZZIZ:  Before we go on to try to describe some of these things, which I think all of us will have ideas for the FDA, I'd like just to remind you that we do need to have the third question answered because, obviously, that will really determine where we're going.  So, let's move on to number 3, and then following that, we can elaborate as much as we'd like because that is what we're paid highly to be here to do.
		(Laughter.)
		DR. AZZIZ:  So, do the data presented support an acceptable risk-benefit profile for the 4 milligram dose of Uprima?  That is the question on the table now.
		Comments about specifically this before we vote.  Dr. Califf.
		DR. CALIFF:  I guess my opening feeling is that the studies have met the specific criteria that I would regard as being acceptable.  That is there's a clinical benefit defined in a tangible way that we can believe in.  It's highly statistically significant, so there is a benefit.
		There's also a risk.  Peter I think has more eloquently than I could described the frustration over the difference between an average drop in blood pressure, for example, an idiosyncratic clinical events, which really do need to be prespecified and recorded as part of phase III clinical trials.  We're just stuck with that and I don't think we can do much about it.
		But I think given the patient who's not drinking and not on a bunch of cardiac meds and doesn't have three vessel disease and is not going to drive a car for the next hour or so, I would say this meets my criteria.
		DR. AZZIZ:  Any other comments before we vote?  Dr. Greene.
		DR. GREENE:  There are two questions that I consider in voting on this.  One is what is the disease that we're treating.  Although as important as this is, it's not cancer.  This is not the cure for cancer, and this may be very important for some people, but it's not cancer.  That is my first thought.
		The second thought is that this is a medication which is going to be given, if you will, or taken at home, not directly or immediately under the supervision of a physician.  This isn't like a medication that's administered to an in-patient in the hospital.  So, when I think about the risk-benefit ratio for a cancer chemotherapeutic agent, you're treating a life-threatening disease and it's being administered in a hospital setting, let's say, under direct physician supervision. 
		So, I think those are two issues that I think about as I think about voting on this question.  The ratio that we would demand for safety I think is different for this than it would be, let's say, for a cancer chemotherapeutic agent.
		DR. AZZIZ:  Dr. Hanno?
		DR. HANNO:  I think that, as Dr. Jacobs has pointed out a few times, there should be and the indications should reflect the population that the drug was studied in. 
		I think that the 4 milligram dose does seem to have some efficacy.
		I'm a little worried about the alcohol.  When you give people permission to drink alcohol, sometimes they're not going to stop on their own or they're going to lose sight of what they're drinking.  That seems to be a potential risk factor, and I'm wondering whether that needs to be addressed in the label and perhaps alcohol should be something that's contraindicated, or at least it should be stated that it's a known risk factor for severe side effects and not give somebody a safe level of alcohol to drink, but rather try and stop people from drinking alcohol with this.  
		Then I don't know whether we should consider a warning on a label about eating prior to taking this drug.  In some cases it might make it less palatable, but I think that it's something to consider given the data on the nausea. 
		DR. AZZIZ:  Dr. O'Leary?
		DR. O'LEARY:  I agree with Dr. Hanno.  Patients are, I think, pretty used to asking, can I take this drug with alcohol, and I'm not sure why often they ask that.  But I would favor the label saying this drug should not be taken with alcohol, just the way a whole bunch of other drugs that we commonly prescribe for people are labeled.  Then that would take away the concern to some degree.  I mean, people are still going to drink and take it anyway, but if the label clearly said, it's not recommended that you have any alcohol when you're taking this drug.
		DR. AZZIZ:  Dr. Jacobs.
		DR. JACOBS:  The acceptable risk:benefit profile.  The risk is about what many other drugs out there are.  For hypertension, it's very similar in its risk.  Its benefit profile may be underestimated because any urologist has guys in the office when you say you can't have Viagra, you'll have a heart attack and die, they'll just look back at you and say, that's all right.  I don't mind.  Give me the pill.  And that's very common.  Whereas, maybe everybody in this room doesn't value erections as greatly as some of these patients, there's a large number of patients out there where this is their raison d'etre, and that's the only reason they're on earth.
		DR. AZZIZ:  Any other comments before we vote on the risk-benefit ratio for the 4 milligram dose?
		(No response.)
		DR. AZZIZ:  Let's go ahead and go around the table then.  Again, do the data presented support an acceptable risk-benefit profile for the 4 milligram dose of Uprima? 
		Dr. Jacobs.
		DR. JACOBS:  Yes.
		DR. O'LEARY:  O'Leary, yes.
		DR. DONATUCCI:  Donatucci, yes.
		DR. LIPPERT:  Lippert, yes.
		DR. CALIFF:  Califf, yes.
		DR. AZZIZ:  Azziz, yes.
		DR. KOWEY:  Kowey, yes.
		DR. D'AGOSTINO:  D'Agostino, yes.
		MS. SCOTT:  Scott, no.
		DR. TIEFER:  Tiefer, no.
		DR. GREENE:  Greene, no.
		DR. HANNO:  Hanno, yes.
		DR. AZZIZ:  Thank you.
		Now we need to elaborate and give our recommendations to the FDA.
		DR. KOWEY:  As Dr. Azziz has said several times today, our role is as an advisor.  So, nothing that we tell you is binding obviously.  If you came back and told me several months from now that you decided not to approve this drug, it would not break my heart because I think there are two ways to handle this kind of a problem.  One way is to not approve the drug.  Period.  And the other way is to approve it and then label the hell out of it.  I voted yes with the proviso that you understand that there's got to be a tremendous amount of work done on labeling for this drug.  
		I favor a black box warning in bold letters that says, that if you take this drug, you may pass out and if you pass out, you may injure yourself and you may injure yourself severely.
		I also very, very adamantly favor a patient package insert which is carefully constructed along the lines of what was done for dofetalide and also for Betapace AF, the last two drugs from the Cardio-Renal Advisory Committee that I know about that I was involved with that have detailed instructions given to the patient about what drugs to avoid, what situations to avoid, and how to maximize the safety of the drug, and what kinds of things they can get into trouble with, drug interactions, et cetera.  
		I don't want anybody to interpret that this is an approval that is sort of like "see you later."  This is an approval with the stipulation that there's a tremendous amount of work to do because, as I said earlier, the complications that have been seen with this drug are frightening complications.  And it's also been said by people at this end of the table we're not treating cancer.
		So, as important a drug as it is -- and I said yes because I was listening to these guys who take care of these patients who would like to see this drug available.  And I agree that they're a desperate lot of patients and they do need to have that drug, and I'd like to see it on the market.  That's why I voted yes.  But don't take that to mean that I don't have grave concerns about the safety of this drug, and if it's not communicated properly to the physicians, what's going to happen is you're going to run into the same withdrawal problems that you had with other drugs that somebody else mentioned earlier.  So, I feel very strongly about that.
		DR. AZZIZ:  Dr. Tiefer.
		DR. TIEFER:  I just wanted to say a word about the secondary effects on the partner.  This is one reason I voted no because when I think of a sexual problem, I know this is not the typical medical model way, but I think of it as a couple's problem not a person's problem.  In my experience, the drugs, the treatments that the patient individually chooses with his physician have serious ramifications on the partner's well-being, for the good sometimes, for the not so good other times. 
		When I heard what Dr. Jacobs said that the guy comes in and says, this is my raison d'etre and I'll die if you don't give it to me, I know that the partner is thinking, having talked to many of these partners, at that very moment.  She's thinking, God, I hope the doctor doesn't give him anything because the last thing in the world I need is to worry about him.  In addition to him taking his this, that, and the other medication, and going for these tests and so on and so forth, now he's going to be taking something else which has a little black boxes, and I, the wife, am just really frightened about this.  It's not to say that she doesn't want to have sex and want her husband to have the pleasure of sex.  But this stressor -- she's more up front about that.  
		So, I just feel that we need to take into account the consequences of this on the other people, the less visible people who are involved with this, and that it's not a matter of such great urgency that we need to approve a drug that's going to have lots of black boxes, which for the wives are just terrifying.
		DR. AZZIZ:  Thank you.
		Dr. Lippert?
		DR. LIPPERT:  Again, I'm repeating myself, but when Viagra came out, there was no patient handout.  I had to write my own.  I'm a urologist, but there were community primary care physicians who were just calling my office begging me for a copy.  My chairman said, no way, you'll be legally responsible.  I really don't think this drug should come out without an available handout for patients that's available when the drug comes out to primary care physicians, to all physicians.  I feel strongly about that.
		DR. AZZIZ:  Dr. Califf?
		DR. CALIFF:  This is also somewhat repetitive, but I think just to get down to what I think the most critical issue is, if we look at the recent messes that we've had, what tends to happen is that the real bad things happen to people who have a confluence of multiple risk factors at the same time, and the people that are going to die with this drug are people on multiple antihypertensives or people with severe coronary disease who are perhaps unlucky.  
		But at least I would argue that the label ought to be very restrictive to start with and then the company ought to have a chance to work sort of backwards into those populations in a little bit more detail because I'm not satisfied with the studies yet related to alcohol, for example, or to multiple antihypertensives at the same time or to nitrates.
		I'd like to see some pretty explicit material that would be given to patients.  Admittedly a lot of them wouldn't pay attention to it or they might go ahead, but then at least they would do so under informed conditions.  I don't think the fact that some people don't have good common sense should disallow others who would use the instructions the opportunity to have access to the treatment.
		DR. AZZIZ:  Dr. Hanno.
		DR. HANNO:  I would agree that the label, if this drug is approved, needs to be extremely restrictive, and later as time goes on and more studies are done, if it turns out to not merit that, then that's fine.  It could be changed.  I think it's going to be used by a lot of non-urologists, primarily family care, primary care people, and the word has to get out that this is not a benign drug, that it has significant safety concerns.  I'm sort of guiding what I'm saying with Dr. Kowey, what he was saying in terms of the danger that's implicit in approving the drug.
		DR. AZZIZ:  Julia?
		MS. SCOTT:  Yes.  I remain very concerned that the population of African Americans is so low in this study.  I think we all know that this is a population that has the highest risk of those diseases, diabetes and hypertension and cardiovascular disease.  So, I'm concerned that we don't know enough about how this drug might act in African Americans.  We also know they have the least access to health care.  So, some of these incidents that have been described as kind of minor could actually be very major for that population.
		I'm also concerned that if this drug does get approved, that there be a registry or something that keeps track of people so that we can track some of these results because it would be a shame to wait until we start having deaths.  I'm very concerned about the side effects, especially in the higher than the 2 milligram.  Actually I'm concerned about the 2 milligram too, but I think they're more pronounced in the 4 milligram.  
		So, I would hope that if the FDA approves this drug, that there is a restricted label, that there is some kind of physician training, because again it's not going to be just urologists who have a better feel for the appropriateness of this, as well as the patient insert, that it clearly state the problems related to alcohol intake as have been described earlier.
		DR. LIPPERT:  Excuse me.  A patient insert won't work if it comes in the box because I don't have the box in my office.  So, there actually has to be a patient handout separate from an insert because I'm not a pharmacist.
		DR. AZZIZ:  That is one thing.  I have a question for Dr. Mann because before we get into recommending things such as educational programs and brochures and so on, how much really can we recommend?  We can do that, but if it has no impact.
		DR. RACZKOWSKI:  From what I've heard, there are two ways that it could be ensured that patients get the information about the labeling.  One is by recommending a unit-of-dose distribution of the drug, which means that whenever the drug is distributed a package insert goes along with it to the patient.  Another option is to use the patient package insert or a med guide, which are different things, and to have them not only as part of the formal labeling of the product, but also distributed by pharmacists to patients when they fill prescriptions.
		DR. AZZIZ:  But you can't regulate physician education, can you?
		DR. RACZKOWSKI:  No.  As a condition for approval, we could demand educational programs, yes.
		DR. AZZIZ:  Very well.  That's what I wanted to make sure before we went off into this tangent.
		Comments?  Dr. Mann.
		DR. MANN:  We heard a fair number of specific comments about the alcohol interaction, anywhere from a contraindication to a black box warning being suggested.  We also heard your strong comments about warning at least in a black box fashion about syncopal events.
		In terms of the nitrate interaction, I would like the panel, if they could, to discuss a little bit more specifically where in the label they think that information might go.  I don't mean for you to fully understand labeling, but in general, labeling things range anywhere from a contraindication statement, which is very strong, meaning absolutely never give this drug with nitrates, to the potential for another black box warning in this regard, or a warning all the way down to a precaution.
		The current label proposed by the sponsor, on page 178 of our red binder that we've presented to you, the first paragraph under Precautions precautions people against concomitant nitrate use.  I'd just like the panel, if they could, to discuss if they feel that is adequate or if they have a different opinion on how to warn about nitrate interactions.
		DR. AZZIZ:  I'd like the two urologists on the panel to begin.  They've been very quiet.  I mean the two cardiologists have been very quiet.  So, perhaps if could get your feedback initially.  Dr. Califf.
		DR. CALIFF:  My initial feeling would be that it should be a contraindication for the time being.  There was a nitrate study.  I'm having trouble remembering all the details.  Maybe we should look at that data one more time.
		DR. KOWEY:  My recollection was that for the short-acting drugs, the means were really not any different than for the long-acting.  There was a statistical difference, but it didn't look all that clinically important.
		DR. MANN:  That's correct.
		DR. KOWEY:  But there were, as you pointed out, a number of outliers and exceptions.
		I agree with Rob.  I think it probably ought to be a contraindication until this is perhaps ferreted out a little bit better and there's more experience.  I don't really think that that should be a major problem clinically.  I don't see why that would be a problem.
		DR. CALIFF:  The combination of syncope and nitrates in any form is pretty scary because it's not uncommon to see syncope caused by nitrates.
		DR. KOWEY:  Well, let me just remind everybody that when we do tilt table testing, if we tilt somebody and they don't go out, and they don't have syncope on a tilt table, one of the ways of provoking it is by giving them nitroglycerin, so for cardioneurogenic syncope, vasovagal syncope, which is what this is.  So, there's a perfect rationale to say since this drug causes vasovagal syncope, that you shouldn't be taking nitrates if you're going to take this drug.  So, I don't have any problem at all with the contraindication statement.
		DR. AZZIZ:  Again, we can black box it or contraindicate it.  Any other comments, please?
		DR. JACOBS:  The data they presented on nitrates on this sure didn't show much of a blood pressure drop with the 5 milligram Uprima dose with nitrates.  Nothing as dramatic as the sildenafil drug that's already out there.  This is one of the benefits of this drug presumably.
		DR. CALIFF:  Well, here's the rub.  It's just like what Peter was talking about with regard to syncope and hypotension in general.  A mean difference in blood pressure is not the same as event rates, which require fairly large studies to detect.  So, if you have an occasional patient, 1 or 2 out of 100, where there's going to be hypotension due to the nitrates per se and you add on top of that, it could really be a mess.
		DR. JACOBS:  Why don't you just say no sex for nitrate patients then?  I mean, sex probably lowers your blood pressure or raises it one way or the other.
		DR. CALIFF:  Well, there is an alternative, which is to do larger studies that really measure event rates and not just mean blood pressures in a small population.  That is quite a reasonable alternative.  I think there are a few million people who might end up taking this drug.
		DR. O'LEARY:  That's I think what Dr. Graboys had suggested before he left, or at least that was my interpretation. 
		Let me just ask you cardiologists a question.  I'm puzzled.  I understand what nitrates and sildenafil do in combination, and that's a direct drug effect.  But you're not suggesting that this drug has some direct effect with nitrates.  It's simply that the drugs in combination ‑‑
		DR. KOWEY:  No.  I'm suggesting that there is a central mechanism for cardioneurogenic syncope.  We know that.  That's been well worked out.  We know that nitrates do something centrally -- centrally, not necessarily on the periphery -- which potentiates the tendency to a vasovagal episode such that, as I said, in somebody that has a tilt table test, if they don't become syncopal with the tilt and they've had spontaneous neurocardiogenic syncope, you give them nitroglycerin and retilt them, and you see the neurocardiogenic response.  So, it's not just an additive effect on blood pressure.  There is a specific trigger that nitroglycerins seem to cause to provoke a vasovagal reaction.
		And that's what this is.  This is not the same thing as Viagra.  I don't think this is the same mechanism of hypotension.
		DR. O'LEARY:  We know it's not.
		DR. KOWEY:  Viagra is a vasodilator.  This is not acting by a vasodilatory mechanism.  It's acting by a mechanism which provokes a vasovagal response.  And nitroglycerin potentiates that synergistic effect.  That's why it's perfectly reasonable in my mind until we have more information to say no nitrates.
		DR. AZZIZ:  Very well.
		Any other comments about the nitrate issue?  Marianne.
		DR. MANN:  Thank you for those comments and if there are any others, please let me know.
		DR. AZZIZ:  Just maybe a couple more.
		DR. MANN:  Actually I had one other issue for the panel to address.  Many of the syncopal events that were noted in the sponsor's application occurred with the first dose of study drug or with an increase in study drug dosage and were given in the physician's office to the patients.
		Another potential labeling recommendation that we could take under consideration would be the requirement for all initial doses to be given in a physician's office under physician supervision.  I'd like the panel to address that potential idea for labeling as well, if you don't mind.  Thanks.
		DR. AZZIZ:  Dr. O'Leary?
		DR. O'LEARY:  We have experience with this with another already approved drug, and that's intraurethral prostaglandin.  When that was first approved, it was recommended -- I'm not sure it was part of the labeling, but it was recommended that patients be dosed in the office.  I don't routinely and I don't think most urologists routinely do that anymore, aside from the fact that we don't prescribe very much anymore because the efficacy is not great.
		I can see some potential problems in doing that, simply that the volume of patients that are likely to come forward to request this may be fairly substantial.
		DR. MANN:  Thank you for that comment.  Actually for the intraurethral injections, they are recommended in labeling to be done in the physician's office.  Perhaps this is one lesson learned as to how far we can go with labeling recommendations to assure patient safety, to assure that our directions are truly followed in real life, and that was a very relevant comment you made in that regard.
		DR. DONATUCCI:  Can I make a comment? 
		There is a second part, of course.  While we stopped doing it in the office, every time we give the patient a prescription for that, they are carefully instructed about the possibility of syncope and what to do.  But I would hazard to say probably that particular product that we're discussing right now, the transurethral alprostadil, is a product used primarily by urologists who are familiar with that.
		DR. AZZIZ:  Dr. Lippert?
		DR. LIPPERT:  I just want to say I'm still following the recommendations, and I still check blood pressures when I give the first dose of Muse in the office.
		DR. O'LEARY:  Maybe you could talk to that other agency -- 
		DR. AZZIZ:  To come and look at Dr. O'Leary's ‑‑
		(Laughter.)
		DR. O'LEARY:  No, no.  I'm suggesting one of the reasons why we stopped titrating in the office is because that other agency up the road, the Health Care Financing Administration, stopped paying for it.
		DR. AZZIZ:  It's a very good point.
		I just have a couple comments.  I'm not the urologist.  But a recommendation to have those doses in the office doesn't necessarily guarantee very much.  All the crashing and burning we saw were in physician's offices.  In a busy practice, I don't know what it guarantees other than somebody can code the person faster perhaps, maybe.
		The second thing is we do need to come back to the issue of education.  Dr. Lippert says stuff in the box isn't read, and so the company, if they're going to market this, needs to produce a brochure both for the patient and for the partner because I think it's an important issue.  This is what you need to expect from your partner.  And given to the patients.  They need to be in the physician's office, given to the patients, a colorful brochure.  Otherwise, it just isn't going to get read.  Whether this is signed for when they get the drug or something of that nature, that's perfectly fine.
		DR. TIEFER:  One of the other things that's more popular over time are videos that are being given to patients along with drugs by urologists.  This has been quite common over the last few years.  You have the opportunity to put a little sex education in the video along with the drug education.
		DR. AZZIZ:  Then we'd have all the 15-year-old boys standing for the video.
		(Laughter.)
		DR. TIEFER:  No.  Sex education is not XXX movies, unfortunately, Dr. Azziz.
		(Laughter.)
		DR. AZZIZ:  Dr. Greene.
		DR. GREENE:  Two comments.  One is that with respect to that, I'm not sure how long would you advise the patient remain in the doctor's office?  Because some of the adverse events literally were on the way home from the doctor's office after what appeared to be an uneventful first administration.  So, I don't know.  How long do you tell the patient to stay in the doctor's office?  It might be safer to tell the patient to go home and taking it lying down in bed.  So, I'm not sure. 
		One other last comment from the voice of doom.  In other medications that have been removed from the market because of adverse events -- such things as cisapride was mentioned, fen/phen, recently troglitazone -- at least in those occasions, the problems with the medications were not obvious and did not occur in the studies of the drugs initially.  As Dr. Califf mentioned, showing a modest decrease on average is not the same as finding out what percentage of people will have a very dramatic fall in their blood pressure.  Studying only 3,000 patients is not going to tell you about a lethal problem in 1 in every 10,000 patients.  So, that's my last concern from the voice of doom.
		DR. KOWEY:  This problem of safety, obviously, in the cardiovascular end of things has become so important lately.  We've thought a lot about sample sizes and detection thresholds and where you get enough people in the study to really make yourself sure.  Unfortunately, I guess at the end of the day, there's always a leap of faith when a drug is approved it's going to be used in about 100 times more people tomorrow than it was used in all the clinical trials.  So, I don't know if there's any way to really do that. 
		I just want to add my comment about office initiation.  I don't think it's necessary.  In fact, I agree completely.  I think it's probably safer, for this particular kind of a drug, if you do what Dr. Donatucci suggested, tell the patient what to do when they get home.  It's probably much, much more effective.
		DR. O'LEARY:  Dr. Azziz?
		DR. AZZIZ:  Dr. O'Leary.
		DR. O'LEARY:  One other comment.  I don't want to be a voice of doom necessarily, but this drug will be given in a population of men who have a significant risk of sudden death to begin with just because of their age.  So, let's be real clear that some of the patients who take this drug are going to die.  Now, that's the reality.  Now, whether that's due to the drug or not is something different.  From what I've seen, it doesn't suggest to me that there's anything that this drug will do to directly contribute to death.  Is that fair?  I just want to make sure that we're all clear about that.  Some of these men are going to die.
		MS. SCOTT:  Well, we're all going to die.
		DR. O'LEARY:  Right.
		DR. KOWEY:  The fact that there weren't any deaths in the program is good.  That's good.  That's a very good thing, in fact, in 3,000 patients that got the drug.  There had to be some people in there that had pretty bad vascular disease.  Had to be.  Nobody died and nobody, in fact, had a cardiac arrest and was resuscitated.  Nobody had symptoms that sounded like VT.  So, all that's good.  But it still doesn't answer the ultimate question of where your detection threshold is and what you'll tolerate.
		DR. AZZIZ:  I think what you're hearing, Marianne, is that we'd like some post-marketing surveillance data, whatever you all think is necessary, because while the committee seems to have recommended this, having been on a number of these, the committee is pretty uncomfortable with the safety profile.  We're going to need more data on nitrates and heart disease and diabetics and alcoholics and so on and so forth that we don't have the data now sufficiently.
		DR. MANN:  Would such data in a wider population of patients studied be more useful to you pre-marketing or post-marketing?  Could you comment on that? 
		DR. AZZIZ:  That's a tricky question.  Often you will not get the experience with the patients unless you actually market the drug, as we found out with lots of drugs.  You can never market in my opinion a drug that has no side effects.  It just doesn't exist.  If you take a larger number of patients, eventually somebody is going to die.  So, that's my bias. 
		Dr. Califf?
		DR. CALIFF:  I finally found a handout on the nitrate studies.  There were 20 on short-acting nitrates and 20 patients on long-acting nitrates.  To me, this is totally inadequate, completely and utterly inadequate.  And it's true that if you don't study things, you won't see them.  So, in terms of pre-marketing data, I don't think it's impossible to get pre-marketing data.  We just need studies that are done in the patient populations in whom the drug is going to be used after it gets on the market, probably with larger numbers.  But that's not going to change what happened today.
		The problem I think with the post-marketing surveillance issue is it's pretty hard to come up with a non-randomized, post-marketing scheme that's going to help you in this situation because, as Dr. O'Leary pointed out, a lot of these people are going to die in proximity to taking the drug, totally not due to the drug but due to the underlying disease.  So, in absence of randomization, I don't know how you draw inferences from post-marketing rates.
		DR. AZZIZ:  In answer to your question about pre- and post-marketing data, as Dr. Califf just brought up, the alcohol issue has been looked at fairly well in some studies, not perfectly, but fairly well.  The nitrate studies are basically insufficient and inadequate, and unless we can simply contraindicate nitrates, period, anything else that needs to be brought up needs to be restudied before this drug is marketed. 
		Julia?
		MS. SCOTT:  Also, I think the pre-marketing is necessary for African Americans.  I just think the number is just too low and too many studies have shown differences among African Americans in terms of side effects and the like.  So, I do think you need to study that.
		DR. AZZIZ:  Any further comments?
		DR. TIEFER:  I just want to say one more point about sublingual training.  Nobody has mentioned this.
		DR. AZZIZ:  Training.
		DR. TIEFER:  I just thought it was interesting.  In their initial trials, they discovered that if they didn't offer the patients some training in the use of a sublingual drug, that the drug wasn't absorbed properly, wasn't utilized properly.  So, somewhere along the line, this has to be part of this patient information.
		DR. AZZIZ:  Very good.
		Any other comments?
		(No response.)
		DR. AZZIZ:  I think Dr. Mann has some closing comments.  Correct?
		DR. MANN:  Yes, I do.  I just want to thank you all for your participation today. 
		In addition, I want to draw attention to two committee members who have served us for many years and done extremely well.  That is Julia Scott, our patient advocate, and our Chair himself, Dr. Ricardo Azziz.  I want to assure you both that we very much valued your input and expertise these past few years on our advisory panel.  We do not throw your recommendations into the closet.
		(Laughter.)
		DR. MANN:  We actually consider them very highly, and although we do not pay you very much, we know, our heartfelt thanks hopefully will suffice somewhat. 
		We also have a small plaque to give you both before you leave, and we just want to give you a round of applause for all of your participation.
		(Applause.)
		DR. AZZIZ:  Thank you very much and thanks to everybody for staying long.
		(Whereupon, at 3:55 p.m., the subcommittee was adjourned.)